TY  - JOUR
AB  - BACKGROUND: Climate change threatens human health and general welfare via multiple dimensions. However, the associations of short-term exposure to temperature variability, a crucial aspect of climate change, with myocardial infarction (MI) hospital admissions remains unclear. METHODS AND FINDINGS: This population-based nationwide study employed a time-stratified, case-crossover design to investigate the association between ambient temperature variability and MI hospital admissions among 233,617 patients recorded in the SWEDEHEART registry in Sweden between 2005 and 2019. High-resolution (1 × 1 km) daily mean ambient temperature was assigned to patients' residential areas. Temperature variability was calculated as the difference between the same-day (as the MI event) ambient temperature and the average temperature over the preceding 7 days. An upward temperature shift represents a rise in the current day's temperature relative to the 7-day average, while a downward temperature shift indicates a corresponding decrease. A conditional logistic regression model with distributed lag non-linear model was applied to estimate the association between ambient temperature variability and total MI (encompassing all MI types), ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) hospital admissions at lag 0-6 days. Potential effect modifiers, such as sex, history of diseases, and season, were also examined. The patients had an average age of 70.6 years, and 34.5% of them were female. Our study found that an upward temperature shift was associated with increased risks of total MI (encompassing all MI types), STEMI, and NSTEMI hospital admissions at lag 0 day, with odds ratios (OR, 95% confidence intervals [CIs]) of 1.009 (1.005, 1.013; p < 0.001), 1.014 (1.006, 1.022; p < 0.001), and 1.007 (1.001, 1.012; p = 0.014) per 1 °C increase, respectively. These associations attenuated and became non-significant over lags 1-6 days. Furthermore, a downward temperature shift was associated with increased risks of hospital admissions for total MI (encompassing all MI types) at a lag of 2 days with an OR (95% CI): 1.003 (1.001, 1.005; p = 0.014), and for STEMI at lags 2 and 3 days with ORs (95% CI): 1.006 (1.002, 1.010; p = 0.001) and 1.005 (1.001, 1.008; p = 0.011), per 1 °C decrease, respectively. Conversely, higher downward temperature shifts were associated with decreased risks of total MI (encompassing all MI types) and NSTEMI at lag 0 day. No significant associations were observed at other lag days for downward temperature shifts. Males and patients with diabetes had higher MI hospitalization risks from upward temperature shift exposure, while downward temperature shift exposure in cold seasons posed greater MI hospitalization risks. A methodological limitation was the use of ambient temperature variability as a proxy for personal exposure, which, while practical for large-scale studies, may not precisely reflect individual temperature exposure. CONCLUSIONS: This nationwide study contributes insights that short-term exposures to higher temperature variability-greater upward or downward temperature shifts-are associated with an increased risk of MI hospitalization. Our finding highlights the cardiovascular health threats posed by higher temperature variability, which are anticipated to increase in frequency and intensity due to climate change.
AU  - Ni, W.
AU  - Stafoggia, M.*
AU  - Zhang, S.
AU  - Ljungman, P.*
AU  - Breitner-Busch, S.
AU  - de Bont, J.*
AU  - Jernberg, T.*
AU  - Atar, D.*
AU  - Schneider, A.E.
AU  - Agewall, S.*
C1  - 74670
C2  - 57550
CY  - 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
TI  - Short-term exposure to ambient temperature variability and myocardial infarction hospital admissions: A nationwide case-crossover study in Sweden.
JO  - PLoS Med.
VL  - 22
IS  - 5
PB  - Public Library Science
PY  - 2025
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: Taxes on sugar-sweetened beverages (SSBs) have been implemented globally to reduce the burden of cardiometabolic diseases by disincentivizing consumption through increased prices (e.g., 1 peso/litre tax in Mexico) or incentivizing industry reformulation to reduce SSB sugar content (e.g., tiered structure of the United Kingdom [UK] Soft Drinks Industry Levy [SDIL]). In Germany, where no tax on SSBs is enacted, the health and economic impact of SSB taxation using the experience from internationally implemented tax designs has not been evaluated. The objective of this study was to estimate the health and economic impact of national SSBs taxation scenarios in Germany. METHODS AND FINDINGS: In this modelling study, we evaluated a 20% ad valorem SSB tax with/without taxation of fruit juice (based on implemented SSB taxes and recommendations) and a tiered tax (based on the UK SDIL) in the German adult population aged 30 to 90 years from 2023 to 2043. We developed a microsimulation model (IMPACTNCD Germany) that captures the demographics, risk factor profile and epidemiology of type 2 diabetes, coronary heart disease (CHD) and stroke in the German population using the best available evidence and national data. For each scenario, we estimated changes in sugar consumption and associated weight change. Resulting cases of cardiometabolic disease prevented/postponed and related quality-adjusted life years (QALYs) and economic impacts from healthcare (medical costs) and societal (medical, patient time, and productivity costs) perspectives were estimated using national cost and health utility data. Additionally, we assessed structural uncertainty regarding direct, body mass index (BMI)-independent cardiometabolic effects of SSBs and cross-validated results with an independently developed cohort model (PRIMEtime). We found that SSB taxation could reduce sugar intake in the German adult population by 1 g/day (95%-uncertainty interval [0.05, 1.65]) for a 20% ad valorem tax on SSBs leading to reduced consumption through increased prices (pass-through of 82%) and 2.34 g/day (95%-UI [2.32, 2.36]) for a tiered tax on SSBs leading to 30% reduction in SSB sugar content via reformulation. Through reductions in obesity, type 2 diabetes, and cardiovascular disease (CVD), 106,000 (95%-UI [57,200, 153,200]) QALYs could be gained with a 20% ad valorem tax and 192,300 (95%-UI [130,100, 254,200]) QALYs with a tiered tax. Respectively, €9.6 billion (95%-UI [4.7, 15.3]) and €16.0 billion (95%-UI [8.1, 25.5]) costs could be saved from a societal perspective over 20 years. Impacts of the 20% ad valorem tax were larger when additionally taxing fruit juice (252,400 QALYs gained, 95%-UI [176,700, 325,800]; €11.8 billion costs saved, 95%-UI [€6.7, €17.9]), but impacts of all scenarios were reduced when excluding direct health effects of SSBs. Cross-validation with PRIMEtime showed similar results. Limitations include remaining uncertainties in the economic and epidemiological evidence and a lack of product-level data. CONCLUSIONS: In this study, we found that SSB taxation in Germany could help to reduce the national burden of noncommunicable diseases and save a substantial amount of societal costs. A tiered tax designed to incentivize reformulation of SSBs towards less sugar might have a larger population-level health and economic impact than an ad valorem tax that incentivizes consumer behaviour change only through increased prices.
AU  - Emmert-Fees, K.
AU  - Amies-Cull, B.*
AU  - Wawro, N.
AU  - Linseisen, J.*
AU  - Staudigel, M.*
AU  - Peters, A.
AU  - Cobiac, L.J.*
AU  - O'Flaherty, M.*
AU  - Scarborough, P.*
AU  - Kypridemos, C.*
AU  - Laxy, M.
C1  - 68915
C2  - 53767
CY  - 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
TI  - Projected health and economic impacts of sugar-sweetened beverage taxation in Germany: A cross-validation modelling study.
JO  - PLoS Med.
VL  - 20
IS  - 11
PB  - Public Library Science
PY  - 2023
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: Hypertension represents one of the major risk factors for cardiovascular morbidity and mortality globally. Early detection and treatment of this condition is vital to prevent complications. However, hypertension often goes undetected, and even if detected, not every patient receives adequate treatment. Identifying simple and effective interventions is therefore crucial to fight this problem and allow more patients to receive the treatment they need. Therefore, we aim at investigating the impact of a population-based blood pressure (BP) screening and the subsequent "low-threshold" information treatment on long-term cardiovascular disease (CVD) morbidity and mortality. METHODS AND FINDINGS: We examined the impact of a BP screening embedded in a population-based cohort study in Germany and subsequent personalized "light touch" information treatment, including a hypertension diagnosis and a recommendation to seek medical attention. We pooled four waves of the KORA study, carried out between 1984 and 1996 (N = 14,592). Using a sharp multivariate regression discontinuity (RD) design, we estimated the impact of the information treatment on CVD mortality and morbidity over 16.9 years. Additionally, we investigated potential intermediate outcomes, such as hypertension awareness, BP, and behavior after 7 years. No evidence of effect of BP screening was observed on CVD mortality (hazard ratio (HR) = 1.172 [95% confidence interval (CI): 0.725, 1.896]) or on any (fatal or nonfatal) long-term CVD event (HR = 1.022 [0.636, 1.641]) for individuals just above (versus below) the threshold for hypertension. Stratification for previous self-reported diagnosis of hypertension at baseline did not reveal any differential effect. The intermediate outcomes, including awareness of hypertension, were also unaffected by the information treatment. However, these results should be interpreted with caution since the analysis might not be sufficiently powered to detect a potential intervention effect. CONCLUSIONS: The study does not provide evidence of an effect of the assessed BP screening and subsequent information treatment on BP and behavior, but also on long-term CVD mortality and morbidity. Future studies should consider larger datasets to detect possible effects and a shorter follow-up for the intermediate outcomes (i.e., BP and behavior) to detect short-, medium-, and long-term effects of the intervention along the causal pathway.
AU  - Pedron, S.
AU  - Hanselmann, M.*
AU  - Burns, J.*
AU  - Peters, A.
AU  - Heier, M.
AU  - Schwettmann, L.
AU  - Bor, J.H.*
AU  - Barnighausen, T.*
AU  - Laxy, M.
C1  - 67127
C2  - 53492
CY  - 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
TI  - The effect of population-based blood pressure screening on long-term cardiometabolic morbidity and mortality in Germany: A regression discontinuity analysis.
JO  - PLoS Med.
VL  - 19
IS  - 12
PB  - Public Library Science
PY  - 2022
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). METHODS AND FINDINGS: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds. CONCLUSIONS: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.
AU  - Guida, F.*
AU  - Tan, V.Y.*
AU  - Corbin, L.J.*
AU  - Smith-Byrne, K.*
AU  - Alcala, K.*
AU  - Langenberg, C.*
AU  - Stewart, I.D.*
AU  - Butterworth, A.S.*
AU  - Surendran, P.*
AU  - Achaintre, D.*
AU  - Adamski, J.
AU  - Amiano Exezarreta, P.*
AU  - Bergmann, M.M.*
AU  - Bull, C.J.*
AU  - Dahm, C.C.*
AU  - Gicquiau, A.*
AU  - Giles, G.G.*
AU  - Gunter, M.J.*
AU  - Haller, T.*
AU  - Langhammer, A.*
AU  - Larose, T.L.*
AU  - Ljungberg, B.*
AU  - Metspalu, A.*
AU  - Milne, R.L.*
AU  - Müller, D.C.*
AU  - Nøst, T.H.*
AU  - Pettersen Sørgjerd, E.*
AU  - Prehn, C.
AU  - Riboli, E.*
AU  - Rinaldi, S.*
AU  - Rothwell, J.A.*
AU  - Scalbert, A.*
AU  - Schmidt, J.A.*
AU  - Severi, G.*
AU  - Sieri, S.*
AU  - Vermeulen, R.*
AU  - Vincent, E.E.*
AU  - Waldenberger, M.
AU  - Timpson, N.J.*
AU  - Johansson, M.*
C1  - 63033
C2  - 51221
CY  - 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
TI  - The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium.
JO  - PLoS Med.
VL  - 18
IS  - 9
PB  - Public Library Science
PY  - 2021
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BackgroundNon-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning.Methods and findingsWe utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n= 795) or at high risk of developing the disease (n= 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (<5% or >= 5%) available for 1,514 participants. We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and random forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operating characteristic area under the curve (ROCAUC) of 0.84 (95% CI 0.82, 0.86;p <0.001), which compared with a ROCAUC of 0.82 (95% CI 0.81, 0.83;p <0.001) for a model including 9 clinically accessible variables. The IMI DIRECT prediction models outperformed existing noninvasive NAFLD prediction tools. One limitation is that these analyses were performed in adults of European ancestry residing in northern Europe, and it is unknown how well these findings will translate to people of other ancestries and exposed to environmental risk factors that differ from those of the present cohort. Another key limitation of this study is that the prediction was done on a binary outcome of liver fat quantity (<5% or >= 5%) rather than a continuous one.ConclusionsIn this study, we developed several models with different combinations of clinical and omics data and identified biological features that appear to be associated with liver fat accumulation. In general, the clinical variables showed better prediction ability than the complex omics variables. However, the combination of omics and clinical variables yielded the highest accuracy. We have incorporated the developed clinical models into a web interface (see:) and made it available to the community.
AU  - Atabaki-Pasdar, N.*
AU  - Ohlsson, M.*
AU  - Viñuela, A.*
AU  - Frau, F.*
AU  - Pomares-Millan, H.*
AU  - Haid, M.
AU  - Jones, A.G.*
AU  - Thomas, E.L.*
AU  - Koivula, R.W.*
AU  - Kurbasic, A.*
AU  - Mutie, P.M.*
AU  - Fitipaldi, H.*
AU  - Fernández, J.*
AU  - Dawed, A.Y.*
AU  - Giordano, G.N.*
AU  - Forgie, I.M.*
AU  - McDonald, T.J.*
AU  - Rutters, F.*
AU  - Cederberg, H.*
AU  - Chabanova, E.*
AU  - Dale, M.*
AU  - Masi, F.*
AU  - Thomas, C.E.*
AU  - Allin, K.H.*
AU  - Hansen, T.H.*
AU  - Heggie, A.*
AU  - Hong, M.G.*
AU  - Elders, P.J.M.*
AU  - Kennedy, G.*
AU  - Kokkola, T.*
AU  - Pedersen, H.K.*
AU  - Mahajan, A.*
AU  - McEvoy, D.*
AU  - Pattou, F.*
AU  - Raverdy, V.*
AU  - Häussler, R.S.*
AU  - Sharma, S.
AU  - Thomsen, H.S.*
AU  - Vangipurapu, J.*
AU  - Vestergaard, H.*
AU  - 't Hart, L.M.*
AU  - Adamski, J.
AU  - Musholt, P.B.*
AU  - Brage, S.*
AU  - Brunak, S.*
AU  - Dermitzakis, E.*
AU  - Frost, G.*
AU  - Hansen, T.*
AU  - Laakso, M.*
AU  - Pedersen, O.*
AU  - Ridderstråle, M.*
AU  - Ruetten, H.*
AU  - Hattersley, A.T.*
AU  - Walker, M.*
AU  - Beulens, J.W.J.*
AU  - Mari, A.*
AU  - Schwenk, J.M.*
AU  - Gupta, R.*
AU  - McCarthy, M.I.*
AU  - Pearson, E.R.*
AU  - Bell, J.D.*
AU  - Pavo, I.*
AU  - Franks, P.W.*
C1  - 59419
C2  - 48806
CY  - 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
TI  - Predicting and elucidating the etiology of fatty liver disease: A machine learning modeling and validation study in the IMI DIRECT cohorts.
JO  - PLoS Med.
VL  - 17
IS  - 6
PB  - Public Library Science
PY  - 2020
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - Author summaryWhy was this study done? Maternal smoking during pregnancy is an important risk factor for various birth complications and childhood overweight. It is not clear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy. The associations of paternal smoking with birth and childhood outcomes also remain unknown. What did the researchers do and find? We conducted an individual participant data meta-analysis using data from 229,158 families from 28 pregnancy and birth cohorts from Europe and North America to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. We observed that smoking in the first trimester only did not increase the risk of preterm birth and small size for gestational age but was associated with a higher risk of childhood overweight, as compared to nonsmoking. Reducing the number of cigarettes during pregnancy, without quitting, was still associated with higher risks of these adverse outcomes. Paternal smoking seems to be associated, independently of maternal smoking, with the risks of childhood overweight. What do these findings mean? Population strategies should focus on parental smoking prevention before or at the start of, rather than during, pregnancy. Future studies are needed to assess the specific associations of smoking in the preconception and childhood periods with offspring outcomes.Background Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. Methods and findings We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35],Pvalue = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15],Pvalue = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23],Pvalue < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48],Pvalue < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to <= 4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from >= 10 to 5-9 and <= 4 cigarettes/day, respectively [Pvalues < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27],Pvalue < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. Conclusions We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.
AU  - Philips, E.M.*
AU  - Santos, S.*
AU  - Aurrekoetxea, J.J.*
AU  - Barros, H.*
AU  - von Berg, A.*
AU  - Bergström, A.*
AU  - Bird, P.K.*
AU  - Brescianini, S.*
AU  - Ní Chaoimh, C.*
AU  - Charles, M.A.*
AU  - Chatzi, L.*
AU  - Chévrier, C.*
AU  - Chrousos, G.P.*
AU  - Costet, N.*
AU  - Criswell, R.*
AU  - Crozier, S.*
AU  - Eggesbø, M.*
AU  - Fantini, M.P.*
AU  - Farchi, S.*
AU  - Forastiere, F.*
AU  - van Gelder, M.M.H.J.*
AU  - Georgiu, V.*
AU  - Godfrey, K.M.*
AU  - Gori, D.*
AU  - Hanke, W.*
AU  - Heude, B.*
AU  - Hryhorczuk, D.*
AU  - Iñiguez, C.*
AU  - Inskip, H.*
AU  - Karvonen, A.M.*
AU  - Kenny, L.C.*
AU  - Kull, I.*
AU  - Lawlor, D.A.*
AU  - Lehmann, I.*
AU  - Magnus, P.*
AU  - Manios, Y.*
AU  - Melén, E.*
AU  - Mommers, M.*
AU  - Morgen, C.S.*
AU  - Moschonis, G.*
AU  - Murray, D.*
AU  - Nohr, E.A.*
AU  - Nybo Andersen, A.M.*
AU  - Oken, E.*
AU  - Oostvogels, A.J.J.M.*
AU  - Papadopoulou, E.*
AU  - Pekkanen, J.*
AU  - Pizzi, C.*
AU  - Polanska, K.*
AU  - Porta, D.*
AU  - Richiardi, L.*
AU  - Rifas-Shiman, S.L.*
AU  - Roeleveld, N.*
AU  - Rusconi, F.*
AU  - Santos, A.C.*
AU  - Sørensen, T.I.A.*
AU  - Standl, M.
AU  - Stoltenberg, C.*
AU  - Sunyer, J.*
AU  - Thiering, E.
AU  - Thijs, C.*
AU  - Torrent, M.*
AU  - Vrijkotte, T.G.M.*
AU  - Wright, J.*
AU  - Zvinchuk, O.*
AU  - Gaillard, R.*
AU  - Jaddoe, V.W.V.*
C1  - 59918
C2  - 49118
CY  - 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
TI  - Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births.
JO  - PLoS Med.
VL  - 17
IS  - 8
PB  - Public Library Science
PY  - 2020
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BackgroundMaternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact.Methods and findingsWe conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0-5.0 years), mid (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestylerelated characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations.ConclusionsIn this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.
AU  - Voerman, E.*
AU  - Santos, S.*
AU  - Patro Golab, B.*
AU  - Amiano, P.*
AU  - Ballester, F.*
AU  - Barros, H.*
AU  - Bergström, A.*
AU  - Charles, M.A.*
AU  - Chatzi, L.*
AU  - Chévrier, C.*
AU  - Chrousos, G.P.*
AU  - Corpeleijn, E.*
AU  - Costet, N.*
AU  - Crozier, S.*
AU  - Devereux, G.*
AU  - Eggesbø, M.*
AU  - Ekström, S.*
AU  - Fantini, M.P.*
AU  - Farchi, S.*
AU  - Forastiere, F.*
AU  - Georgiu, V.*
AU  - Godfrey, K.M.*
AU  - Gori, D.*
AU  - Grote, V.*
AU  - Hanke, W.*
AU  - Hertz-Picciotto, I.*
AU  - Heude, B.*
AU  - Hryhorczuk, D.*
AU  - Huang, R.C.*
AU  - Inskip, H.*
AU  - Iszatt, N.*
AU  - Karvonen, A.M.*
AU  - Kenny, L.C.*
AU  - Koletzko, B.*
AU  - Küpers, L.K.*
AU  - Lagström, H.*
AU  - Lehmann, I.*
AU  - Magnus, P.*
AU  - Majewska, R.*
AU  - Mäkelä, J.*
AU  - Manios, Y.*
AU  - McAuliffe, F.M.*
AU  - McDonald, S.W.*
AU  - Mehegan, J.*
AU  - Mommers, M.*
AU  - Morgen, C.S.*
AU  - Mori, T.A.*
AU  - Moschonis, G.*
AU  - Murray, D.*
AU  - Chaoimh, C.N.*
AU  - Nohr, E.A.*
AU  - Nybo Andersen, A.M.*
AU  - Oken, E.*
AU  - Oostvogels, A.J.J.M.*
AU  - Pac, A.*
AU  - Papadopoulou, E.*
AU  - Pekkanen, J.*
AU  - Pizzi, C.*
AU  - Polanska, K.*
AU  - Porta, D.*
AU  - Richiardi, L.*
AU  - Rifas-Shiman, S.L.*
AU  - Ronfani, L.*
AU  - Santos, A.C.*
AU  - Standl, M.
AU  - Stoltenberg, C.*
AU  - Thiering, E.
AU  - Thijs, C.*
AU  - Torrent, M.*
AU  - Tough, S.C.*
AU  - Trnovec, T.*
AU  - Turner, S.*
AU  - van Rossem, L.*
AU  - von Berg, A.*
AU  - Vrijheid, M.*
AU  - Vrijkotte, T.G.M.*
AU  - West, J.*
AU  - Wijga, A.*
AU  - Wright, J.*
AU  - Zvinchuk, O.*
AU  - Sørensen, T.I.A.*
AU  - Lawlor, D.A.*
AU  - Gaillard, R.*
AU  - Jaddoe, V.W.V.*
C1  - 55482
C2  - 46359
CY  - 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
TI  - Maternal body mass index, gestational weight gain, and the risk of overweight and obesity across childhood: An individual participant data meta-analysis.
JO  - PLoS Med.
VL  - 16
IS  - 2
PB  - Public Library Science
PY  - 2019
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes. METHODS AND FINDINGS: The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and monitored until 31 May 2016. The risk (positive predictive value) for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. In the children with the HLA risk genotypes, risk for developing multiple islet autoantibodies was 5.8% (95% CI 5.0%-6.6%) by age 6 years, and risk for diabetes by age 10 years was 3.7% (95% CI 3.0%-4.4%). Risk for developing multiple islet autoantibodies was 11.0% (95% CI 8.7%-13.3%) in children with a merged genetic score of >14.4 (upper quartile; n = 907) compared to 4.1% (95% CI 3.3%-4.9%, P < 0.001) in children with a genetic score of ≤14.4 (n = 2,591). Risk for developing diabetes by age 10 years was 7.6% (95% CI 5.3%-9.9%) in children with a merged score of >14.4 compared with 2.7% (95% CI 1.9%-3.6%) in children with a score of ≤14.4 (P < 0.001). Of 173 children with multiple islet autoantibodies by age 6 years and 107 children with diabetes by age 10 years, 82 (sensitivity, 47.4%; 95% CI 40.1%-54.8%) and 52 (sensitivity, 48.6%, 95% CI 39.3%-60.0%), respectively, had a score >14.4. Scores were higher in European versus US children (P = 0.003). In children with a merged score of >14.4, risk for multiple islet autoantibodies was similar and consistently >10% in Europe and in the US; risk was greater in males than in females (P = 0.01). Limitations of the study include that the genetic scores were originally developed from case-control studies of clinical diabetes in individuals of mainly European decent. It is, therefore, possible that it may not be suitable to all populations. CONCLUSIONS: A type 1 diabetes genetic score identified infants without family history of type 1 diabetes who had a greater than 10% risk for pre-symptomatic type 1 diabetes, and a nearly 2-fold higher risk than children identified by high-risk HLA genotypes alone. This finding extends the possibilities for enrolling children into type 1 diabetes primary prevention trials.
AU  - Bonifacio, E.*
AU  - Beyerlein, A.
AU  - Hippich, M.
AU  - Winkler, C.
AU  - Vehik, K.*
AU  - Weedon, M.N.*
AU  - Laimighofer, M.
AU  - Hattersley, A.T.*
AU  - Krumsiek, J.
AU  - Frohnert, B.I.*
AU  - Steck, A.K.*
AU  - Hagopian, W.A.*
AU  - Krischer, J.P.*
AU  - Lernmark, A.*
AU  - Rewers, M.J.*
AU  - She, J.X.*
AU  - Toppari, J.*
AU  - Akolkar, B.*
AU  - Oram, R.A.*
AU  - Rich, S.S.*
AU  - Ziegler, A.-G.
C1  - 53359
C2  - 44705
TI  - Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children.
JO  - PLoS Med.
VL  - 15
IS  - 4
PY  - 2018
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BackgroundClimate change is likely to further worsen ozone pollution in already heavily polluted areas, leading to increased ozone-related health burdens. However, little evidence exists in China, the world's largest greenhouse gas emitter and most populated country. As China is embracing an aging population with changing population size and falling age-standardized mortality rates, the potential impact of population change on ozone-related health burdens is unclear. Moreover, little is known about the seasonal variation of ozone-related health burdens under climate change. We aimed to assess near-term (mid-21st century) future annual and seasonal excess mortality from short-term exposure to ambient ozone in 104 Chinese cities under 2 climate and emission change scenarios and 6 population change scenarios.Methods and findingsWe collected historical ambient ozone observations, population change projections, and baseline mortality rates in 104 cities across China during April 27, 2013, to October 31, 2015 (2013-2015), which included approximately 13% of the total population of mainland China. Using historical ozone monitoring data, we performed bias correction and spatially down-scaled future ozone projections at a coarse spatial resolution (2.0 degrees x 2.5 degrees) for the period April 27, 2053, to October 31, 2055 (2053-2055), from a global chemistry-climate model to a fine spatial resolution (0.25 degrees x 0.25 degrees) under 2 Intergovernmental Panel on Climate Change Representative Concentration Pathways (RCPs): RCP4.5, a moderate global warming and emission scenario where global warming is between 1.5 degrees C and 2.0 degrees C, and RCP8.5, a high global warming and emission scenario where global warming exceeds 2.0 degrees C. We then estimated the future annual and seasonal ozone-related acute excess mortality attributable to both climate and population changes using cause-specific, age-group-specific, and season-specific concentration-response functions (CRFs). We used Monte Carlo simulations to obtain empirical confidence intervals (eCIs), quantifying the uncertainty in CRFs and the variability across ensemble members (i.e., 3 predictions of future climate and air quality from slightly different starting conditions) of the global model. Estimates of future changes in annual ozone-related mortality are sensitive to the choice of global warming and emission scenario, decreasing under RCP4.5 (-24.0%) due to declining ozone precursor emissions but increasing under RCP8.5 (10.7%) due to warming climate in 2053-2055 relative to 2013-2015. Higher ambient ozone occurs under the high global warming and emission scenario (RCP8.5), leading to an excess 1,476 (95% eCI: 898 to 2,977) non-accidental deaths per year in 2053-2055 relative to 2013-2015. Future ozone-related acute excess mortality from cardiovascular diseases was 5-8 times greater than that from respiratory diseases. Ozone concentrations increase by 15.1 parts per billion (10(-9)) in colder months (November to April), contributing to a net yearly increase of 22.3% (95% eCI: 7.7% to 35.4%) in ozone-related mortality under RCP8.5. An aging population, with the proportion of the population aged 65 years and above increased from 8% in 2010 to 24%-33% in 2050, will substantially amplify future ozone-related mortality, leading to a net increase of 23,838 to 78,560 deaths (110% to 363%). Our analysis was mainly limited by using a single global chemistry-climate model and the statistical downscaling approach to project ozone changes under climate change.ConclusionsOur analysis shows increased future ozone-related acute excess mortality under the high global warming and emission scenario RCP8.5 for an aging population in China. Comparison with the lower global warming and emission scenario RCP4.5 suggests that climate change mitigation measures are needed to prevent a rising health burden from exposure to ambient ozone pollution in China.
AU  - Chen, K.
AU  - Fiore, A.M.*
AU  - Chen, R.*
AU  - Jiang, L.*
AU  - Jones, B.C.*
AU  - Schneider, A.E.
AU  - Peters, A.
AU  - Bi, J.*
AU  - Kan, H.*
AU  - Kinney, P.L.*
C1  - 53864
C2  - 45048
CY  - 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
TI  - Future ozone-related acute excess mortality under climate and population change scenarios in China: A modeling study.
JO  - PLoS Med.
VL  - 15
IS  - 7
PB  - Public Library Science
PY  - 2018
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - Background: The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression. Methods and findings: Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and “asymptomatic Alzheimer’s disease” (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes—sphingolipids and glycerophospholipids—that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer’s Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer’s Disease [EASE-AD] ). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio [HR] = 4.430, 95% confidence interval [CI] = 1.703–11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516–7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373–9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047–4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples. Conclusions: We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD.
AU  - Varma, V.R.*
AU  - Oommen, A.M.*
AU  - Varma, S.*
AU  - Casanova, R.*
AU  - An, Y.*
AU  - Andrews, R.M.*
AU  - O'Brien, R.M.*
AU  - Pletnikova, O.*
AU  - Troncoso, J.C.*
AU  - Toledo, J.B.*
AU  - Baillie, R.A.*
AU  - Arnold, M.
AU  - Kastenmüller, G.
AU  - Nho, K.*
AU  - Doraiswamy, P.M.*
AU  - Saykin, A.J.*
AU  - Kaddurah-Daouk, R.*
AU  - Legido-Quigley, C.*
AU  - Thambisetty, M.*
C1  - 52966
C2  - 44693
CY  - San Francisco
TI  - Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study.
JO  - PLoS Med.
VL  - 15
IS  - 1
PB  - Public Library Science
PY  - 2018
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable. METHODS AND FINDINGS: We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90-1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69-1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92-1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was -0.40 (95% CI -1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry. This research has been conducted using the UK Biobank Resource and data from the SUNLIGHT, GABRIEL and EAGLE Eczema consortia. CONCLUSIONS: In this study, we found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE, suggesting that efforts to increase vitamin D are unlikely to reduce risks of atopic disease.
AU  - Manousaki, D.*
AU  - Paternoster, L.*
AU  - Standl, M.
AU  - Moffatt, M.F.*
AU  - Farrall, M.*
AU  - Bouzigon, E.*
AU  - Strachan, D.P.*
AU  - Demenais, F.*
AU  - Lathrop, M*
AU  - Cookson, W.O.C.M.*
AU  - Richards, J.B.*
C1  - 51091
C2  - 42682
CY  - San Francisco
TI  - Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: A Mendelian randomization study.
JO  - PLoS Med.
VL  - 14
IS  - 5
PB  - Public Library Science
PY  - 2017
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
AU  - Wheeler, E.*
AU  - Leong, A.*
AU  - Liu, C.-T.*
AU  - Hivert, M.F.*
AU  - Strawbridge, R.J.*
AU  - Podmore, C.*
AU  - Li, M.*
AU  - Yao, J.*
AU  - Sim, X.*
AU  - Hong, J.*
AU  - Chu, A.Y.*
AU  - Zhang, W.*
AU  - Wang, X.*
AU  - Chen, P.*
AU  - Maruthur, N.M.*
AU  - Porneala, B.C.*
AU  - Sharp, S.J.*
AU  - Jia, Y.P.*
AU  - Kabagambe, E.K.*
AU  - Chang, L.C.*
AU  - Chen, W.M.*
AU  - Elks, C.E.*
AU  - Evans, D.S.*
AU  - Fan, Q.*
AU  - Giulianini, F.*
AU  - Go, M.J.*
AU  - Hottenga, J.J.*
AU  - Hu, Y.*
AU  - Jackson, A.U.*
AU  - Kanoni, S.*
AU  - Kim, Y.J.*
AU  - Kleber, M.E.*
AU  - Ladenvall, C.*
AU  - Lecoeur, C.*
AU  - Lim, S.H.*
AU  - Lu, Y.*
AU  - Mahajan, A.*
AU  - Marzi, C.
AU  - Nalls, M.A.*
AU  - Navarro, P.*
AU  - Nolte, I.M.*
AU  - Rose, L.M.*
AU  - Rybin, D.V.*
AU  - Sanna, S.*
AU  - Shi, Y.*
AU  - Stram, D.O.*
AU  - Takeuchi, F.*
AU  - Tan, S.P.*
AU  - van der Most, P.J.*
AU  - van Vliet-Ostaptchouk, J.V.*
AU  - Wong, A.*
AU  - Yengo, L.*
AU  - Zhao, W.*
AU  - Goel, A.*
AU  - Martinez Larrad, M.T.*
AU  - Radke, D.*
AU  - Salo, P.*
AU  - Tanaka, T.*
AU  - van Iperen, E.P.A.*
AU  - Abecasis, G.*
AU  - Afaq, S.*
AU  - Alizadeh, B.Z.*
AU  - Bertoni, A.G.*
AU  - Bonnefond, A.*
AU  - Böttcher, Y.*
AU  - Bottinger, E.P.*
AU  - Campbell, H.*
AU  - Carlson, O.D.*
AU  - Chen, C.H.*
AU  - Cho, Y.S.*
AU  - Garvey, W.T.*
AU  - Gieger, C.
AU  - Goodarzi, M.O.*
AU  - Grallert, H.
AU  - Hamsten, A.*
AU  - Hartman, C.A.*
AU  - Herder, C.*
AU  - Hsiung, C.A.*
AU  - Huang, J.*
AU  - Igase, M.*
AU  - Isono, M.*
AU  - Katsuya, T.*
AU  - Khor, C.C.*
AU  - Kiess, W.*
AU  - Kohara, K.*
AU  - Kovacs, P.*
AU  - Lee, J.*
AU  - Lee, W.-J.*
AU  - Lehne, B.*
AU  - Li, H.*
AU  - Liu, J.*
AU  - Lobbens, S.*
AU  - Luan, J.*
AU  - Lyssenko, V.*
AU  - Meitinger, T.
AU  - Miki, T.*
AU  - Miljkovic, I.*
AU  - Moon, S.*
AU  - Mulas, A.*
AU  - Müller, G.*
AU  - Müller-Nurasyid, M.
AU  - Nagaraja, R.*
AU  - Nauck, M.*
AU  - Pankow, J.S.*
AU  - Polasek, O.*
AU  - Prokopenko, I.*
AU  - Ramos, P.S.*
AU  - Rasmussen-Torvik, L.J.*
AU  - Rathmann, W.*
AU  - Rich, S.S.*
AU  - Robertson, N.R.*
AU  - Roden, M.*
AU  - Roussel, R.*
AU  - Rudan, I.*
AU  - Scott, R.A.*
AU  - Scott, W.R.*
AU  - Sennblad, B.*
AU  - Siscovick, D.S.*
AU  - Strauch, K.
AU  - Sun, L.*
AU  - Swertz, M.A.*
AU  - Tajuddin, S.M.*
AU  - Taylor, K.D.*
AU  - Teo, Y.Y.*
AU  - Tham, Y.C.*
AU  - Tönjes, A.*
AU  - Wareham, N.J.*
AU  - Willemsen, G.*
AU  - Wilsgaard, T.*
AU  - Hingorani, A.D.*
AU  - Egan, J.*
AU  - Ferrucci, L.*
AU  - Hovingh, G.K.*
AU  - Jula, A.*
AU  - Kivimaki, M.*
AU  - Kumari, M.*
AU  - Njølstad, I.*
AU  - Palmer, C.N.A.*
AU  - Serrano Ríos, M.*
AU  - Stumvoll, M.*
AU  - Watkins, H.*
AU  - Aung, T.*
AU  - Blüher, M.*
AU  - Boehnke, M.*
AU  - Boomsma, D.I.*
AU  - Bornstein, S.R.*
AU  - Chambers, J.C.*
AU  - Chasman, D.I.*
AU  - Chen, Y.I.*
AU  - Chen, Y.T.*
AU  - Cheng, C.Y.*
AU  - Cucca, F.*
AU  - de Geus, E.J.C.*
AU  - Deloukas, P.*
AU  - Evans, M.K.*
AU  - Fornage, M.*
AU  - Friedlander, Y.*
AU  - Froguel, P.*
AU  - Groop, L.*
AU  - Gross, M.D.*
AU  - Harris, T.B.*
AU  - Hayward, C.*
AU  - Heng, C.K.*
AU  - Ingelsson, E.*
AU  - Kato, N.*
AU  - Kim, B.J.*
AU  - Koh, W.P.*
AU  - Kooner, J.S.*
AU  - Körner, A.*
AU  - Kuh, D.*
AU  - Kuusisto, J.*
AU  - Laakso, M.*
AU  - Lin, X.*
AU  - Liu, Y.*
AU  - Loos, R.J.F.*
AU  - Magnusson, P.K.E.*
AU  - März, W.*
AU  - McCarthy, M.I.*
AU  - Oldehinkel, A.J.*
AU  - Ong, K.K.*
AU  - Pedersen, N.L.*
AU  - Pereira, M.A.*
AU  - Peters, A.
AU  - Ridker, P.M.*
AU  - Sabanayagam, C.*
AU  - Sale, M.M.*
AU  - Saleheen, D.*
AU  - Saltevo, J.*
AU  - Schwarz, P.E.H.*
AU  - Sheu, W.H.H.*
AU  - Snieder, H.*
AU  - Spector, T.D.*
AU  - Tabara, Y.*
AU  - Tuomilehto, J.*
AU  - van Dam, R.M.*
AU  - Wilson, J.G.*
AU  - Wilson, J.F.*
AU  - Wolffenbuttel, B.H.R.*
AU  - Wong, T.Y.*
AU  - Wu, J.Y.*
AU  - Yuan, J.M.*
AU  - Zonderman, A.B.*
AU  - Soranzo, N.*
AU  - Guo, X.*
AU  - Roberts, D.J.*
AU  - Florez, J.C*
AU  - Sladek, R.*
AU  - Dupuis, J.*
AU  - Morris, A.P.*
AU  - Tai, E.S.*
AU  - Selvin, E.*
AU  - Rotter, J.I.*
AU  - Langenberg, C.*
AU  - Barroso, I.*
AU  - Meigs, J.B.*
C1  - 51856
C2  - 43522
CY  - San Francisco
TI  - Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.
JO  - PLoS Med.
VL  - 14
IS  - 9
PB  - Public Library Science
PY  - 2017
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - Background C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. Methods and Findings We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRS(CRP)), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRS(GWAS)). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRS(CRP) and GRS(GWAS), respectively. CRP GRS(GWAS) showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 x 10(-6)). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 x 10(-4), 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 x 10(-4)) showed a statistically significant (p < 2.45 x 10(-4)) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRS(GWAS) showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 x 10(-5)) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m(2) (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. Conclusions Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRS(CRP) or GRS(GWAS)-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.
AU  - Prins, B.P.*
AU  - Abbasi, A.*
AU  - Wong, A.*
AU  - Vaez, A.*
AU  - Nolte, I.M.*
AU  - Franceschini, N.*
AU  - Stuart, P.E.*
AU  - Achury, J.G.*
AU  - Mistry, V.*
AU  - Bradfield, J.P.*
AU  - Valdes, A.M.*
AU  - Bras, J.*
AU  - Shatunov, A.*
AU  - PAGE Consortium (*)
AU  - International Stroke Genetics Consortium (*)
AU  - Systemic Sclerosis Consortium (*)
AU  - Treat OA Consortium (*)
AU  - DIAGRAM Consortium (*)
AU  - CARDIoGRAMplusC4D Consortium (*)
AU  - ALS Consortium (*)
AU  - International Parkinson's Disease Genomics Consortium (IPDGC) (*)
AU  - Autism Spectrum Disorder Working Group (*)
AU  - CKDGen Consortium (*)
AU  - GERAD1 Consortium (*)
AU  - ICBP Consortium (Meitinger, T.
AU  - Wichmann, H.-E.)
AU  - Schizophrenia Working Group of the Psychiatric Genomics Consortium (*)
AU  - Inflammation Working Group of the CHARGE Consortium (*)
AU  - Lu, C.*
AU  - Han, B.*
AU  - Raychaudhuri, S.*
AU  - Bevan, S.*
AU  - Mayes, M.D.*
AU  - Tsoi, L.C.*
AU  - Evangelou, E.*
AU  - Nair, R.P.*
AU  - Grant, S.F.A.*
AU  - Polychronakos, C.*
AU  - Radstake, T.R.D.*
AU  - van Heel, D.A.*
AU  - Dunstan, M.L.*
AU  - Wood, N.W.*
AU  - Al-Chalabi, A.*
AU  - Dehghan, A.*
AU  - Hakonarson, H.*
AU  - Markus, H.S.*
AU  - Elder, J.T.*
AU  - Knight, J.*
AU  - Arking, D.E.*
AU  - Spector, T.D.*
AU  - Koeleman, B.P.C.*
AU  - van Duijn, C.M.*
AU  - Martin, J.*
AU  - Morris, A.P.*
AU  - Weersma, R.K.*
AU  - Wijmenga, C.*
AU  - Munroe, P.B.*
AU  - Perry, J.R.B.*
AU  - Pouget, J.G.*
AU  - Jamshidi, Y.*
AU  - Snieder, H.*
AU  - Alizadeh, B.Z.*
C1  - 49138
C2  - 41653
CY  - San Francisco
TI  - Investigating the causal relationship of c-reactive protein with 32 complex somatic and psychiatric outcomes: A large-scale cross-consortium mendelian randomization study.
JO  - PLoS Med.
VL  - 13
IS  - 6
PB  - Public Library Science
PY  - 2016
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). METHODS AND FINDINGS: We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. CONCLUSIONS: Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure--or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications--may reduce AD risk.
AU  - Østergaard, S.D.*
AU  - Mukherjee, S.*
AU  - Sharp, S.J.*
AU  - Proitsi, P.*
AU  - Lotta, L.A.*
AU  - Day, F.*
AU  - Perry, J.R.*
AU  - Boehme, K.L.*
AU  - Walter, S.*
AU  - Kauwe, J.S.*
AU  - Gibbons, L.E.*
AU  - Alzheimer's Disease Neuroimaging Initiative (*)
AU  - Genetic and Environmental Risk for Alzheimer's Disease (GERAD1) Consortium (Klopp, N.
AU  - Wichmann, H.-E.)
AU  - EPIC-Interact Consortium (Scott, R.A.*)
AU  - Larson, E.B.*
AU  - Powell, J.F.*
AU  - Langenberg, C.*
C1  - 47191
C2  - 39152
TI  - Associations between potentially modifiable risk factors and Alzheimer disease: A mendelian randomization study.
JO  - PLoS Med.
VL  - 12
IS  - 6
PY  - 2015
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. METHODS AND FINDINGS: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). CONCLUSIONS: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
AU  - Fall, T.*
AU  - Hägg, S.*
AU  - Mägi, R.*
AU  - Ploner, A.*
AU  - Fischer, K.*
AU  - Horikoshi, M.*
AU  - Sarin, A.P.*
AU  - Thorleifsson, G.*
AU  - Ladenvall, C.*
AU  - Kals, M.*
AU  - Kuningas, M.*
AU  - Draisma, H.H.*
AU  - Ried, J.S.
AU  - van Zuydam, N.*
AU  - Huikari, V.*
AU  - Mangino, M.*
AU  - Sonestedt, E.*
AU  - Benyamin, B.*
AU  - Nelson, C.P.*
AU  - Rivera, N.V.*
AU  - Kristiansson, K.*
AU  - Shen, H.Y.*
AU  - Havulinna, A.S.*
AU  - Dehghan, A.*
AU  - Donnelly, L.A.*
AU  - Kaakinen, M.*
AU  - Nuotio, M.L.*
AU  - Robertson, N.*
AU  - de Bruijn, R.F.*
AU  - Ikram, M.A.*
AU  - Amin, N.*
AU  - Balmforth, A.J.*
AU  - Braund, P.S.*
AU  - Doney, A.S.*
AU  - Döring, A.
AU  - Elliott, P.*
AU  - Esko, T.*
AU  - Franco, O.H.*
AU  - Gretarsdottir, S.*
AU  - Hartikainen, A.L.*
AU  - Heikkilä, K.*
AU  - Herzig, K.H.*
AU  - Holm, H.*
AU  - Hottenga, J.J.*
AU  - Hyppönen, E.*
AU  - Illig, T.
AU  - Isaacs, A.*
AU  - Isomaa, B.*
AU  - Karssen, L.C.*
AU  - Kettunen, J.*
AU  - Koenig, W.*
AU  - Kuulasmaa, K.*
AU  - Laatikainen, T.*
AU  - Laitinen, J.*
AU  - Lindgren, C.*
AU  - Lyssenko, V.*
AU  - Läärä, E.*
AU  - Rayner, N.W.*
AU  - Männistö, S.*
AU  - Pouta, A.*
AU  - Rathmann, W.*
AU  - Rivadeneira, F.*
AU  - Ruokonen, A.*
AU  - Savolainen, M.J.*
AU  - Sijbrands, E.J.*
AU  - Small, K.S.*
AU  - Smit, J.H.*
AU  - Steinthorsdottir, V.*
AU  - Syvanen, A.C.*
AU  - Taanila, A.*
AU  - Tobin, M.D.*
AU  - Uitterlinden, A.G.*
AU  - Willems, S.M.*
AU  - Willemsen, G.*
AU  - Witteman, J.*
AU  - Perola, M.*
AU  - Evans, A.*
AU  - Ferrieres, J.*
AU  - Virtamo, J.*
AU  - Kee, F.*
AU  - Tregouet, D.A.*
AU  - Arveiler, D.*
AU  - Amouyel, P.*
AU  - Ferrario, M.M.*
AU  - Brambilla, P.*
AU  - Hall, A.S.*
AU  - Heath, A.C.*
AU  - Madden, P.A.*
AU  - Martin, N.G.*
AU  - Montgomery, G.W.*
AU  - Whitfield, J.B.*
AU  - Jula, A.*
AU  - Knekt, P.*
AU  - Oostra, B.*
AU  - van Duijn, C.M.*
AU  - Penninx, B.W.*
AU  - Davey Smith, G.*
AU  - Kaprio, J.*
AU  - Samani, N.J.*
AU  - Gieger, C.
AU  - Peters, A.
AU  - Wichmann, H.-E.
AU  - Boomsma, D.I.*
AU  - de Geus, E.J.*
AU  - Tuomi, T.*
AU  - Power, C.*
AU  - Hammond, C.J.*
AU  - Spector, T.D.*
AU  - Lind, L.*
AU  - Orho-Melander, M.*
AU  - Palmer, C.N.*
AU  - Morris, A.D.*
AU  - Groop, L.*
AU  - Jarvelin, M.R.*
AU  - Salomaa, V.*
AU  - Vartiainen, E.*
AU  - Hofman, A.*
AU  - Ripatti, S.*
AU  - Metspalu, A.*
AU  - Thorsteinsdottir, U.*
AU  - Stefansson, K.*
AU  - Pedersen, N.L.*
AU  - McCarthy, M.I.*
AU  - Ingelsson, E.*
AU  - Prokopenko, I.*
AU  - ENGAGE Consortium (*)
C1  - 26140
C2  - 32089
TI  - The role of adiposity in cardiometabolic traits: A mendelian randomization analysis.
JO  - PLoS Med.
VL  - 10
IS  - 6
PB  - Public Library of Science
PY  - 2013
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. METHODS AND FINDINGS: We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p = 0.001) per 10 µg/dl increase in serum iron. CONCLUSIONS: Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made.  
AU  - Pichler, I.*
AU  - del Greco, M.F.*
AU  - Gögele, M.*
AU  - Lill, C.M.*
AU  - Bertram, L.*
AU  - Do, C.B.*
AU  - Eriksson, N.*
AU  - Foroud, T.*
AU  - Myers, R.H.*
AU  - PD GWAS Consortium (*)
AU  - Nalls, M.*
AU  - Keller, M.F.*
AU  - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T.
AU  - Lichtner, P.
AU  - Winkelmann, J.*)
AU  - Wellcome Trust Case Consortium (WTCCC) (*)
AU  - Benyamin, B.*
AU  - Whitfield, J.B.*
AU  - Genetics of Iron Status Consortium (*)
AU  - Pramstaller, P.P.*
AU  - Hicks, A.A.*
AU  - Thompson, J.R.*
AU  - Minelli, C.*
C1  - 29153
C2  - 33636
SP  - 4270-4276
TI  - Serum iron levels and the risk of Parkinson disease: A mendelian randomization study.
JO  - PLoS Med.
VL  - 10
IS  - 6
PY  - 2013
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
AU  - Vimaleswaran, K.S.*
AU  - Berry, D.J.*
AU  - Lu, C.*
AU  - Tikkanen, E.*
AU  - Pilz, S.*
AU  - Hiraki, L.T.*
AU  - Cooper, J.D.*
AU  - Dastani, Z.*
AU  - Li, R.*
AU  - Houston, D.K.*
AU  - Wood, A.R.*
AU  - Michaelsson, K.*
AU  - Vandenput, L.*
AU  - Zgaga, L.*
AU  - Yerges-Armstrong, L.M.*
AU  - McCarthy, M.I.*
AU  - Dupuis, J.*
AU  - Kaakinen, M.*
AU  - Kleber, M.E.*
AU  - Jameson, K.*
AU  - Arden, N.*
AU  - Raitakari, O.*
AU  - Viikari, J.*
AU  - Lohman, K.K.*
AU  - Ferrucci, L.*
AU  - Melhus, H.*
AU  - Ingelsson, E.*
AU  - Byberg, L.*
AU  - Lind, L.*
AU  - Lorentzon, M.*
AU  - Salomaa, V.*
AU  - Campbell, H.*
AU  - Dunlop, M.*
AU  - Mitchell, B.D.*
AU  - Herzig, K.H.*
AU  - Pouta, A.*
AU  - Hartikainen, A.L.*
AU  - GIANT Consortium (Heid, I.M.
AU  - Gieger, C.
AU  - Wichmann, H.-E.
AU  - Grallert, H.
AU  - Illig, T.
AU  - Peters, A.
AU  - Heinrich, J.
AU  - Thiering, E.)
AU  - Streeten, E.A.*
AU  - Theodoratou, E.*
AU  - Jula, A.*
AU  - Wareham, N.J.*
AU  - Ohlsson, C.*
AU  - Frayling, T.M.*
AU  - Kritchevsky, S.B.*
AU  - Spector, T.D.*
AU  - Richards, J.B.*
AU  - Lehtimäki, T.*
AU  - Ouwehand, W.H.*
AU  - Kraft, P.*
AU  - Cooper, C.*
AU  - Marz, W.*
AU  - Power, C.*
AU  - Loos, R.J.*
AU  - Wang, T.J.*
AU  - Jarvelin, M.R.*
AU  - Whittaker, J.C.*
AU  - Hingorani, A.D.*
AU  - Hyppönen, E.*
C1  - 24378
C2  - 31530
TI  - Causal relationship between obesity and vitamin D status: Bi-directional Mendelian randomization analysis of multiple cohorts.
JO  - PLoS Med.
VL  - 10
IS  - 2
PB  - Public Library of Science
PY  - 2013
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so "Mendelian randomization" studies using this variant as an instrumental variable could help test causality. METHODS AND FINDINGS: Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98-1.07; p = 0.28) overall, and 1.01 (0.95-1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09-1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04-1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09-1.28) in the 72 smaller ones (total 15,498 cases). CONCLUSIONS: The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.
AU  - Clarke, R.*
AU  - Bennett, D.A.*
AU  - Parish, S.*
AU  - Verhoef, P.*
AU  - Dötsch-Klerk, M.*
AU  - Lathrop, M*
AU  - Xu, P.*
AU  - Nørdestgaard, B.G.*
AU  - Holm, H.*
AU  - Hopewell, J.C.*
AU  - Saleheen, D.*
AU  - Tanaka, T.*
AU  - Anand, S.S.*
AU  - Chambers, J.C.*
AU  - Kleber, M.E.*
AU  - Ouwehand, W.H.*
AU  - Yamada, Y.*
AU  - Elbers, C.*
AU  - Peters, B.*
AU  - Stewart, A.F.*
AU  - Reilly, M.M.*
AU  - Thorand, B.
AU  - Yusuf, S.*
AU  - Engert, J.C.*
AU  - Assimes, T.L.*
AU  - Kooner, J.*
AU  - Danesh, J.*
AU  - Watkins, H.*
AU  - Samani, N.J.*
AU  - Collins, R.*
AU  - Peto, R*
AU  - MTHFR Studies Collaborative Group (*)
C1  - 7318
C2  - 29680
TI  - Homocysteine and coronary heart disease: Meta-analysis of MTHFR case-control studies, avoiding publication bias.
JO  - PLoS Med.
VL  - 9
IS  - 2
PB  - Public Library of Science
PY  - 2012
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). METHODS AND FINDINGS: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction)  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. CONCLUSIONS: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
AU  - Kilpeläinen, T.O.*
AU  - Qi, L.*
AU  - Brage, S.*
AU  - Sharp, S.J.*
AU  - Sonestedt, E.*
AU  - Demerath, E.*
AU  - Ahmad, T.*
AU  - Mora, S.
AU  - Kaakinen, M.*
AU  - Sandholt, C.H.*
AU  - Holzapfel, C.
AU  - Autenrieth, C.S.
AU  - Hyppönen, E.*
AU  - Cauchi, S.*
AU  - He, M.*
AU  - Kutalik, Z.*
AU  - Kumari, M.*
AU  - Stancáková, A.*
AU  - Meidtner, K.*
AU  - Balkau, B.*
AU  - Tan, J.T.*
AU  - Mangino, M.*
AU  - Timpson, N.J.*
AU  - Song, Y.*
AU  - Zillikens, M.C.*
AU  - Jablonski, K.A.*
AU  - Garcia, M.E.*
AU  - Johansson, S.*
AU  - Bragg-Gresham, J.L.*
AU  - Wu, Y.*
AU  - van Vliet-Ostaptchouk, J.V.*
AU  - Onland-Moret, N.C.*
AU  - Zimmermann, E.*
AU  - Rivera, N.V.*
AU  - Tanaka, T.*
AU  - Stringham, H.M.*
AU  - Silbernagel, G.*
AU  - Kanoni, S.*
AU  - Feitosa, M.F.*
AU  - Snitker, S.*
AU  - Ruiz, J.R.*
AU  - Metter, J.*
AU  - Larrad, M.T.*
AU  - Atalay, M.*
AU  - Hakanen, M.*
AU  - Amin, N.*
AU  - Cavalcanti-Proença, C.*
AU  - Grøntved, A.*
AU  - Hallmans, G.*
AU  - Jansson, J.O.*
AU  - Kuusisto, J.*
AU  - Kähönen, M.*
AU  - Lutsey, P.L.*
AU  - Nolan, J.J.*
AU  - Palla, L.*
AU  - Pedersen, O.*
AU  - Perusse, L.*
AU  - Renström, F.*
AU  - Scott, R.A.*
AU  - Shungin, D.*
AU  - Sovio, U.*
AU  - Tammelin, T.H.*
AU  - Rönnemaa, T.*
AU  - Lakka, T.A.*
AU  - Uusitupa, M.*
AU  - Rios, M.S.*
AU  - Ferrucci, L.*
AU  - Bouchard, C.*
AU  - Meirhaeghe, A.*
AU  - Fu, M.*
AU  - Walker, M.*
AU  - Borecki, I.B.*
AU  - Dedoussis, G.V.*
AU  - Fritsche, A.*
AU  - Ohlsson, C.*
AU  - Boehnke, M.*
AU  - Bandinelli, S.*
AU  - van Duijn, C.M.*
AU  - Ebrahim, S.*
AU  - Lawlor, D.A.*
AU  - Gudnason, V.*
AU  - Harris, T.B.*
AU  - Sørensen, T.I.*
AU  - Mohlke, K.L.*
AU  - Hofman, A.*
AU  - Uitterlinden, A.G.*
AU  - Tuomilehto, J.*
AU  - Lehtimäki, T.*
AU  - Raitakari, O.*
AU  - Isomaa, B.*
AU  - Njølstad, P.R.*
AU  - Florez, J.C*
AU  - Liu, S.*
AU  - Ness, A.*
AU  - Spector, T.D.*
AU  - Tai, E.S.*
AU  - Froguel, P.*
AU  - Boeing, H.*
AU  - Laakso, M.*
AU  - Marmot, M.*
AU  - Bergmann, S.*
AU  - Power, C.*
AU  - Khaw, K.T.*
AU  - Chasman, D.*
AU  - Ridker, P.*
AU  - Hansen, T.*
AU  - Monda, KL.*
AU  - Illig, T.
AU  - Jarvelin, M.R.*
AU  - Wareham, N.J.*
AU  - Hu, F.B.*
AU  - Groop, L.C.*
AU  - Orho-Melander, M.*
AU  - Ekelund, U.*
AU  - Franks, P.W.*
AU  - Loos, R.J.*
C1  - 6718
C2  - 29300
TI  - Physical activity attenuates the influence of FTO variants on obesity risk: A meta-analysis of 218,166 adults and 19,268 children.
JO  - PLoS Med.
VL  - 8
IS  - 11
PB  - Public Library of Science
PY  - 2011
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - BACKGROUND: Early repolarization pattern (ERP) on electrocardiogram was associated with idiopathic ventricular fibrillation and sudden cardiac arrest in a case-control study and with cardiovascular mortality in a Finnish community-based sample. We sought to determine ERP prevalence and its association with cardiac and all-cause mortality in a large, prospective, population-based case-cohort study (Monitoring of Cardiovascular Diseases and Conditions [MONICA]/KORA [Cooperative Health Research in the Region of Augsburg]) comprised of individuals of Central-European descent. METHODS AND FINDINGS: Electrocardiograms of 1,945 participants aged 35-74 y, representing a source population of 6,213 individuals, were analyzed applying a case-cohort design. Mean follow-up was 18.9 y. Cause of death was ascertained by the 9th revision of the International Classification of Disease (ICD-9) codes as documented in death certificates. ERP-attributable effects on mortality were determined by a weighted Cox proportional hazard model adjusted for covariables. Prevalence of ERP was 13.1% in our study. ERP was associated with cardiac and all-cause mortality, most pronounced in those of younger age and male sex; a clear ERP-age interaction was detected (p = 0.005). Age-stratified analyses showed hazard ratios (HRs) for cardiac mortality of 1.96 (95% confidence interval [CI] 1.05-3.68, p = 0.035) for both sexes and 2.65 (95% CI 1.21-5.83, p = 0.015) for men between 35-54 y. An inferior localization of ERP further increased ERP-attributable cardiac mortality to HRs of 3.15 (95% CI 1.58-6.28, p = 0.001) for both sexes and to 4.27 (95% CI 1.90-9.61, p<0.001) for men between 35-54 y. HRs for all-cause mortality were weaker but reached significance. CONCLUSIONS: We found a high prevalence of ERP in our population-based cohort of middle-aged individuals. ERP was associated with about a 2- to 4-fold increased risk of cardiac mortality in individuals between 35 and 54 y. An inferior localization of ERP was associated with a particularly increased risk. Please see later in the article for the Editors' Summary.
AU  - Sinner, M.F.*
AU  - Reinhard, W.*
AU  - Müller, M.
AU  - Beckmann, B.M.*
AU  - Martens, E.*
AU  - Perz, S.*
AU  - Pfeufer, A.
AU  - Winogradow, J.
AU  - Stark, K.
AU  - Meisinger, C.
AU  - Wichmann, H.-E.
AU  - Peters, A.
AU  - Riegger, G.A.J.*
AU  - Steinbeck, G.*
AU  - Hengstenberg, C.*
AU  - Kääb, S.
C1  - 5152
C2  - 27513
TI  - Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: A population-based prospective cohort study (MONICA/KORA).
JO  - PLoS Med.
VL  - 7
IS  - 7
PB  - Public Library of Science
PY  - 2010
SN  - 1549-1277
ER  - 

TY  - JOUR
AU  - Mascalzoni, D.*
AU  - Hicks, A.*
AU  - Pramstaller, P.*
AU  - Wjst, M.
C1  - 1268
C2  - 25582
SP  - 1302-1305
TI  - Informed consent in the genomics era.
JO  - PLoS Med.
VL  - 5
IS  - 9
PB  - Public Library of Science
PY  - 2008
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - Whatever does not exist does not have a name (African proverb). A new survey conducted by Emmanuel Addo-Yobo and colleagues, and published in PLoS Medicine [1], shows an increase in the prevalence of asthma and allergic diseases in children in Ghana between 1993 and 2003. In this essay, we discuss the context for this new study by exploring what is known about the epidemiology of asthma in Africa.  
AU  - Wjst, M.
AU  - Boakye, D.*
C1  - 5840
C2  - 24437
SP  - 203-205
TI  - Asthma in Africa.
JO  - PLoS Med.
VL  - 4
IS  - 2
PB  - Public Library of Science
PY  - 2007
SN  - 1549-1277
ER  - 

TY  - JOUR
AB  - Background The space and time distribution of risk factors for allergic diseases may provide insights into disease mechanisms. Allergy is believed to vary by month of birth, but multinational studies taking into account latitude have not been conducted. Methods and Findings A questionnaire was distributed in 54 centres to a representative sample of 20- to 44-y-old men and women mainly in Europe but also including regions in North Africa, India, North America, Australia, and New Zealand. Data from 200,682 participants were analyzed. The median prevalence of allergic rhinitis was 22%, with a substantial variation across centres. Overall, allergic rhinitis decreased with geographical latitude, but there were many exceptions. No increase in prevalence during certain winters could be observed. Also, no altered risk by birth month was found, except borderline reduced risks in September and October. Effect estimates obtained by a multivariate analysis of total and specific IgE values in 18,085 individuals also excluded major birth month effects and confirmed the independent effect of language grouping. Conclusion Neither time point of first exposure to certain allergens nor early infections during winter months seems to be a major factor for adult allergy. Although there might be effects of climate or environmental UV exposure by latitude, influences within language groups seem to be more important, reflecting so far unknown genetic or cultural risk factors.
AU  - Wjst, M.
AU  - André, E.
C1  - 2532
C2  - 23112
SP  - 978-986
TI  - Latitude, birth date and allergy.
JO  - PLoS Med.
VL  - 2
IS  - 10
PB  - Public Library of Science
PY  - 2005
SN  - 1549-1277
ER  -