TY  - JOUR
AU  - Birkenfeld, A.L.
AU  - Bergman, M.*
AU  - Stefan, N.*
C1  - 75013
C2  - 57698
SP  - 2491-2492
TI  - Tirzepatide for obesity treatment and diabetes prevention.
JO  - N. Engl. J. Med.
VL  - 392
IS  - 24
PY  - 2025
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: Semaglutide at a dose of 2.4 mg has established weight-loss and cardiovascular benefits, and cagrilintide at a dose of 2.4 mg has shown promising results in early-phase trials; the efficacy of the combination (known as CagriSema) on weight loss in persons with either overweight and coexisting conditions or obesity is unknown. METHODS: In a phase 3a, 68-week, multicenter, double-blind, placebo-controlled and active-controlled trial, we enrolled adults without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher or a BMI of 27 or higher with at least one obesity-related complication. Participants were randomly assigned in a ratio of 21:3:3:7 to receive the combination of semaglutide at a dose of 2.4 mg and cagrilintide at a dose of 2.4 mg, semaglutide alone at a dose of 2.4 mg, cagrilintide alone at a dose of 2.4 mg, or placebo, plus lifestyle interventions for all groups. The coprimary end points were the relative change in body weight and a reduction of 5% or more in body weight from baseline to week 68 with cagrilintide-semaglutide as compared with placebo. Body-weight reductions of 20% or more, 25% or more, and 30% or more were assessed as confirmatory secondary end points. Effect estimates were assessed with the treatment-policy estimand (consistent with the intention-to-treat principle). Safety was assessed. RESULTS: A total of 3417 participants underwent randomization, with 2108 assigned to receive cagrilintide-semaglutide, 302 to receive semaglutide, 302 to receive cagrilintide, and 705 to receive placebo. The estimated mean percent change in body weight from baseline to week 68 was -20.4% with cagrilintide-semaglutide as compared with -3.0% with placebo (estimated difference, -17.3 percentage points; 95% confidence interval, -18.1 to -16.6; P<0.001). Participants receiving cagrilintide-semaglutide were more likely than those receiving placebo to reach weight-loss targets of 5% or more, 20% or more, 25% or more, and 30% or more (P<0.001 for all comparisons). Gastrointestinal adverse events (affecting 79.6% in the cagrilintide-semaglutide group and 39.9% in the placebo group), including nausea, vomiting, diarrhea, constipation, or abdominal pain, were mainly transient and mild-to-moderate in severity. CONCLUSIONS: Cagrilintide-semaglutide provided significant and clinically relevant body-weight reductions in adults with overweight or obesity, as compared with placebo. (Funded by Novo Nordisk; REDEFINE 1 ClinicalTrials.gov number, NCT05567796.).
AU  - Garvey, W.T.*
AU  - Blüher, M.
AU  - Osorto Contreras, C.K.*
AU  - Davies, M.J.*
AU  - Winning Lehmann, E.*
AU  - Pietiläinen, K.H.*
AU  - Rubino, D.*
AU  - Sbraccia, P.*
AU  - Wadden, T.*
AU  - Zeuthen, N.*
AU  - Wilding, J.P.H.*
C1  - 74999
C2  - 57685
CY  - Waltham Woods Center, 860 Winter St,, Waltham, Ma 02451-1413 Usa
SP  - 635-647
TI  - Coadministered cagrilintide and semaglutide in adults with overweight or obesity.
JO  - N. Engl. J. Med.
VL  - 393
IS  - 7
PB  - Massachusetts Medical Soc
PY  - 2025
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: Five risk factors account for approximately 50% of the global burden of cardiovascular disease. How the presence or absence of classic risk factors affects lifetime estimates of cardiovascular disease and death from any cause remains unclear. METHODS: We harmonized individual-level data from 2,078,948 participants across 133 cohorts, 39 countries, and 6 continents. Lifetime risk of cardiovascular disease and death from any cause was estimated up to 90 years of age according to the presence or absence of arterial hypertension, hyperlipidemia, underweight and overweight or obesity, diabetes, and smoking at 50 years of age. Differences in life span (in terms of additional life-years free of cardiovascular disease or death from any cause) according to the presence or absence of these risk factors were also estimated. Risk-factor trajectories were analyzed to predict lifetime differences according to risk-factor variation. RESULTS: The lifetime risk of cardiovascular disease was 24% (95% confidence interval [CI], 21 to 30) among women and 38% (95% CI, 30 to 45) among men for whom all five risk factors were present. In the comparison between participants with none of the risk factors and those with all the risk factors, the estimated number of additional life-years free of cardiovascular disease was 13.3 (95% CI, 11.2 to 15.7) for women and 10.6 (95% CI, 9.2 to 12.9) for men; the estimated number of additional life-years free of death was 14.5 (95% CI, 9.1 to 15.3) for women and 11.8 (95% CI, 10.1 to 13.6) for men. As compared with no changes in the presence of all risk factors, modification of hypertension at an age of 55 to less than 60 years was associated with the most additional life-years free of cardiovascular disease, and modification of smoking at an age of 55 to less than 60 years was associated with the most additional life-years free of death. CONCLUSIONS: The absence of five classic risk factors at 50 years of age was associated with more than a decade greater life expectancy than the presence of all five risk factors, in both sexes. Persons who modified hypertension and smoking in midlife had the most additional life-years free of cardiovascular disease and death from any cause, respectively. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov number, NCT05466825.).
AU  - Global Cardiovascular Risk Consortium (Peters, A.)
AU  - Global Cardiovascular Risk Consortium (Thorand, B.)
C1  - 73976
C2  - 57285
TI  - Global effect of cardiovascular risk factors on lifetime estimates.
JO  - N. Engl. J. Med.
PY  - 2025
SN  - 0028-4793
ER  - 

TY  - JOUR
AU  - Krischer, J.P.*
AU  - Lernmark, *
AU  - Hagopian, W.A.*
AU  - Rewers, M.J.*
AU  - McIndoe, R.*
AU  - Toppari, J.*
AU  - Ziegler, A.-G.
AU  - Akolkar, B.*
C1  - 68040
C2  - 54518
CY  - Waltham Woods Center, 860 Winter St,, Waltham, Ma 02451-1413 Usa
SP  - 474-475
TI  - SARS-CoV-2 - no increased islet autoimmunity or type 1 diabetes in teens.
JO  - N. Engl. J. Med.
VL  - 389
IS  - 5
PB  - Massachusetts Medical Soc
PY  - 2023
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).
AU  - Magnussen, C.*
AU  - Ojeda, F.M.*
AU  - Leong, D.P.*
AU  - Alegre-Diaz, J.*
AU  - Amouyel, P.*
AU  - Aviles-Santa, L.*
AU  - de Bacquer, D.*
AU  - Ballantyne, C.M.*
AU  - Bernabe-Ortiz, A.*
AU  - Bobak, M.*
AU  - Brenner, H.*
AU  - Carrillo-Larco, R.M.*
AU  - de Lemos, J.*
AU  - Dobson, A.*
AU  - Dörr, M.*
AU  - Donfrancesco, C.*
AU  - Drygas, W.*
AU  - Dullaart, R.P.*
AU  - Engström, G.*
AU  - Ferrario, M.M.*
AU  - Ferrieres, J.*
AU  - de Gaetano, G.*
AU  - Goldbourt, U.*
AU  - Gonzalez, C.*
AU  - Grassi, G.*
AU  - Hodge, A.M.*
AU  - Hveem, K.*
AU  - Iacoviello, L.*
AU  - Ikram, M.K.*
AU  - Irazola, V.*
AU  - Jobe, M.*
AU  - Jousilahti, P.*
AU  - Kaleebu, P.*
AU  - Kavousi, M.*
AU  - Kee, F.*
AU  - Khalili, D.*
AU  - Koenig, W.*
AU  - Kontsevaya, A.*
AU  - Kuulasmaa, K.*
AU  - Lackner, K.J.*
AU  - Leistner, D.M.*
AU  - Lind, L.*
AU  - Linneberg, A.*
AU  - Lorenz, T.*
AU  - Lyngbakken, M.N.*
AU  - Malekzadeh, R.*
AU  - Malyutina, S.*
AU  - Mathiesen, E.B.*
AU  - Melander, O.*
AU  - Metspalu, A.*
AU  - Miranda, J.J.*
AU  - Moitry, M.*
AU  - Mugisha, J.*
AU  - Nalini, M.*
AU  - Nambi, V.*
AU  - Ninomiya, T.*
AU  - Oppermann, K.*
AU  - d'Orsi, E.*
AU  - Pajak, A.*
AU  - Palmieri, L.*
AU  - Panagiotakos, D.*
AU  - Perianayagam, A.*
AU  - Peters, A.
AU  - Poustchi, H.*
AU  - Prentice, A.M.*
AU  - Prescott, E.*
AU  - Risérus, U.*
AU  - Salomaa, V.*
AU  - Sans, S.*
AU  - Sakata, S.*
AU  - Schöttker, B.*
AU  - Schutte, A.E.*
AU  - Sepanlou, S.G.*
AU  - Sharma, S.K.*
AU  - Shaw, J.E.*
AU  - Simons, L.A.*
AU  - Söderberg, S.*
AU  - Tamosiunas, A.*
AU  - Thorand, B.
AU  - Tunstall-Pedoe, H.*
AU  - Twerenbold, R.*
AU  - Vanuzzo, D.*
AU  - Veronesi, G.*
AU  - Waibel, J.*
AU  - Wannamethee, S.G.*
AU  - Watanabe, M.*
AU  - Wild, P.S.*
AU  - Yao, Y.*
AU  - Zeng, Y.*
AU  - Ziegler, A.*
AU  - Blankenberg, S.*
C1  - 67941
C2  - 54419
CY  - Waltham Woods Center, 860 Winter St,, Waltham, Ma 02451-1413 Usa
SP  - 1273-1285
TI  - Global effect of modifiable risk factors on cardiovascular disease and mortality.
JO  - N. Engl. J. Med.
VL  - 389
IS  - 14
PB  - Massachusetts Medical Soc
PY  - 2023
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. METHODS: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. RESULTS: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONS: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).
AU  - Anker, S.D.*
AU  - Butler, J.*
AU  - Filippatos, G.*
AU  - Ferreira, J.P.*
AU  - Bocchi, E.*
AU  - Böhm, M.*
AU  - Brunner-La Rocca, H.P.*
AU  - Choi, D.J.*
AU  - Chopra, V.*
AU  - Chuquiure-Valenzuela, E.*
AU  - Giannetti, N.*
AU  - Gomez-Mesa, J.E.*
AU  - Janssens, S.*
AU  - Januzzi, J.L. Jr.*
AU  - Gonzalez-Juanatey, J.R.*
AU  - Merkely, B.*
AU  - Nicholls, S.J.*
AU  - Perrone, S.V.*
AU  - Piña, I.L.*
AU  - Ponikowski, P.*
AU  - Senni, M.*
AU  - Sim, D.*
AU  - Spinar, J.*
AU  - Squire, I.*
AU  - Taddei, S.*
AU  - Tsutsui, H.*
AU  - Verma, S.*
AU  - Vinereanu, D.*
AU  - Zhang, J.*
AU  - Carson, P.*
AU  - Lam, C.S.P.*
AU  - Marx, N.*
AU  - Zeller, C.*
AU  - Sattar, N.*
AU  - Jamal, W.*
AU  - Schnaidt, S.*
AU  - Schnee, J.M.*
AU  - Brueckmann, M.*
AU  - Pocock, S.J.*
AU  - Zannad, F.*
AU  - Packer, M.*
AU  - EMPEROR-Preserved Trial Investigators (Birkenfeld, A.L.)
C1  - 64166
C2  - 51712
SP  - 1451-1461
TI  - Empagliflozin in heart failure with a preserved ejection fraction.
JO  - N. Engl. J. Med.
VL  - 385
IS  - 16
PY  - 2021
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unclear. METHODS: In this double-blind trial, we randomly assigned patients with CKD and type 2 diabetes to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300 and an estimated glomerular filtration rate (eGFR) of 25 to 90 ml per minute per 1.73 m2 of body-surface area (stage 2 to 4 CKD) or a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of at least 60 ml per minute per 1.73 m2 (stage 1 or 2 CKD). Patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary outcome, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The first secondary outcome was a composite of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes. Safety was assessed as investigator-reported adverse events. RESULTS: A total of 7437 patients underwent randomization. Among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3686 patients (12.4%) in the finerenone group and in 519 of 3666 (14.2%) in the placebo group (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; P = 0.03), with the benefit driven primarily by a lower incidence of hospitalization for heart failure (hazard ratio, 0.71; 95% CI, 0.56 to 0.90). The secondary composite outcome occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 1.01). The overall frequency of adverse events did not differ substantially between groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%). CONCLUSIONS: Among patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo. (Funded by Bayer; FIGARO-DKD ClinicalTrials.gov number, NCT02545049.).
AU  - Pitt, B.*
AU  - Filippatos, G.*
AU  - Agarwal, R.K.*
AU  - Anker, S.D.*
AU  - Bakris, G.L.*
AU  - Rossing, P.*
AU  - Joseph, A.*
AU  - Kolkhof, P.*
AU  - Nowack, C.*
AU  - Schloemer, P.*
AU  - Ruilope, L.M.*
AU  - FIGARO-DKD Investigators (Birkenfeld, A.L.)
C1  - 64167
C2  - 51711
SP  - 2252-2263
TI  - Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
JO  - N. Engl. J. Med.
VL  - 385
IS  - 24
PY  - 2021
SN  - 0028-4793
ER  - 

TY  - JOUR
AU  - von Mutius, E.
AU  - Martinez, F.D.*
C1  - 58175
C2  - 48156
CY  - Waltham Woods Center, 860 Winter St,, Waltham, Ma 02451-1413 Usa
SP  - 574-575
TI  - Vitamin D supplementation during pregnancy and the prevention of childhood asthma.
JO  - N. Engl. J. Med.
VL  - 382
IS  - 6
PB  - Massachusetts Medical Soc
PY  - 2020
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BackgroundEstablishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide.MethodsWe assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of >= 50 years with established cardiovascular or chronic kidney disease, or age of >= 60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome).ResultsA total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide.ConclusionsIn this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo.
AU  - Husain, M.*
AU  - Birkenfeld, A.L.
AU  - Donsmark, M.*
AU  - Dungan, K.*
AU  - Eliaschewitz, F.G.*
AU  - Franco, D.R.*
AU  - Jeppesen, O.K.*
AU  - Lingvay, I.*
AU  - Mosenzon, O.*
AU  - Pedersen, S.D.*
AU  - Tack, C.J.*
AU  - Thomsen, M.*
AU  - Vilsbøll, T.*
AU  - Warren, M.L.*
AU  - Bain, S.C.*
C1  - 56285
C2  - 46964
CY  - Waltham Woods Center, 860 Winter St,, Waltham, Ma 02451-1413 Usa
SP  - 841-851
TI  - Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
JO  - N. Engl. J. Med.
VL  - 381
IS  - 9
PB  - Massachusetts Medical Soc
PY  - 2019
SN  - 0028-4793
ER  - 

TY  - JOUR
AU  - Körner, A.*
AU  - Tschöp, M.H.
AU  - Blüher, M.*
C1  - 56882
C2  - 47333
CY  - Waltham Woods Center, 860 Winter St,, Waltham, Ma 02451-1413 Usa
TI  - Five-year outcomes of gastric bypass in adolescents as compared with adults.
JO  - N. Engl. J. Med.
VL  - 381
IS  - 9
PB  - Massachusetts Medical Soc
PY  - 2019
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BackgroundData regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes.MethodsIn 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days.ResultsAmong 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set.ConclusionsA risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes.
AU  - Neumann, J.T.*
AU  - Twerenbold, R.*
AU  - Ojeda, F.*
AU  - Sörensen, N.A.*
AU  - Chapman, A.R.*
AU  - Shah, A.S.V.*
AU  - Anand, A.*
AU  - Boeddinghaus, J.*
AU  - Nestelberger, T.*
AU  - Badertscher, P.*
AU  - Mokhtari, A.*
AU  - Pickering, J.W.*
AU  - Troughton, R.W.*
AU  - Greenslade, J.*
AU  - Parsonage, W.*
AU  - Mueller-Hennessen, M.*
AU  - Gori, T.*
AU  - Jernberg, T.*
AU  - Morris, N.*
AU  - Liebetrau, C.*
AU  - Hamm, C.*
AU  - Katus, H.A.*
AU  - Münzel, T.*
AU  - Landmesser, U.*
AU  - Salomaa, V.*
AU  - Iacoviello, L.*
AU  - Ferrario, M.M.*
AU  - Giampaoli, S.*
AU  - Kee, F.*
AU  - Thorand, B.
AU  - Peters, A.
AU  - Borchini, R.*
AU  - Jørgensen, T.*
AU  - Söderberg, S.*
AU  - Sans, S.*
AU  - Tunstall-Pedoe, H.*
AU  - Kuulasmaa, K.*
AU  - Renné, T.*
AU  - Lackner, K.J.*
AU  - Worster, A.*
AU  - Body, R.*
AU  - Ekelund, U.*
AU  - Kavsak, P.A.*
AU  - Keller, T.*
AU  - Lindahl, B.*
AU  - Wild, P.*
AU  - Giannitsis, E.*
AU  - Than, M.*
AU  - Cullen, L.A.*
AU  - Mills, N.L.*
AU  - Mueller, C.*
AU  - Zeller, T.*
AU  - Westermann, D.*
AU  - Blankenberg, S.*
C1  - 56422
C2  - 47066
CY  - Waltham Woods Center, 860 Winter St,, Waltham, Ma 02451-1413 Usa
SP  - 2529-2540
TI  - Application of high-sensitivity troponin in suspected myocardial infarction.
JO  - N. Engl. J. Med.
VL  - 380
IS  - 26
PB  - Massachusetts Medical Soc
PY  - 2019
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
AU  - Stitziel, N.O.*
AU  - Stirrups, K.E.*
AU  - Masca, N.G.D.*
AU  - Erdmann, J.*
AU  - Ferrario, P.G.*
AU  - Koenig, I.R.*
AU  - Weeke, P.E.*
AU  - Webb, T.R.*
AU  - Auer, P.L.*
AU  - Schick, U.M.*
AU  - Lu, Y.*
AU  - Zhang, H.*
AU  - Dubé, M.-P.*
AU  - Goel, A.*
AU  - Farrall, M.*
AU  - Peloso, G.M.*
AU  - Won, H.*
AU  - Do, R.*
AU  - van Iperen, E.P.*
AU  - Kanoni, S.*
AU  - Kruppa, J.*
AU  - Mahajan, A.*
AU  - Scott, R.A.*
AU  - Willenborg, C.*
AU  - Braund, P.S.*
AU  - van Capelleveen, J.C.*
AU  - Doney, A.S.F.*
AU  - Donnelly, L.A.*
AU  - Asselta, R.*
AU  - Merlini, P.A.*
AU  - Duga, S.*
AU  - Marziliano, N.*
AU  - Denny, J.C.*
AU  - Shaffer, C.M.*
AU  - El-Mokhtari, N.E.*
AU  - Franke, A.*
AU  - Gottesman, O.*
AU  - Heilmann, S.*
AU  - Hengstenberg, C.*
AU  - Hoffmann, P.*
AU  - Holmen, O.L.*
AU  - Hveem, K.*
AU  - Jansson, J.*
AU  - Jöckel, K.-H.*
AU  - Kessler, T.*
AU  - Kriebel, J.
AU  - Laugwitz, K.L.*
AU  - Marouli, E.*
AU  - Martinelli, N.*
AU  - McCarthy, M.I.*
AU  - van Zuydam, N.*
AU  - Meisinger, C.
AU  - Esko, T.*
AU  - Mihailov, E.*
AU  - Escher, S.A.*
AU  - Alver, M.*
AU  - Moebus, S.*
AU  - Morris, A.D.*
AU  - Müller-Nurasyid, M.
AU  - Nikpay, M.*
AU  - Olivieri, O.*
AU  - Perreault, L.L.*
AU  - AlQarawi, A.*
AU  - Robertson, N.R.*
AU  - Akinsanya, K.O.*
AU  - Reilly, D.F.*
AU  - Vogt, T.F.*
AU  - Yin, W.*
AU  - Asselbergs, F.W.*
AU  - Kooperberg, C.*
AU  - Jackson, R.D.*
AU  - Stahl, E.A.*
AU  - Strauch, K.
AU  - Varga, T.V.*
AU  - Waldenberger, M.
AU  - Zeng, L.*
AU  - Kraja, A.T.*
AU  - Liu, C.*
AU  - Ehret, G.B.*
AU  - Newton-Cheh, C.*
AU  - Chasman, D.I.*
AU  - Chowdhury, R.*
AU  - Ferrario, M.*
AU  - Ford, I.*
AU  - Jukema, J.W.*
AU  - Kee, F.*
AU  - Kuulasmaa, K.*
AU  - Nørdestgaard, B.G.*
AU  - Perola, M.*
AU  - Saleheen, D.*
AU  - Sattar, N.*
AU  - Surendran, P.*
AU  - Tregouet, D.*
AU  - Young, R.*
AU  - Howson, J.M.M.*
AU  - Butterworth, A.S.*
AU  - Danesh, J.*
AU  - Ardissino, D.*
AU  - Bottinger, E.P.*
AU  - Erbel, R.*
AU  - Franks, P.W.*
AU  - Girelli, D.*
AU  - Hall, A.S.*
AU  - Hovingh, G.K.*
AU  - Kastrati, A.*
AU  - Lieb, W.*
AU  - Meitinger, T.
AU  - Kraus, W.E.*
AU  - Shah, S.H.*
AU  - McPherson, R.*
AU  - Orho-Melander, M.*
AU  - Melander, O.*
AU  - Metspalu, A.*
AU  - Palmer, C.N.A.*
AU  - Peters, A.
AU  - Rader, D.J.*
AU  - Reilly, M.P.*
AU  - Loos, R.J.F.*
AU  - Reiner, A.P.*
AU  - Roden, D.M.*
AU  - Tardif, J.-C.*
AU  - Thompson, J.R.*
AU  - Wareham, N.J.*
AU  - Watkins, H.
AU  - Willer, C.J.*
AU  - Kathiresan, S.*
AU  - Deloukas, P.*
AU  - Samani, N.J.*
AU  - Schunkert, H.*
C1  - 48401
C2  - 41077
CY  - Waltham
SP  - 1134-1144
TI  - Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease.
JO  - N. Engl. J. Med.
VL  - 374
IS  - 12
PB  - Massachusetts Medical Soc
PY  - 2016
SN  - 0028-4793
ER  - 

TY  - JOUR
AU  - Stitziel, N.O.*
AU  - Stirrups, K.E.*
AU  - Masca, N.G.D.*
AU  - Erdmann, J.*
AU  - Ferrario, P.G.*
AU  - Koenig, I.R.*
AU  - Weeke, P.E.*
AU  - Webb, T.R.*
AU  - Auer, P.L.*
AU  - Schick, U.M.*
AU  - Lu, Y.*
AU  - Zhang, H.*
AU  - Dubé, M.-P.*
AU  - Goel, A.*
AU  - Farrall, M.*
AU  - Peloso, G.M.*
AU  - Won, H.*
AU  - Do, R.*
AU  - van Iperen, E.*
AU  - Kanoni, S.*
AU  - Kruppa, J.*
AU  - Mahajan, A.*
AU  - Scott, R.A.*
AU  - Willenborg, C.*
AU  - Braund, P.S.*
AU  - van Capelleveen, J.C.*
AU  - Doney, A.S.F.*
AU  - Donnelly, L.A.*
AU  - Asselta, R.*
AU  - Merlini, P.A.*
AU  - Duga, S.*
AU  - Marziliano, N.*
AU  - Denny, J.C.*
AU  - Shaffer, C.M.*
AU  - El-Mokhtari, N.E.*
AU  - Franke, A.*
AU  - Gottesman, O.*
AU  - Heilmann, S.*
AU  - Hengstenberg, C.*
AU  - Hoffmann, P.*
AU  - Holmen, O.L.*
AU  - Hveem, K.*
AU  - Jansson, J.*
AU  - Joeckel, K.*
AU  - Kessler, T.*
AU  - Kriebel, J.
AU  - Laugwitz, K.L.*
AU  - Marouli, E.*
AU  - Martinelli, N.*
AU  - McCarthy, M.I.*
AU  - van Zuydam, N.R.*
AU  - Meisinger, C.
AU  - Esko, T.*
AU  - Mihailov, E.*
AU  - Escher, S.A.*
AU  - Alver, M.*
AU  - Moebus, S.*
AU  - Morris, A.D.*
AU  - Müller-Nurasyid, M.
AU  - Nikpay, M.*
AU  - Olivieri, O.*
AU  - Perreault, L.L.*
AU  - AlQarawi, A.*
AU  - Robertson, N.R.*
AU  - Akinsanya, K.O.*
AU  - Reilly, D.F.*
AU  - Vogt, T.F.*
AU  - Yin, W.*
AU  - Asselbergs, F.W.*
AU  - Kooperberg, C.*
AU  - Jackson, R.D.*
AU  - Stahl, E.A.*
AU  - Strauch, K.
AU  - Varga, T.V.*
AU  - Waldenberger, M.
AU  - Zeng, L.*
AU  - Kraja, A.T.*
AU  - Liu, C.*
AU  - Ehret, G.B.*
AU  - Newton-Cheh, C.*
AU  - Chasman, D.I.*
AU  - Chowdhury, R.*
AU  - Ferrario, M.*
AU  - Ford, I.*
AU  - Jukema, J.W.*
AU  - Kee, F.*
AU  - Kuulasmaa, K.*
AU  - Nørdestgaard, B.G.*
AU  - Perola, M.*
AU  - Saleheen, D.*
AU  - Sattar, N.*
AU  - Surendran, P.*
AU  - Tregouet, D.*
AU  - Young, R.*
AU  - Howson, J.M.M.*
AU  - Butterworth, A.S.*
AU  - Danesh, J.*
AU  - Ardissino, D.*
AU  - Bottinger, E.P.*
AU  - Erbel, R.*
AU  - Franks, P.W.*
AU  - Girelli, D.*
AU  - Hall, A.S.*
AU  - Hovingh, G.K.*
AU  - Kastrati, A.*
AU  - Lieb, W.*
AU  - Meitinger, T.
AU  - Kraus, W.E.*
AU  - Shah, S.H.*
AU  - McPherson, R.*
AU  - Orho-Melander, M.*
AU  - Melander, O.*
AU  - Metspalu, A.*
AU  - Palmer, C.N.A.*
AU  - Peters, A.
AU  - Rader, D.J.*
AU  - Reilly, M.P.*
AU  - Loos, R.J.F.*
AU  - Reiner, A.P.*
AU  - Roden, D.M.*
AU  - Tardif, J.-C.*
AU  - Thompson, J.R.*
AU  - Wareham, N.J.*
AU  - Watkins, H.*
AU  - Willer, C.J.*
AU  - Kathiresan, S.*
AU  - Deloukas, P.*
AU  - Samani, N.J.*
AU  - Schunkert, H.*
C1  - 50962
C2  - 42602
CY  - Waltham
SP  - 1898-1898
TI  - Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease (vol 374, pg 1134, 2016).
JO  - N. Engl. J. Med.
VL  - 374
IS  - 19
PB  - Massachusetts Medical Soc
PY  - 2016
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - Background Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. Methods We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples from patients. Results Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. Conclusions Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.).
AU  - Claussnitzer, M.
AU  - Dankel, S.N.*
AU  - Kim, K.H.*
AU  - Quon, G.*
AU  - Meuleman, W.*
AU  - Haugen, C.*
AU  - Glunk, V.*
AU  - Sousa, I.S.*
AU  - Beaudry, J.L.*
AU  - Puviindran, V.*
AU  - Abdennur, N.A.*
AU  - Liu, J.*
AU  - Svensson, P.A.*
AU  - Hsu, Y.H.*
AU  - Drucker, D.J.*
AU  - Mellgren, G.*
AU  - Hui, C.C.*
AU  - Hauner, H.
AU  - Kellis, M.*
C1  - 46604
C2  - 37666
CY  - Waltham
SP  - 895-907
TI  - FTO obesity variant circuitry and adipocyte browning in humans.
JO  - N. Engl. J. Med.
VL  - 373
IS  - 10
PB  - Massachusetts Medical Soc
PY  - 2015
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. RESULTS We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quar-tile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. CONCLUSIONS There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association.
AU  - Nelson, C.P.*
AU  - Hamby, S.E.*
AU  - Saleheen, D.*
AU  - Hopewell, J.C.*
AU  - Zeng, L.*
AU  - Assimes, T.L.*
AU  - Kanoni, S.*
AU  - Willenborg, C.*
AU  - Burgess, S.L.*
AU  - Amouyel, P.*
AU  - Anand, S.*
AU  - Blankenberg, S.*
AU  - Boehm, B.O.*
AU  - Clarke, R.J.*
AU  - Collins, R.*
AU  - Dedoussis, G.*
AU  - Farrall, M.*
AU  - Franks, P.W.*
AU  - Groop, L.*
AU  - Hall, A.S.*
AU  - Hamsten, A.*
AU  - Hengstenberg, C.*
AU  - Hovingh, G.K.*
AU  - Ingelsson, E.*
AU  - Kathiresan, S.*
AU  - Kee, F.*
AU  - Koenig, I.R.*
AU  - Kooner, J.*
AU  - Lehtimaeki, T.*
AU  - Maerz, W.*
AU  - McPherson, R.*
AU  - Metspalu, A.*
AU  - Nieminen, M.S.*
AU  - O'Donnell, C.J.*
AU  - Palmer, C.N.A.*
AU  - Peters, A.
AU  - Perola, M.*
AU  - Reilly, M.P.*
AU  - Ripatti, S.*
AU  - Roberts, R.*
AU  - Salomaa, V.*
AU  - Shah, S.H.*
AU  - Schreiber, S.*
AU  - Siegbahn, A.*
AU  - Thorsteinsdottir, U.*
AU  - Veronesi, G.*
AU  - Wareham, N.J.*
AU  - Willer, C.J.*
AU  - Zalloua, P.A.*
AU  - Erdmann, J.*
AU  - Deloukas, P.*
AU  - Watkins, H.*
AU  - Schunkert, H.*
AU  - Danesh, J.*
AU  - Thompson, J.R.*
AU  - Samani, N.J.*
AU  - CARDIoGRAMplusC4D Consortium (Meisinger, C.)
C1  - 44855
C2  - 37067
CY  - Waltham
SP  - 1608-1618
TI  - Genetically determined height and coronary artery disease.
JO  - N. Engl. J. Med.
VL  - 372
IS  - 17
PB  - Massachusetts Medical Soc
PY  - 2015
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - Background Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol-producing adrenal adenomas is not well understood. Methods We performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors. We also performed genomewide copy-number analysis in 35 patients with cortisol-secreting bilateral adrenal hyperplasias. We studied the effects of these genetic defects both clinically and in vitro. Results Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas (c.617A→C in 7 and c.595_596insCAC in 1). Overall, PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; these mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors. Among 35 patients with cortisol-producing hyperplasias, 5 (including 2 first-degree relatives) carried a germline copy-number gain (duplication) of the genomic region on chromosome 19 that includes PRKACA. In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, whereas cells from patients with germline chromosomal gains showed increased protein levels of the PKA catalytic subunit; in both instances, basal PKA activity was increased. Conclusions Genetic alterations of the catalytic subunit of PKA were found to be associated with human disease. Germline duplications of this gene resulted in bilateral adrenal hyperplasias, whereas somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas. (Funded by the European Commission Seventh Framework Program and others.).
AU  - Beuschlein, F.*
AU  - Fassnacht, M.*
AU  - Assié, G.*
AU  - Calebiro, D.*
AU  - Stratakis, C.A.*
AU  - Osswald, A.*
AU  - Ronchi, C.L.*
AU  - Wieland, T.
AU  - Sbiera, S.*
AU  - Faucz, F.R.*
AU  - Schaak, K.*
AU  - Schmittfull, A.
AU  - Schwarzmayr, T.
AU  - Barreau, O.*
AU  - Vezzosi, D.*
AU  - Rizk-Rabin, M.*
AU  - Zabel, U.*
AU  - Szarek, E.*
AU  - Salpea, P.*
AU  - Forlino, A.*
AU  - Vetro, A.*
AU  - Zuffardi, O.*
AU  - Kisker, C.*
AU  - Diener, S.
AU  - Meitinger, T.
AU  - Lohse, M.J.*
AU  - Reincke, M.*
AU  - Bertherat, J.*
AU  - Strom, T.M.
AU  - Allolio, B.*
C1  - 30709
C2  - 33787
CY  - Waltham
SP  - 1019-1028
TI  - Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.
JO  - N. Engl. J. Med.
VL  - 370
IS  - 11
PB  - Massachusetts Medical Soc
PY  - 2014
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10-20), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10 -10). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10-6). CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease.
AU  - TG and HDL Working Group (Crosby, J.R.*
AU  - Peloso, G.M.*
AU  - Auer, P.L.*
AU  - Peters, A.
AU  - Reiner, A.P.*
AU  - Boerwinkle, E.*
AU  - Kathiresan, S.*)
C1  - 31771
C2  - 34771
CY  - Waltham
SP  - 22-31
TI  - Loss-of-function mutations in APOC3, triglycerides, and coronary disease.
JO  - N. Engl. J. Med.
VL  - 371
IS  - 1
PB  - Massachusetts Medical Soc
PY  - 2014
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS: We studied 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS: The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3-DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4-DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS: Children with the HLA haplotype DR3-DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
AU  - Liu, E.
AU  - Lee, H.S.*
AU  - Aronsson, C.A.*
AU  - Hagopian, W.A.*
AU  - Koletzko, S.*
AU  - Rewers, M.J.*
AU  - Eisenbarth, G.S.*
AU  - Bingley, P.J.*
AU  - Bonifacio, E.
AU  - Simell, V.*
AU  - Agardh, D.*
AU  - TEDDY Study Group (Ziegler, A.-G.
AU  - Beyerlein, A.
AU  - Bonifacio, E.
AU  - Hummel, M.
AU  - Hummel, S.
AU  - Foterek, K.
AU  - Kersting, M.
AU  - Knopff, A.
AU  - Koletzko, S.
AU  - Peplow, C.
AU  - Roth, R.
AU  - Stock, J.
AU  - Strauss, E.
AU  - Warncke, K.
AU  - Winkler, C.)
C1  - 31733
C2  - 34710
CY  - Waltham
SP  - 42-49
TI  - Risk of pediatric celiac disease according to HLA haplotype and country.
JO  - N. Engl. J. Med.
VL  - 371
IS  - 1
PB  - Massachusetts Medical Soc
PY  - 2014
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).
AU  - Navon Elkan, P.*
AU  - Pierce, S.B.*
AU  - Segel, R.*
AU  - Walsh, T.*
AU  - Barash, J.*
AU  - Padeh, S.*
AU  - Zlotogorski, A.*
AU  - Berkun, Y.*
AU  - Press, J.J.*
AU  - Mukamel, M.*
AU  - Voth, I.*
AU  - Hashkes, P.J.*
AU  - Harel, L.*
AU  - Hoffer, V.*
AU  - Ling, E.*
AU  - Yalcinkaya, F.*
AU  - Kasapcopur, O.*
AU  - Lee, M.K.*
AU  - Klevit, R.E.*
AU  - Renbaum, P.*
AU  - Weinberg-Shukron, A.*
AU  - Sener, E.F.*
AU  - Schormair, B.
AU  - Zeligson, S.*
AU  - Marek-Yagel, D.*
AU  - Strom, T.M.
AU  - Shohat, M.*
AU  - Singer, A.*
AU  - Rubinow, A.*
AU  - Pras, E.*
AU  - Winkelmann, J.
AU  - Tekin, M.*
AU  - Anikster, Y.*
AU  - King, M.C.*
AU  - Levy-Lahad, E.*
C1  - 30800
C2  - 33880
CY  - Waltham
SP  - 921-931
TI  - Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.
JO  - N. Engl. J. Med.
VL  - 370
IS  - 10
PB  - Massachusetts Medical Soc
PY  - 2014
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - To the Editor: Besides showing futility in the use of dipeptidyl peptidase 4 (DPP-4) inhibitors to reduce cardiovascular outcomes, the studies by Scirica et al.(1) and White et al.(2) (Oct. 3 issue) have raised concerns regarding increased rates of heart failure associated with these agents. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 (SAVOR-TIMI 53) trial, reported by Scirica et al., showed a 27% increase in hospitalization for heart failure among patients with diabetes who received saxagliptin as compared with patients with diabetes who received placebo (3.5% vs. 2.8%; hazard ...
AU  - Stand, E.
C1  - 30568
C2  - 33702
CY  - Waltham
SP  - 483-484
TI  - Saxagliptin, alogliptin, and cardiovascular outcomes.
JO  - N. Engl. J. Med.
VL  - 370
IS  - 5
PB  - Massachusetts Medical Soc
PY  - 2014
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - Background: Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. Methods: We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. Results: With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P = 0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P = 0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). Conclusions: Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.)
AU  - Stitziel, N.O.*
AU  - Won, H.*
AU  - Morrison, A.C.*
AU  - Peloso, G.M.*
AU  - Do, R.*
AU  - Lange, L.A.*
AU  - Fontanillas, P.*
AU  - Gupta, N.*
AU  - Duga, S.*
AU  - Goel, A.K.*
AU  - Farrall, M.J.*
AU  - Saleheen, D.*
AU  - Ferrario, P.*
AU  - König, I.R.*
AU  - Asselta, R.*
AU  - Merlini, P.A.*
AU  - Marziliano, N.*
AU  - Notarangelo, M.F.*
AU  - Schick, U.M.*
AU  - Auer, P.L.*
AU  - Assimes, T.L.*
AU  - Reilly, M.P.*
AU  - Wilensky, R.L.*
AU  - Rader, D.J.*
AU  - Kees Hovingh, G.*
AU  - Meitinger, T.
AU  - Kessler, T.*
AU  - Kastrati, A.*
AU  - Laugwitz, K.L.*
AU  - Siscovick, D.S.*
AU  - Rotter, J.I.*
AU  - Hazen, S.L.*
AU  - Tracy, R.P.*
AU  - Cresci, S.G.*
AU  - Spertus, J.A.*
AU  - Jackson, R.D.*
AU  - Schwartz, S.M.*
AU  - Natarajan, P.*
AU  - Crosby, J.R.*
AU  - Muzny, D.M.*
AU  - Ballantyne, C.M.*
AU  - Rich, S.S.*
AU  - O'Donnell, C.J.*
AU  - Abecasis, G.R.*
AU  - Sunyaev, S.R.*
AU  - Nickerson, D.A.*
AU  - Buring, J.E.*
AU  - Ridker, P.M.*
AU  - Chasman, D.I.*
AU  - Austin, E.*
AU  - Ye, Z.*
AU  - Kullo, I.J.*
AU  - Weeke, P.E.*
AU  - Shaffer, C.M.*
AU  - Bastarache, L.A.*
AU  - Denny, J.C.*
AU  - Roden, D.M.*
AU  - Palmer, C.N.A.*
AU  - Deloukas, P.*
AU  - Lin, D.*
AU  - Tang, Z.*
AU  - Erdmann, J.*
AU  - Schunkert, H.*
AU  - Danesh, J.*
AU  - Marrugat, J.*
AU  - Elosua, R.*
AU  - Ardissino, D.*
AU  - McPherson, R.M.*
AU  - Watkins, H.*
AU  - Reiner, A.P.*
AU  - Wilson, J.G.*
AU  - Altshuler, D.*
AU  - Gibbs, R.A.L.*
AU  - Lander, E.S.*
AU  - Boerwinkle, E.E.*
AU  - Gabriel, S.B.*
AU  - Kathiresan, S.*
C1  - 42968
C2  - 35933
SP  - 2072-2082
TI  - Inactivating mutations in NPC1L1 and protection from coronary heart disease.
JO  - N. Engl. J. Med.
VL  - 371
IS  - 22
PY  - 2014
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. METHODS: We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. RESULTS: The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (<10%), "intermediate" (10% to <20%), and "high" (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. CONCLUSIONS: In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.).
AU  - Emerging Risk Factors Collaboration (Döring, A.
AU  - Meisinger, C.)
AU  - Kaptoge, S.*
AU  - di Angelantonio, E.*
AU  - Pennells, L.*
AU  - Wood, A.M.*
AU  - White, I.R.*
AU  - Gao, P.*
AU  - Walker, M.*
AU  - Thompson, A.*
AU  - Sarwar, N.*
AU  - Caslake, M.*
AU  - Butterworth, A.S.*
AU  - Amouyel, P.*
AU  - Assmann, G.*
AU  - Bakker, S.J.*
AU  - Barr, E.L.*
AU  - Barrett-Connor, E.*
AU  - Benjamin, E.J.*
AU  - Björkelund, C.*
AU  - Brenner, H.*
AU  - Brunner, E.*
AU  - Clarke, R.*
AU  - Cooper, J.A.*
AU  - Cremer, P.*
AU  - Cushman, M.*
AU  - Dagenais, G.R.*
AU  - D'Agostino, R.B. S.r.*
AU  - Dankner, R.*
AU  - Davey Smith, G.*
AU  - Deeg, D.*
AU  - Dekker, J.M.*
AU  - Engström, G.*
AU  - Folsom, A.R.*
AU  - Fowkes, F.G.*
AU  - Gallacher, J.*
AU  - Gaziano, J.M.*
AU  - Giampaoli, S.*
AU  - Gillum, R.F.*
AU  - Hofman, A.*
AU  - Howard, B.V.*
AU  - Ingelsson, E.*
AU  - Iso, H.*
AU  - Jørgensen, T.*
AU  - Kiechl, S.*
AU  - Kitamura, A.*
AU  - Kiyohara, Y.*
AU  - Koenig, W.*
AU  - Kromhout, D.*
AU  - Kuller, L.H.*
AU  - Lawlor, D.A.*
AU  - Meade, T.W.*
AU  - Nissinen, A.*
AU  - Nørdestgaard, B.G.*
AU  - Onat, A.*
AU  - Panagiotakos, D.B.*
AU  - Psaty, B.M.*
AU  - Rodriguez, B.*
AU  - Rosengren, A.*
AU  - Salomaa, V.*
AU  - Kauhanen, J.*
AU  - Salonen, J.T.*
AU  - Shaffer, J.A.*
AU  - Shea, S.*
AU  - Ford, I.*
AU  - Stehouwer, C.D.*
AU  - Strandberg, T.E.*
AU  - Tipping, R.W.*
AU  - Tosetto, A.*
AU  - Wassertheil-Smoller, S.*
AU  - Wennberg, P.*
AU  - Westendorp, R.G.*
AU  - Whincup, P.H.*
AU  - Wilhelmsen, L.*
AU  - Woodward, M.*
AU  - Lowe, G.D.*
AU  - Wareham, N.J.*
AU  - Khaw, K.T.*
AU  - Sattar, N.*
AU  - Packard, C.J.*
AU  - Gudnason, V.*
AU  - Ridker, P.M.*
AU  - Pepys, M.B.*
AU  - Thompson, S.G.*
AU  - Danesh, J.*
C1  - 23113
C2  - 30991
SP  - 1310-1320
TI  - C-reactive protein, fibrinogen, and cardiovascular disease prediction.
JO  - N. Engl. J. Med.
VL  - 367
IS  - 14
PB  - Massachusetts Medical Society
PY  - 2012
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: Chemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy. METHODS: We analyzed the expression, methylation, and function of TFAP2E in colorectal-cancer cell lines in vitro and in patients with colorectal cancer. We examined an initial cohort of 74 patients, followed by four cohorts of patients (total, 220) undergoing chemotherapy or chemoradiation. RESULTS: TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P<0.001). Conversely, the probability of response among patients with hypomethylation was approximately six times that in the entire population (overall estimated risk ratio, 5.74; 95% confidence interval, 3.36 to 9.79). Epigenetic alterations of TFAP2E were independent of mutations in key regulatory cancer genes, microsatellite instability, and other genes that affect fluorouracil metabolism. CONCLUSIONS: TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer. Functional assays confirm that TFAP2E-dependent resistance is mediated through DKK4. In patients who have colorectal cancer with TFAP2E hypermethylation, targeting of DKK4 may be an option to overcome TFAP2E-mediated drug resistance. (Funded by Deutsche Forschungsgemeinschaft and others.).
AU  - Ebert, M.P.*
AU  - Tänzer, M.*
AU  - Balluff, B.
AU  - Burgermeister, E.*
AU  - Kretzschmar, A.K.*
AU  - Hughes, D.J.*
AU  - Tetzner, R.*
AU  - Lofton-Day, C.*
AU  - Rosenberg, R.*
AU  - Reinacher-Schick, A.C.*
AU  - Schulmann, K.*
AU  - Tannapfel, A.*
AU  - Hofheinz, R.*
AU  - Röcken, C.*
AU  - Keller, G.*
AU  - Langer, R.*
AU  - Specht, K.*
AU  - Porschen, R.*
AU  - Stöhlmacher-Williams, J.*
AU  - Schuster, T.*
AU  - Ströbel, P.*
AU  - Schmid, R.M.*
C1  - 7194
C2  - 29539
SP  - 44-53
TI  - TFAP2E-DKK4 and chemoresistance in colorectal cancer.
JO  - N. Engl. J. Med.
VL  - 366
IS  - 1
PB  - Massachusetts Medical Soc.
PY  - 2012
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: Dupuytren's disease is a benign fibromatosis of the hands and fingers that leads to flexion contractures. We hypothesized that multiple genetic and environmental factors influence susceptibility to this disease and sought to identify susceptibility genes to better understand its pathogenesis. METHODS: We conducted a genomewide association study of 960 Dutch persons with Dupuytren's disease and 3117 controls (the discovery set) to test for association between the disease and genetic markers. We tested the 35 single-nucleotide polymorphisms (SNPs) most strongly associated with Dupuytren's disease (P<1×10(-4)) in the discovery set in three additional, independent case series comprising a total of 1365 affected persons and 8445 controls from Germany, the United Kingdom, and The Netherlands. RESULTS: Initially, we observed a significant genomewide association between Dupuytren's disease and 8 SNPs at three loci. Tests of replication and joint analysis of all data from 2325 patients with Dupuytren's disease and 11,562 controls yielded an association with 11 SNPs from nine different loci (P<5.0×10(-8)). Six of these loci contain genes known to be involved in the Wnt-signaling pathway: WNT4 (rs7524102) (P=2.8×10(-9); odds ratio, 1.28), SFRP4 (rs16879765) (P=5.6×10(-39); odds ratio, 1.98), WNT2 (rs4730775) (P=3.0×10(-8); odds ratio, 0.83), RSPO2 (rs611744) (P=7.9×10(-15); odds ratio, 0.75), SULF1 (rs2912522) (P=2.0×10(-13); odds ratio, 0.72), and WNT7B (rs6519955) (P=3.2×10(-33); odds ratio, 1.54). CONCLUSIONS: This study implicates nine different loci involved in genetic susceptibility to Dupuytren's disease. The fact that six of these nine loci harbor genes encoding proteins in the Wnt-signaling pathway suggests that aberrations in this pathway are key to the process of fibromatosis in Dupuytren's disease.
AU  - Dolmans, G.H.*
AU  - Werker, P.M.*
AU  - Hennies, H.C.*
AU  - Furniss, D.*
AU  - Festen, E.A.*
AU  - Franke, L.*
AU  - Becker, K.*
AU  - van der Vlies, P.*
AU  - Wolffenbuttel, B.H.*
AU  - Tinschert, S.*
AU  - Toliat, M.R.*
AU  - Nothnagel, M.*
AU  - Franke, A.*
AU  - Klopp, N.
AU  - Wichmann, H.-E.
AU  - Nürnberg, P.*
AU  - Giele, H.*
AU  - Ophoff, R.A.*
AU  - Wijmenga, C*
AU  - Dutch Dupuytren Study Group (*)
AU  - German Dupuytren Study Group (*)
AU  - LifeLines Cohort Study (*)
AU  - BSSH-GODD Consortium (*)
C1  - 6732
C2  - 29169
SP  - 307-317
TI  - Wnt signaling and Dupuytren's disease.
JO  - N. Engl. J. Med.
VL  - 365
IS  - 4
PB  - Massachusetts Medical Society
PY  - 2011
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain. METHODS: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies. RESULTS: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths. CONCLUSIONS: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).
AU  - Emerging Risk Factors Collaboration (Döring, A.
AU  - Meisinger, C.)
AU  - Seshasai, S.R.*
AU  - Kaptoge, S.*
AU  - Thompson, A.
AU  - di Angelantonio, E.*
AU  - Gao, P.*
AU  - Sarwar, N.*
AU  - Whincup, P.H.*
AU  - Mukamal, K.J.*
AU  - Gillum, R.F.*
AU  - Holme, I.*
AU  - Njølstad, I.*
AU  - Fletcher, A.*
AU  - Nilsson, P.*
AU  - Lewington, S.*
AU  - Collins, R.*
AU  - Gudnason, V.*
AU  - Thompson, S.G.*
AU  - Sattar, N.*
AU  - Selvin, E.*
AU  - Hu, F.B.*
AU  - Danesh, J.*
C1  - 6689
C2  - 29126
SP  - 829-841
TI  - Diabetes mellitus, fasting glucose, and risk of cause-specific death.
JO  - N. Engl. J. Med.
VL  - 364
IS  - 9
PB  - Massachusetts Medical Society
PY  - 2011
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - The simultaneous occurrence of psoriasis driven by type 1 helper T (Th1) cells and type 17 helper T (Th17) cells and atopic eczema dominated by type 2 helper T (Th2) cells is rare. Here, we describe three patients with co-occurring psoriasis and atopic eczema with an antagonistic course and distinct T-cell infiltrates in lesions from psoriasis and those from atopic eczema. Sensitized patients with psoriasis had a reaction to epicutaneous allergen challenge, with clinically and histologically verified eczema lesions containing a large number of allergen-reactive T cells. These findings support a causative role for T cells triggered by specific antigens in both psoriasis and atopic eczema.
AU  - Eyerich, S.
AU  - Onken, A.T.*
AU  - Weidinger, S.*
AU  - Franke, A.*
AU  - Nasorri, F.*
AU  - Pennino, D.*
AU  - Grosber, M.*
AU  - Pfab, F.*
AU  - Schmidt-Weber, C.B.
AU  - Mempel, M.*
AU  - Hein, R.*
AU  - Ring, J.*
AU  - Cavani, A.*
AU  - Eyerich, K.*
C1  - 6914
C2  - 29424
SP  - 231-238
TI  - Mutual antagonism of T cells causing psoriasis and atopic eczema.
JO  - N. Engl. J. Med.
VL  - 365
IS  - 3
PB  - Massachusetts Medical Soc
PY  - 2011
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - BACKGROUND: Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. METHODS: We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. RESULTS: We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P=3×10(−9)); rs9273349 on chromosome 6, implicating HLA-DQ (P=7×10(−14)); rs1342326 on chromosome 9, flanking IL33 (P=9×10(−10)); rs744910 on chromosome 15 in SMAD3 (P=4×10(−9)); and rs2284033 on chromosome 22 in IL2RB (P=1.1×10(−8)). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P=6×10(−23)). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. CONCLUSIONS: Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)
AU  - Moffatt, M.F.*
AU  - Gut, I.G.*
AU  - Demenais, F.*
AU  - Strachan, D.P.*
AU  - Bouzigon, E.*
AU  - Heath, S.*
AU  - von Mutius, E.*
AU  - Farrall, M.*
AU  - Lathrop, M*
AU  - Cookson, W.O.C.M.*
AU  - GABRIEL Consortium (Heinrich, J.)
C1  - 5262
C2  - 27875
SP  - 1211-1221
TI  - A large-scale, consortium-based genomewide association study of asthma.
JO  - N. Engl. J. Med.
VL  - 363
IS  - 13
PB  - Massachusetts Medical Society
PY  - 2010
SN  - 0028-4793
ER  - 

TY  - JOUR
AU  - Nalls, M.A.*
AU  - Biffi, A.*
AU  - Matarin, M.*
AU  - Anderson, C.D.*
AU  - Chasman, D.I.*
AU  - Bevan, S.*
AU  - Spencer, C.C.*
AU  - Gschwendtner, A.*
AU  - Sale, M.M.*
AU  - Wu, L.*
AU  - Saleheen, D.*
AU  - Deary, I.J.*
AU  - Langefeld, C.*
AU  - Peddareddygari, L.R.*
AU  - Cole, J.W.*
AU  - Arapelli, S.K.*
AU  - Aucutt-Walter, N.*
AU  - Brott, T.G.*
AU  - Broderick, J.P.*
AU  - Brown, D.L.*
AU  - Brown, M.*
AU  - Brown, R.D. Jr.*
AU  - Buring, J.E.*
AU  - Cortellini, L.*
AU  - Danesh, J.*
AU  - Deka, R.*
AU  - Elias, G.A.*
AU  - Ferrucci, L.*
AU  - Frossard, P.*
AU  - Furie, K.*
AU  - Gibbs, J.R.*
AU  - Greenberg, S.M.*
AU  - Gul, M.*
AU  - Hardy, J.*
AU  - Harris, S.E.*
AU  - Hernandez, D.G.*
AU  - Hsu, F.C.*
AU  - Indugula, S.*
AU  - Jackson, C.*
AU  - Kissela, B.*
AU  - Liu, L.*
AU  - Metter, E.J.*
AU  - Mitchell, B.D.*
AU  - Murphy, L.*
AU  - Mychaleckyj, J.C.*
AU  - O'Connell, J.R.*
AU  - Paré, G.*
AU  - Parker, A.N.*
AU  - Patel, R.K.*
AU  - Poole, D.*
AU  - Rasheed, A.*
AU  - Richie, A.*
AU  - Rothwell, P.M.*
AU  - Rose, L.*
AU  - Ross, O.A.*
AU  - Rost, N.S.*
AU  - Schwab, K.*
AU  - Sen, S.*
AU  - Silliman, S.L.*
AU  - Soto-Ortolaza, A.I.*
AU  - Starr, J.M.*
AU  - Stine, O.C.*
AU  - Stamova, B.*
AU  - Xu, H.*
AU  - Wichmann, H.-E.*
AU  - Young, L.E.*
AU  - Young, W.*
AU  - Zaidi, M.*
AU  - Zhang, H.*
AU  - Kittner, S.J.*
AU  - Grewal, R.P.*
AU  - Woo, D.*
AU  - Sudlow, C.*
AU  - Kamal, A.K.*
AU  - Wang, X.*
AU  - Sharp, F.R.*
AU  - Worrall, B.B.*
AU  - Dichgans, M.*
AU  - Markus, H.S.*
AU  - Ridker, P.M.*
AU  - de Bakker, P.I.*
AU  - Singleton, A.B.*
AU  - Meschia, J.F.*
AU  - Rosand, J.*
AU  - Bramon, E.*
AU  - Casas, J.*
AU  - Corvin, A.*
AU  - Craddock, N.*
AU  - Deloukas, P.*
AU  - Jankowski, J.*
AU  - Markus, H.*
AU  - Mathew, C.G.*
AU  - McCarthy, M.*
AU  - Palmer, C.*
AU  - Plomin, R.*
AU  - Sawcer, S.*
AU  - Trembath, R.C.*
AU  - Viswanathan, A.*
AU  - Wood, N.*
AU  - Peltonen, L.*
AU  - Donnelly, P.*
AU  - Bellinguez, C.*
AU  - Davison, D.*
AU  - Freeman, C.*
AU  - Strange, A.*
AU  - Langford, C.*
AU  - Hunt, S.E.*
AU  - Edkins, S.*
AU  - Gwilliam, R.*
AU  - Blackburn, H.*
AU  - Bumpstead, S.J.*
AU  - Dronov, S.*
AU  - Gillman, M.*
AU  - Gray, E.*
AU  - Hammond, N.*
AU  - Jayakumar, A.*
AU  - McCann, O.T.*
AU  - Liddle, J.*
AU  - Perez, M.L.*
AU  - Potter, S.*
AU  - Ravindrarajah, R.*
AU  - Ricketts, M.*
AU  - Waller, M.*
AU  - Weston, P.*
AU  - Widaa, S.*
AU  - Whittaker, P.*
AU  - Blackwell, J.*
AU  - McCarthy, M.I.*
AU  - Attwood, A.P.*
AU  - Stephens, J.*
AU  - Sambrook, J.*
AU  - Ouwehand, W.H.*
AU  - McArdle, W.L.*
AU  - Ring, S.M.*
AU  - Strachan, D.P.*
AU  - Winney, B.*
AU  - Bodmer, W.F.*
AU  - Klopp, N.
C1  - 5757
C2  - 27463
SP  - 1547-1550
TI  - Failure to validate association between 12p13 variants and ischemic stroke.
JO  - N. Engl. J. Med.
VL  - 362
IS  - 16
PB  - Massachusetts Medical Society
PY  - 2010
SN  - 0028-4793
ER  - 

TY  - JOUR
AB  - Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. METHODS: We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS: Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10(-6)) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). CONCLUSIONS: We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.
AU  - Samani, N.J.*
AU  - Erdmann, J.*
AU  - Hall, A.S.*
AU  - Hengstenberg, C.*
AU  - Mangino, M.*
AU  - Mayer, B.*
AU  - Dixon, R.J.*
AU  - Meitinger, T.
AU  - Braund, P.*
AU  - Wichmann, H.-E.
AU  - Barrett, J.H.*
AU  - König, I.R.*
AU  - Stevens, S.E.*
AU  - Szymczak, S.*
AU  - Tregouet, D.A.*
AU  - Iles, M.M.*
AU  - Pahlke, F.*
AU  - Pollard, H.*
AU  - Lieb, W.*
AU  - Cambien, F.*
AU  - Fischer, M.*
AU  - Ouwehand, W.*
AU  - Blankenberg, S.*
AU  - Balmforth, AJ.*
AU  - Baessler, A.*
AU  - Ball, S.G.*
AU  - Strom, T.M.*
AU  - Braenne, I.*
AU  - Gieger, C.
AU  - Deloukas, P.*
AU  - Tobin, M.D.*
AU  - Ziegler, A.*
AU  - Thompson, J.R.*
AU  - Schunkert, H.*
AU  - Wellcome Trust Case Consortium (WTCCC) (*)
AU  - CARDIOGENICS Consortium (*)
C1  - 3174
C2  - 24777
SP  - 443-453
TI  - Genomewide association analysis of coronary artery disease.
JO  - N. Engl. J. Med.
VL  - 357
IS  - 5
PB  - MMS
PY  - 2007
SN  - 0028-4793
ER  - 

TY  - JOUR
AU  - Peters, A.
AU  - von Klot, S.
AU  - Heier, M.
AU  - Trentinaglia, I.
AU  - Hörmann, A.
AU  - Wichmann, H.-E.
AU  - Löwel, H.
C1  - 1403
C2  - 22243
SP  - 1721-1730
TI  - Exposure to traffic and the onset of myocardial infarction.
JO  - N. Engl. J. Med.
VL  - 351
PY  - 2004
SN  - 0028-4793
ER  - 

TY  - JOUR
AU  - Plötz, S.G.
AU  - Simon, H.-W.*
AU  - Darsow, U.*
AU  - Simon, D.*
AU  - Vassina, E.*
AU  - Yousefi, S.*
AU  - Hein, R.*
AU  - Smith, T.*
AU  - Behrendt, H.
AU  - Ring, J.*
C1  - 9978
C2  - 21755
SP  - 2334-2339
TI  - Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis.
JO  - N. Engl. J. Med.
VL  - 349
PY  - 2003
SN  - 0028-4793
ER  - 

TY  - JOUR
AU  - Schmidt, J.
AU  - Hüfner, M.
AU  - Döhner, H.
AU  - Möller, B.
AU  - Ho, A.D.
AU  - Hunnstein, W.
C1  - 17172
C2  - 10285
TI  - Evidence for an Osteoblast Activating Factor in a Patient With Peripherical T-Cell Lymphoma (PTCL) and Osteopetrosis.
JO  - N. Engl. J. Med.
PY  - 1988
SN  - 0028-4793
ER  -