TY  - JOUR
AB  - Objective Inhibition of the renal sodium-glucose cotransporter 2 (SGLT2) is a novel concept in the therapy of diabetes mellitus. In this study, we first assessed whether common single nucleotide polymorphisms (SNPs) in the SGLT2-encoding gene SLC5A2 affect diabetes-related metabolic traits in subjects at risk for type 2 diabetes and, second, whether these have pharmacogenetic relevance by interfering with the response to empagliflozin treatment in patients with type 2 diabetes. Patients and methods Samples from a metabolically well-phenotyped cross-sectional study population (total N=2600) at increased risk for type 2 diabetes and pooled pharmacogenetic samples from patients from four phase III trials of empagliflozin (in total: 603 receiving empagliflozin, 305 receiving placebo) were genotyped for five common SNPs (minor allele frequencies >= 5%) present in the SLC5A2 gene locus. Results In the cross-sectional study, none of the SLC5A2 SNPs significantly influenced metabolic traits such as body fat, insulin sensitivity/resistance, insulin release, HbA(1c), plasma glucose, or systolic blood pressure when multiple testing was taken into account (all P >= 0.0083). Further, no relevant effect on response to treatment with empagliflozin on HbA(1c), fasting glucose, weight, or systolic blood pressure was observed for the SNPs tested in the pharmacogenetic study. Conclusion Common genetic variants in the SLC5A2 gene neither affects diabetes-related metabolic traits nor have a clinically relevant impact on response to treatment with the SGLT2 inhibitor empagliflozin.
AU  - Zimdahl, H.*
AU  - Haupt, A.*
AU  - Brendel, M.D.*
AU  - Bour, L.*
AU  - Machicao, F.
AU  - Salsali, A.*
AU  - Broedl, U.C.*
AU  - Woerle, H.*
AU  - Häring, H.-U.
AU  - Staiger, H.
C1  - 50996
C2  - 42904
CY  - Philadelphia
SP  - 135-142
TI  - Influence of common polymorphisms in the SLC5A2 gene on metabolic traits in subjects at increased risk of diabetes and on response to empagliflozin treatment in patients with diabetes.
JO  - Pharmacogenet. Genomics
VL  - 27
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2017
SN  - 0960-314X
ER  - 

TY  - CONF
AU  - Wjst, M.
AU  - Werner, M.*
C1  - 64089
C2  - 51864
SP  - 21-33
TI  - Methods of genotyping.
JO  - Pharmacogenet. Genomics
PY  - 2016
SN  - 0960-314X
ER  - 

TY  - JOUR
AB  - Genome-wide studies have identified single nucleotide polymorphisms associated with smoking behaviour and nicotine dependence. Less is known about genetic determinants of smoking cessation, but rs4680 in COMT has recently been shown to explain a substantial proportion of the variation in cessation in the general population. We attempted to replicate the reported, clinically relevant effect in a population-based retrospective cohort analysis of 1443 ever-heavy smokers, of whom 925 had reached abstinence. In Cox regression models, neither rs4680 nor two polymorphisms nearby were associated with smoking cessation. The adjusted relative cessation rate (95% confidence interval) in rs4680 methionine carriers in reference to valine homozygotes was 0.97 (0.83-1.12). The absence of a significant effect of rs4680 in this statistically well-powered study - the 95% confidence interval even excluding the previously reported effect - highlights the need for rigorous replication efforts and suggests that rs4680 genotype should not yet be considered informative for smoking patient care.
AU  - Breitling, L.P.*
AU  - Dahmen, N.*
AU  - Illig, T.
AU  - Rujescu, D.*
AU  - Nitz, B.
AU  - Raum, E.*
AU  - Winterer, G.*
AU  - Rothenbacher, D.*
AU  - Brenner, H.*
C1  - 1664
C2  - 26650
CY  - United States
SP  - 657-659
TI  - Variants in COMT and spontaneous smoking cessation: Retrospective cohort analysis of 925 cessation events.
JO  - Pharmacogenet. Genomics
VL  - 19
IS  - 8
PB  - Lippincott Williams & Wilkins
PY  - 2009
SN  - 0960-314X
ER  - 

TY  - JOUR
AB  - Outcome and survival in anthracycline-based and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of invasive breast cancer are unpredictable. Insights into treatment prediction are expected from studies searching for an association between genetic polymorphisms and treatment outcome effects. A common feature of treatment with chemoreagents is therapeutically induced DNA damage. Therefore, we tested the hypothesis of a relationship between event-free survival and genotype distributions of seven polymorphic DNA repair enzymes and four cell cycle regulators. BASIC METHODS: This case-case comparison included 180 patients with primary invasive breast cancer diagnosed between 1986 and 2000 and subjected to adjuvant chemotherapy (anthracycline/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil). Ninety-two patients were reported without recurrence and 88 were reported with recurrences or dead. Median clinical follow-up was 61.7 months. Constitutional DNA isolated from archived tissues was genotyped at 19 loci by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Statistical analyses included adjusted risk estimates, Kaplan-Meier analyses, Cox proportional hazard model, and permutation testing. MAIN RESULTS: Carriers of the XRCC1_1196_AA genotype had a reduced risk for recurrence/death (odds ratio adjusted 0.19; 95% confidence interval: 0.06-0.61), which was observed in survival analyses of all patients (P=0.003) and patients treated with chemotherapy but not radiotherapy (P=0.006). Multivariate analysis confirmed XRCC1 as a potential treatment predictor (hazard ratio 0.62; 95% confidence interval: 0.43-0.89). The result was stable upon permutation testing. No other significant associations were observed. CONCLUSION: The DNA repair enzyme XRCC1 is a potential treatment predictor for the outcome and survival of anthracycline and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of invasive breast cancer.
AU  - Jaremko, M.*
AU  - Justenhoven, C.*
AU  - Schroth, W.*
AU  - Abraham, B.K.*
AU  - Fritz, P.*
AU  - Vollmert, C.
AU  - Illig, T.
AU  - Simon, W.
AU  - Schwab, M.*
AU  - Brauch, H.*
C1  - 4586
C2  - 24600
SP  - 529-538
TI  - Polymorphism of the DNA repair enzyme XRCC1 is associated with treatment prediction in anthracycline and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of patients with primary invasive breast cancer.
JO  - Pharmacogenet. Genomics
VL  - 17
PB  - Lippincott Williams & Wilkins
PY  - 2007
SN  - 0960-314X
ER  -