Pharmacogenomic association of nonsynonymous SNPs in SIGLEC12, A1BG, and the selectin region and cardiovascular outcomes

We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the INternational VErapamil SR–Trandolapril STudy (INVEST), where participants were randomized to a β-blocker strategy or a calcium channel blocker strategy. Genome-spanning single nucleotide polymorphism (SNP)×treatment interaction analyses of nonsynonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top 3 signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and A1BG rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (INVEST whites and Hispanics combined interaction P=0.0038 and 0.0036, respectively). A genetic risk score, including rs16982743, rs893184, and rs4525 in F5, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the INVEST study and in the Nordic Diltiazem study (meta-analysis interaction P=2.39×10−5). In patients with a genetic risk score of 0 or 1, calcium channel blocker treatment was associated with lower risk (odds ratio [95% confidence interval]=0.60 [0.42–0.86]), and in those with a genetic risk score of 2 to 3, calcium channel blocker treatment was associated with higher risk (odds ratio [95% confidence interval]=1.31 [1.08–1.59]). These results suggest that cardiovascular outcomes may differ based on SIGLEC12, A1BG, F5 genotypes, and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection

Association of Apolipoprotein E Genotype with Duration of Time to Achieve a Stable Warfarin Dose in African-American Patients

Study Objective. To test the hypothesis that genotypes for proteins affecting vitamin K availability influence the duration of time required to achieve a stable warfarin dose in African-American patients. Design. Retrospective cohort study Setting. Pharmacist-managed antithrombosis clinic. Patients. Ninety-two African-American adults whose warfarin therapy was initiated between September 2, 1999, and July 8, 2009. Measurements and Main Results, During a routine anticoagulation clinic visit, a sample was collected from each patient for genetic analysis. Genotyping was performed for the following variants: apolipoprotein E epsilon 2, epsilon 3, and epsilon 4; NAD(P)H:quinone oxidoreductase (NQO1)*2; cytochrome P450 (CYP) 4F2 V433M; CYP2C9*2, *3, *5, *8, and *11; and vitamin K epoxide reductase complex 1 (VKORC1) -1639G>A. Patients' medical records were then reviewed, and data were collected retrospectively for each anticoagulation clinic visit during the first 6 months of warfarin therapy or until dose stabilization. The median time required to reach a stable warfarin dose, defined as the dose that produced therapeutic anticoagulation for three consecutive clinic visits, was 83 days. Compared with the 46 patients who achieved a stable warfarin dose within 83 days, the 46 patients who required longer durations for dose stabilization had a higher frequency of the apolipoprotein E epsilon 3/epsilon 3 genotype (37% vs 59%, p=0.037). Sixty-one percent of patients with the epsilon 3/epsilon 3 genotype versus 40% of those with an epsilon 2 or epsilon 4 allele had a delay in achieving a stable dose (p=0.037). Neither the CYP4F2 nor NQO1 genotype was associated with warfarin dose stabilization. Conclusion. Our data support the hypothesis that the apolipoprotein E genotype is associated with duration of time to reach a stable warfarin dose in African-American patients. Further insight into the genetic effects on warfarin dose stabilization could reveal novel methods to improve anticoagulation control during the warfarin initiation period

Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue

Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups