@article {6063, title = {Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.}, journal = {Heart Rhythm}, volume = {10}, year = {2013}, month = {2013 Mar}, pages = {401-8}, abstract = {

BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.

OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans.

METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P<=2.5{\texttimes}10(-8)).

RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98{\texttimes}10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.

CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

}, keywords = {Adult, African Americans, Aged, Arrhythmias, Cardiac, Connexin 43, Electrocardiography, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Heart Rate, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Rest, United States}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2012.11.014}, author = {Deo, R and Nalls, M A and Avery, C L and Smith, J G and Evans, D S and Keller, M F and Butler, A M and Buxbaum, S G and Li, G and Miguel Quibrera, P and Smith, E N and Tanaka, T and Akylbekova, E L and Alonso, A and Arking, D E and Benjamin, E J and Berenson, G S and Bis, J C and Chen, L Y and Chen, W and Cummings, S R and Ellinor, P T and Evans, M K and Ferrucci, L and Fox, E R and Heckbert, S R and Heiss, G and Hsueh, W C and Kerr, K F and Limacher, M C and Liu, Y and Lubitz, S A and Magnani, J W and Mehra, R and Marcus, G M and Murray, S S and Newman, A B and Njajou, O and North, K E and Paltoo, D N and Psaty, B M and Redline, S S and Reiner, A P and Robinson, J G and Rotter, J I and Samdarshi, T E and Schnabel, R B and Schork, N J and Singleton, A B and Siscovick, D and Soliman, E Z and Sotoodehnia, N and Srinivasan, S R and Taylor, H A and Trevisan, M and Zhang, Z and Zonderman, A B and Newton-Cheh, C and Whitsel, E A} } @article {7253, title = {Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.}, journal = {Pharmacogenomics J}, year = {2016}, month = {2016 Dec 13}, abstract = {

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 {\texttimes} 10(-8)), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.The Pharmacogenomics Journal advance online publication, 13 December 2016; doi:10.1038/tpj.2016.90.

}, issn = {1473-1150}, doi = {10.1038/tpj.2016.90}, author = {Floyd, J S and Sitlani, C M and Avery, C L and Noordam, R and Li, X and Smith, A V and Gogarten, S M and Li, J and Broer, L and Evans, D S and Trompet, S and Brody, J A and Stewart, J D and Eicher, J D and Seyerle, A A and Roach, J and Lange, L A and Lin, H J and Kors, J A and Harris, T B and Li-Gao, R and Sattar, N and Cummings, S R and Wiggins, K L and Napier, M D and St{\"u}rmer, T and Bis, J C and Kerr, K F and Uitterlinden, A G and Taylor, K D and Stott, D J and de Mutsert, R and Launer, L J and Busch, E L and M{\'e}ndez-Gir{\'a}ldez, R and Sotoodehnia, N and Soliman, E Z and Li, Y and Duan, Q and Rosendaal, F R and Slagboom, P E and Wilhelmsen, K C and Reiner, A P and Chen, Y-DI and Heckbert, S R and Kaplan, R C and Rice, K M and Jukema, J W and Johnson, A D and Liu, Y and Mook-Kanamori, D O and Gudnason, V and Wilson, J G and Rotter, J I and Laurie, C C and Psaty, B M and Whitsel, E A and Cupples, L A and Stricker, B H} } @article {7491, title = {Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.}, journal = {Pharmacogenomics J}, year = {2017}, month = {2017 Jul 18}, abstract = {

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66\%), African American (15\%) and Hispanic (19\%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 {\texttimes} 10(-8)), we found suggestive evidence (P<5 {\texttimes} 10(-6)) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.The Pharmacogenomics Journal advance online publication, 18 July 2017; doi:10.1038/tpj.2017.10.

}, issn = {1473-1150}, doi = {10.1038/tpj.2017.10}, author = {Seyerle, A A and Sitlani, C M and Noordam, R and Gogarten, S M and Li, J and Li, X and Evans, D S and Sun, F and Laaksonen, M A and Isaacs, A and Kristiansson, K and Highland, H M and Stewart, J D and Harris, T B and Trompet, S and Bis, J C and Peloso, G M and Brody, J A and Broer, L and Busch, E L and Duan, Q and Stilp, A M and O{\textquoteright}Donnell, C J and Macfarlane, P W and Floyd, J S and Kors, J A and Lin, H J and Li-Gao, R and Sofer, T and M{\'e}ndez-Gir{\'a}ldez, R and Cummings, S R and Heckbert, S R and Hofman, A and Ford, I and Li, Y and Launer, L J and Porthan, K and Newton-Cheh, C and Napier, M D and Kerr, K F and Reiner, A P and Rice, K M and Roach, J and Buckley, B M and Soliman, E Z and de Mutsert, R and Sotoodehnia, N and Uitterlinden, A G and North, K E and Lee, C R and Gudnason, V and St{\"u}rmer, T and Rosendaal, F R and Taylor, K D and Wiggins, K L and Wilson, J G and Chen, Y-DI and Kaplan, R C and Wilhelmsen, K and Cupples, L A and Salomaa, V and van Duijn, C and Jukema, J W and Liu, Y and Mook-Kanamori, D O and Lange, L A and Vasan, R S and Smith, A V and Stricker, B H and Laurie, C C and Rotter, J I and Whitsel, E A and Psaty, B M and Avery, C L} }