Gong Yan, Wang Zhiying, Beitelshees Amber L, McDonough Caitrin W, Langaee Taimour Y, Hall Karen, Schmidt Siegfried O F, Curry Robert W, Gums John G, Bailey Kent R, Boerwinkle Eric, Chapman Arlene B, Turner Stephen T, Cooper-DeHoff Rhonda M, Johnson Julie A
From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (Y.G., C.W.M., T.Y.L., J.G.G., R.M.C.-D., J.A.J.), Department of Community Health and Family Medicine, College of Medicine (K.H., S.O.F.S., R.W.C., J.G.G.), and Division of Cardiovascular Medicine, College of Medicine (R.M.C.-D., J.A.J.), University of Florida, Gainesville; Department of Epidemiology, Human Genetics & Environmental Sciences, Center for Human Genetics, University of Texas Health Science Center at Houston (Z.W., E.B.); Department of Medicine and Program in Personalized & Genomic Medicine, University of Maryland, Baltimore (A.L.B.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension (S.T.T.), Mayo Clinic, Rochester, MN; and Department of Medicine, University of Chicago, IL. (A.B.C.).
Hypertension. 2016 Mar;67(3):556-63. doi: 10.1161/HYPERTENSIONAHA.115.06345. Epub 2016 Jan 4.
African Americans suffer a higher prevalence of hypertension compared with other racial/ethnic groups. In this study, we performed a pharmacogenomic genome-wide association study of blood pressure (BP) response to β-blockers in African Americans with uncomplicated hypertension. Genome-wide meta-analysis was performed in 318 African American hypertensive participants in the 2 Pharmacogenomic Evaluation of Antihypertensive Responses studies: 150 treated with atenolol monotherapy and 168 treated with metoprolol monotherapy. The analysis adjusted for age, sex, baseline BP and principal components for ancestry. Genome-wide significant variants with P<5×10(-8) and suggestive variants with P<5×10(-7) were evaluated in an additional cohort of 141 African Americans treated with the addition of atenolol to hydrochlorothiazide treatment. The validated variants were then meta-analyzed in these 3 groups of African Americans. Two variants discovered in the monotherapy meta-analysis were validated in the add-on therapy. African American participants heterozygous for SLC25A31 rs201279313 deletion versus wild-type genotype had better diastolic BP response to atenolol monotherapy, metoprolol monotherapy, and atenolol add-on therapy: -9.3 versus -4.6, -9.6 versus -4.8, and -9.7 versus -6.4 mm Hg, respectively (3-group meta-analysis P=2.5×10(-8), β=-4.42 mm Hg per variant allele). Similarly, LRRC15 rs11313667 was validated for systolic BP response to β-blocker therapy with 3-group meta-analysis P=7.2×10(-8) and β=-3.65 mm Hg per variant allele. In this first pharmacogenomic genome-wide meta-analysis of BP response to β-blockers in African Americans, we identified novel variants that may provide valuable information for personalized antihypertensive treatment in this group.
与其他种族/族裔群体相比，非裔美国人高血压的患病率更高。在本研究中，我们对患有单纯性高血压的非裔美国人进行了一项关于β受体阻滞剂血压（BP）反应的药物基因组全基因组关联研究。在两项抗高血压反应的药物基因组评估研究中，对318名非裔美国高血压参与者进行了全基因组荟萃分析：150名接受阿替洛尔单药治疗，168名接受美托洛尔单药治疗。分析对年龄、性别、基线血压和祖先的主要成分进行了校正。在另外141名接受氢氯噻嗪联合阿替洛尔治疗的非裔美国人队列中，对P<5×10(-8)的全基因组显著变异和P<5×10(-7)的提示性变异进行了评估。然后在这三组非裔美国人中对验证的变异进行荟萃分析。在单药治疗荟萃分析中发现的两个变异在联合治疗中得到了验证。SLC25A31 rs201279313缺失杂合型与野生型基因型的非裔美国参与者对阿替洛尔单药治疗、美托洛尔单药治疗和阿替洛尔联合治疗的舒张压反应更好：分别为-9.3与-4.6、-9.6与-4.8、-9.7与-6.4 mmHg（三组荟萃分析P=2.5×10(-8)，每个变异等位基因β=-4.42 mmHg）。同样，LRRC15 rs11313667在三组荟萃分析中对β受体阻滞剂治疗的收缩压反应得到验证，P=7.2×10(-8)，每个变异等位基因β=-3.65 mmHg。在这项关于非裔美国人对β受体阻滞剂血压反应的首次药物基因组全基因组荟萃分析中，我们鉴定出了可能为该群体个性化抗高血压治疗提供有价值信息的新变异。
