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首页> 外文期刊>Pharmacogenetics and genomics >Targeted sequencing identifies a missense variant in the BEST3 gene associated with antihypertensive response to hydrochlorothiazide
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Targeted sequencing identifies a missense variant in the BEST3 gene associated with antihypertensive response to hydrochlorothiazide

机译：靶向测序识别与氢氯噻嗪的抗高血压反应相关的BEST3基因中的畸形变体

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摘要

Chromosome 12q15 was identified in Genetic Epidemiology of Response Assessment (GERA) and replicated in Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) for its association with blood pressure (BP) response to hydrochlorothiazide (HCTZ). However, the functional variant is unknown and we aimed to identify the likely functional variants through targeted sequencing. The chromosome 12q15 region was sequenced in 397 best and worst responders to HCTZ in PEAR (N= 199) and GERA (N= 198) hypertensive study participants. Logistic regression was used for the association analysis adjusting for age, sex, race, and principal components 1 and 2. For validation, the significant single nucleotide polymorphism was tested for association with the change in systolic (Delta SBP) and diastolic BP (Delta DBP) post-treatment in the entire PEAR (N= 370) and GERA (N= 570) cohorts. A novel missense polymorphism (G A, Pro383Leu) in BEST3, rs61747221, was significantly associated with better HCTZ response (P= 0.0021, odds ratio = 2.05). It was validated in the entire cohort of PEAR (Delta SBP: P= 0.021, beta= -1.60, Delta DBP: P= 0.023, beta = - 1.08) and GERA (Delta SBP: P= 0.028, beta = - 1.95, Delta DBP: P= 0.032, beta = - 1.28). BEST3 encodes the calcium sensitive chloride channel in the vascular smooth muscle implicated in the regulation of BP, especially in response to vasoconstrictors like angiotensin II. These results suggest that BEST3 is involved in the chronic BP lowering mechanism of thiazides and highlight its importance as a genetic predictor of the BP response to thiazide diuretics. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.
机译：在响应评估（GERA）的遗传流行病学中鉴定了染色体12Q15并复制了对氢氯噻嗪（HCTZ）的血压（BP）反应的抗高血压反应（梨）的药物替补反应（梨）的药代表评估。然而，功能变体是未知的，我们旨在通过靶向测序来识别可能的功能变体。染色体12Q15区域在397个最佳和最糟糕的反应者中测序到梨中的HCTZ（n = 199）和Gera（n = 198）高血压研究参与者。 Logistic回归用于年龄，性，种族和主成分1和2的关联分析调整。为了验证，测试了显着的单一核苷酸多态性与收缩（Delta Sbp）和舒张压症（Delta dbp）的变化相关联）在整个梨（n = 370）和gera（n = 570）的队列中治疗。 Best3，RS61747221中的新型小说多态性（G> A，Pro383Leu）与更好的HCTZ响应显着相关（P = 0.0021，差距= 2.05）。它验证在整个梨群（Delta SBP：P = 0.021，Beta = -1.60，Delta DBP：P = 0.023，Beta = - 1.08）和Gera（Delta SBP：P = 0.028，Beta = - 1.95，Delta dbp：p = 0.032，beta = - 1.28）。 Best3在血管平滑肌中的钙敏感的氯化物通道中致力于BP的调节，尤其是抗血管紧张素II等血管收缩剂。这些结果表明，最好的3参与硫化物的慢性BP降低机制，并突出了其重要性作为对噻嗪利尿剂的BP反应的遗传预测因子。版权所有（c）2018 Wolters Kluwer Health，Inc。保留所有权利。

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