Section of Nephrology, University of Chicago, Chicago, Illinois, United States of America.
Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
PLoS One. 2019 Sep 18;14(9):e0221957. doi: 10.1371/journal.pone.0221957. eCollection 2019.
Hypertension (HTN) disproportionately affects African Americans (AAs), who respond better to thiazide diuretics than other antihypertensives. Variants of the APOL1 gene found in AAs are associated with a higher rate of kidney disease and play a complex role in cardiovascular disease.
AA subjects from four HTN trials (n = 961) (GERA1, GERA2, PEAR1, and PEAR2) were evaluated for blood pressure (BP) response based on APOL1 genotype after 4-9 weeks of monotherapy with thiazides, beta blockers, or candesartan. APOL1 G1 and G2 variants were determined by direct sequencing or imputation.
Baseline systolic BP (SBP) and diastolic BP (DBP) levels did not differ based on APOL1 genotype. Subjects with 1-2 APOL1 risk alleles had a greater SBP response to candesartan (-12.2 +/- 1.2 vs -7.5 +/- 1.8 mmHg, p = 0.03; GERA2), and a greater decline in albuminuria with candesartan (-8.3 +/- 3.1 vs +3.7 +/- 4.3 mg/day, p = 0.02). APOL1 genotype did not associate with BP response to thiazides or beta blockers. GWAS was performed to determine associations with BP response to candesartan depending on APOL1 genotype. While no SNPs reached genome wide significance, SNP rs10113352, intronic in CSMD1, predicted greater office SBP response to candesartan (p = 3.7 x 10-7) in those with 1-2 risk alleles, while SNP rs286856, intronic in DPP6, predicted greater office SBP response (p = 3.2 x 10-7) in those with 0 risk alleles.
Hypertensive AAs without overt kidney disease who carry 1 or more APOL1 risk variants have a greater BP and albuminuria reduction in response to candesartan therapy. BP response to thiazides or beta blockers did not differ by APOL1 genotype. Future studies confirming this initial finding in an independent cohort are required.
高血压（HTN）在非裔美国人（AAs）中发病率不成比例，他们对噻嗪类利尿剂的反应优于其他降压药。在 AAs 中发现的 APOL1 基因变体与更高的肾病发生率相关，并在心血管疾病中发挥复杂作用。
在四项 HTN 试验（GERA1、GERA2、PEAR1 和 PEAR2）中，对 961 名 AA 受试者进行了基于噻嗪类、β受体阻滞剂或坎地沙坦单药治疗 4-9 周后 APOL1 基因型的血压（BP）反应评估。APOL1 G1 和 G2 变体通过直接测序或推断确定。
根据 APOL1 基因型，基线收缩压（SBP）和舒张压（DBP）水平没有差异。具有 1-2 个 APOL1 风险等位基因的受试者对坎地沙坦的 SBP 反应更大（-12.2 +/- 1.2 与-7.5 +/- 1.8 mmHg，p = 0.03；GERA2），并且坎地沙坦对白蛋白尿的下降更大（-8.3 +/- 3.1 与+3.7 +/- 4.3 mg/天，p = 0.02）。APOL1 基因型与噻嗪类或β受体阻滞剂的 BP 反应无关。进行了 GWAS 以确定根据 APOL1 基因型与坎地沙坦 BP 反应的关联。虽然没有 SNP 达到全基因组显著性，但 SNP rs10113352，位于 CSMD1 内含子中，预测具有 1-2 个风险等位基因的受试者对坎地沙坦的办公 SBP 反应更大（p = 3.7 x 10-7），而 SNP rs286856，位于 DPP6 内含子中，预测具有 0 个风险等位基因的受试者的办公 SBP 反应更大（p = 3.2 x 10-7）。
没有明显肾脏疾病的高血压 AA 患者，如果携带 1 个或多个 APOL1 风险变体，对坎地沙坦治疗的血压和白蛋白尿降低反应更大。噻嗪类或β受体阻滞剂的 BP 反应与 APOL1 基因型无关。需要在独立队列中进一步研究证实这一初步发现。
