Scurrah Katrina J, Lamantia Angela, Ellis Justine A, Harrap Stephen B
From the Department of Physiology (K.J.S., A.L., S.B.H.), Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health (K.J.S.), and Department of Paediatrics (J.A.E.), The University of Melbourne, Australia; Genes, Environment & Complex Disease Unit, Murdoch Children's Research Institute, Parkville, Victoria, Australia (J.A.E.); and Centre for Social and Early Emotional Development, Faculty of Health, Deakin University, Victoria, Australia (J.A.E.).
Circ Cardiovasc Genet. 2017 Jun;10(3). doi: 10.1161/CIRCGENETICS.116.001595.
Renin-angiotensin-aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene-gene interactions (epistasis).
We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin (), angiotensinogen (), angiotensin-converting enzyme (), angiotensin II type 1 receptor (), and aldosterone synthase (), including sex-SNP or SNP-SNP interactions. Eighty-eight tagSNPs were tested in 2872 white individuals in 809 pedigrees from the Victorian Family Heart Study using variance components models. Three SNPs (rs8075924 and rs4277404 at and rs12721297 at ) were individually associated with lower systolic blood pressure with significant (<0.00076) effect sizes ≈1.7 to 2.5 mm Hg. Sex-specific associations were seen for 3 SNPs in men (rs2468523 and rs2478544 at and rs11658531 at ) and 1 SNP in women (rs12451328 at ). SNP-SNP interaction was suggested (<0.005) for 14 SNP pairs, none of which had shown individual association with systolic blood pressure. Four SNP pairs were at the same gene (2 for , 1 for , and 1 for ). The SNP rs3097 at was represented in 5 separate pairs.
SNPs at key renin-angiotensin-aldosterone system genes associate with systolic blood pressure individually in both sexes, individually in one sex only and only when combined with another SNP. Analyses that incorporate sex-dependent and epistatic effects could reconcile past inconsistencies and account for some of the missing heritability of blood pressure and are generally relevant to SNP association studies for any phenotype.
肾素-血管紧张素-醛固酮系统基因与血压的关联并不一致，这可能是由于未识别的性别依赖性基因效应或基因-基因相互作用（上位性）的影响。
我们测试了肾素（）、血管紧张素原（）、血管紧张素转换酶（）、血管紧张素II 1型受体（）和醛固酮合酶（）的单核苷酸多态性（SNP）与收缩压的关联，包括性别-SNP或SNP-SNP相互作用。使用方差成分模型在来自维多利亚家庭心脏研究的809个家系中的2872名白人个体中测试了88个标签SNP。三个SNP（位于的rs8075924和rs4277404以及位于的rs12721297）分别与较低的收缩压相关，效应大小显著（<0.00076），约为1.7至2.5 mmHg。在男性中，3个SNP（位于的rs2468523和rs2478544以及位于的rs11658531）和在女性中1个SNP（位于的rs12451328）存在性别特异性关联。14对SNP显示出SNP-SNP相互作用（<0.005），其中没有一对与收缩压有个体关联。4对SNP位于同一基因（位于的2对，位于的1对，位于的1对）。位于的SNP rs3097出现在5个不同的对中。
关键肾素-血管紧张素-醛固酮系统基因的SNP在男女中分别与收缩压相关，仅在一种性别中单独相关，且仅在与另一个SNP组合时相关。纳入性别依赖性和上位性效应的分析可以调和过去的不一致性，并解释部分血压遗传力缺失的问题，并且通常与任何表型的SNP关联研究相关。
