Katrina J Scurrah, Angela Lamantia, Justine A Ellis, Stephen B Harrap
{"title":"Familial Analysis of Epistatic and Sex-Dependent Association of Genes of the Renin-Angiotensin-Aldosterone System and Blood Pressure.","authors":"Katrina J Scurrah, Angela Lamantia, Justine A Ellis, Stephen B Harrap","doi":"10.1161/CIRCGENETICS.116.001595","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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).</p><p><strong>Methods and results: </strong>We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin (<i>REN</i>), angiotensinogen (<i>AGT</i>), angiotensin-converting enzyme (<i>ACE</i>), angiotensin II type 1 receptor (<i>AGTR1</i>), and aldosterone synthase (<i>CYP11B2</i>), 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 <i>ACE</i> and rs12721297 at <i>AGTR1</i>) were individually associated with lower systolic blood pressure with significant (<i>P</i><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 <i>AGT</i> and rs11658531 at <i>ACE</i>) and 1 SNP in women (rs12451328 at <i>ACE</i>). SNP-SNP interaction was suggested (<i>P</i><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 <i>REN</i>, 1 for <i>AGT</i>, and 1 for <i>AGTR1</i>). The SNP rs3097 at <i>CYP11B2</i> was represented in 5 separate pairs.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 3","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.116.001595","citationCount":"6","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation: Cardiovascular Genetics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1161/CIRCGENETICS.116.001595","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 6
Abstract
Background: 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).
Methods and results: We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), and aldosterone synthase (CYP11B2), 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 ACE and rs12721297 at AGTR1) were individually associated with lower systolic blood pressure with significant (P<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 AGT and rs11658531 at ACE) and 1 SNP in women (rs12451328 at ACE). SNP-SNP interaction was suggested (P<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 REN, 1 for AGT, and 1 for AGTR1). The SNP rs3097 at CYP11B2 was represented in 5 separate pairs.
Conclusions: 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.
期刊介绍：
Circulation: Genomic and Precision Medicine considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease.
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