Investigations of Renin-Angiotensin Aldosterone System (RAAS) genes in hypertrophy in hypertrophic cardiomyopathy (HCM) founder families

[摘要] ENGLISH ABSTRACT: In hypertrophic cardiomyopathy (HCM), an autosomal dominant disorder, hypertrophy is variablewithin and between families carrying the same causal mutation, suggesting a role for modifier genes.Associations between left ventricular hypertrophy and left ventricular pressure overload suggestedthat sequence variants in genes involved in the Renin-Angiotensin Aldosterone System (RAAS) mayact as hypertrophy modifiers in HCM, but some of these studies may have been confounded by,amongst other things, lack of adjustment for hypertrophy covariates.To investigate this hypothesis, twenty one polymorphic loci spread across six genes (ACE1, AGT,AGTR1, CYP11B2, CMA and ACE2) of the RAAS were genotyped in 353 subjects from 22 SouthAfrican HCM-families, in which founder mutations segregate. Genotypes were compared to 17echocardiographically-derived hypertrophic indices of left ventricular wall thickness at 16 segmentscovering three longitudinal levels. Family-based association was performed by quantitativetransmission disequilibrium testing (QTDT), and mixed effects models to analyse the X-linked geneACE2, with concurrent adjustment for hypertrophy covariates (age, sex, systolic blood pressure (BP),diastolic BP, body surface area, heart rate and mutation status).Strong evidence of linkage in the absence of association was detected between polymorphisms atACE1 and posterior and anterior wall thickness (PW and AW, respectively) at the papillary musclelevel (pap) and apex level (apx). In single-locus analysis, statistically significant associations weregenerated between the CYP11B2 rs3097 polymorphism and PW at the mitral valve level (mit) andboth PWpap and inferior wall thickness (IW)pap. Statistically significant associations weregenerated at three AGTR1 polymorphisms, namely, between rs2640539 and AWmit, rs 3772627 andanterior interventricular septum thickness at pap and rs5182 and both IWpap and AWapx.Furthermore, mixed effects model detected statistically significant association between the ACE2rs879922 polymorphism and both posterior interventricular septum thickness and lateral wallthickness at mit in females only.These data indicate a role for RAAS gene variants, independent of hypertrophy covariates, inmodifying the phenotypic expression of hypertrophy in HCM-affected individuals.

[发布机构] Stellenbosch University