The role of renin-angiotensin-aldosterone system (RAAS) genes in the development of hypertrophy in hypertrophic cardiomyopathy (HCM)

[摘要] Hypertrophic cardiomyopathy (HCM), an inherited primary cardiac disorder mostlycaused by defective sarcomeric proteins, is considered a model for studying leftventricular hypertrophy (LVH) in the absence of increased external loading conditions.The disease manifests extreme variability in the degree and pattern of LVH, even inHCM patients with the same causal mutation. The clinical phenotype of HCM cantherefore be viewed as a product of the effect of sarcomere dysfunction and of additionalgenetic modifiers. Components of the renin-angiotensin-aldosterone system (RAAS) areplausible candidate modifiers because of their effect on blood pressure and their directhypertrophic effect on cardiomyocytes.The present study investigated genes encoding components of the RAAS for associationwith cardiac hypertrophy traits, in 353 individuals comprised of genetically andechocardiographically affected and unaffected family members, belonging to 22 HCMfamilies with HCM founder mutations by employing a multi-SNP approach with TaqManallelic discrimination technology. Gene-gene interaction analysis was also performed toinvestigate the effect of epistasis on hypertrophy. Candidate genes for analysis includedthe angiotensin II type 2 receptor (AT2 receptor), renin, renin-binding protein (RnBP), the(pro)renin receptor, the mineralocorticoid receptor as well as genes encoding subunits ofthe epithelial sodium channels (ENaC) and Na+/K+-ATPase that showed evidence forcardiac expression.The present study demonstrates for the first time that variations in the renin and RnBPgenes play a role in modulating hypertrophy in HCM, independent of blood pressure andconfirms the involvement of the AT2 receptor in hypertrophy in HCM. Additionally wereport an association between Na+/K+-ATPase α1- and β1-subunits as well as the ENaCα- and β-subunits and hypertrophy. Significant evidence for epistasis was found betweenrenin and downstream RAAS effectors, suggesting a complex interplay between theseRAAS variants and the hypertrophic phenotype in HCM. The identification of suchmodifiers for HCM may offer novel targets for hypertrophy research and ultimately antihypertrophictherapy.

[发布机构] Stellenbosch University