Measured haplotype analysis of the aldosterone synthase gene and heart size

Abstract

Gene-association studies of heart size and the aldosterone synthase (CYP11B2) gene have produced inconsistent results, possibly because of limitations in the sample size and/or the number and location of the polymorphisms. An analysis of six polymorphisms spanning 6 kb of the CYP11B2 gene in Caucasian British families revealed a limited number of haplotypes because of strong linkage disequilibrium over this small region. The genotype and haplotype information was used in an association study involving 955 members of 229 families phenotyped for echocardiographic measures of heart size. In a mixed effects linear modelling analysis, the G5937C polymorphism was associated with cardiac wall thickness (P ¼ 0.02), and the intron conversion and A4550C polymorphisms were associated with left ventricular cavity size (P ¼ 0.02 and 0.002, respectively). Measured haplotype analyses confirmed the association of alleles at the intron conversion and G5937C polymorphisms with cardiac wall thickness (P ¼ 0.02), and alleles at the intron conversion polymorphism with left ventricular cavity size (P ¼ 0.04). The polymorphisms contributed to 2.0 -3.4% of the variability in these traits. In summary, genetic polymorphisms at the CYP11B2 gene make a small contribution to quantitative variation in echocardiographic measures of heart size. These results point to the importance of analysing the full extent of genetic variation that captures the haplotype structure of a locus in gene association studies.

Genetic variation in angiotensin II type 2 receptor gene influences extent of left ventricular hypertrophy in hypertrophic cardiomyopathy independent of blood pressure

“…Thus, we estimated the effect size from an analysis of the mean of the 16 untransformed cardiac wall thickness measurements originally used to derive PC1. The resulting effect size was modest (0.48 mm), although comparable to effect sizes reported for other RAAS candidate modifiers, 30,31 which suggests that the eventual hypertrophic phenotype of HCM might be the cumulative result of a number of modifier genes of modest effect.…”

Aldosterone Synthase Promoter Polymorphism Predicts Outcome in African Americans With Heart Failure

“…In a Finnish cohort free of cardiac disease, the Ϫ344C allele was associated with increased left ventricular size and mass (30). In a study of 995 members of 229 families, the CYP11B2 haplotype was linked to left ventricular cavity size and wall thickness (31). In the current GRAHF study cohort, the C allele was associated with a trend towards lower LVEF at 6 months.…”

Role of the C-344T aldosterone synthase gene variant in left ventricular mass and left ventricular structure-related phenotypes

“…Unfortunately, no family-based reports, except the study of Mayosi et al 17 regarding of heart size and the aldosterone synthase gene, have been published. In this study the authors performed a thorough analysis of six polymorphisms spanning 6 kb of the CYP11B2 in white British families, concluding that genetic polymorphisms at the CYP11B2 make a small contribution to quantitative variation in echocardiographic measures of heart size and significant residual familial effect were present for septal wall thickness and left ventricular mass.…”