Functional Alterations of the Nppa Promoter Are Linked to Cardiac Ventricular Hypertrophy in WKY/WKHA Rat Crosses

Abstract

Cardiac left ventricular hypertrophy (LVH) is commonly associated with hypertension, but its variance is determined for more than 50% by blood pressure-independent genetic factors. Because it constitutes one of the most important risk factors for cardiovascular mortality, we have performed a genome-wide scan of the F2 progeny of crosses between inbred WKY and WKHA rats to detect quantitative trait loci (QTL) linked to cardiac mass. In addition to left ventricular mass (LVM), we also measured left ventricle (LV) concentration of atrial natriuretic factor (ANF), because we have previously established that there was a genetic link between these 2 traits in the same animal cross. We found 2 contiguous QTL on chromosome 5 that were linked to either LVM (logarithm of odds [LOD]=3.5) or log(n) (LV ANF) (LOD=12). The 1-LOD support intervals of both QTL shared a region overlapping the locus of natriuretic peptide precursor A (NPPA:) (ie, the ANF-coding gene). We found by sequencing 2 single nucleotide polymorphisms (SNPs) within the first 650 bp of the NPPA: minimal promoters of the genes from both strains. One of these SNPs increased the transcriptional activity of the NPPA: minimal promoter in transfected neonatal cardiomyocytes in keeping with the higher LV concentration of ANF observed in WKY versus WKHA rats. Taken together with the previous reports showing that ANF may protect cardiomyocytes against hypertrophy, our genetic data single out NPPA: as a strong candidate gene for the determination of LVM.