Genetic Variation in NCAM1 Contributes to Left Ventricular Wall Thickness in Hypertensive Families

RATIONALE:Left ventricular (LV) mass and related phenotypes are heritable, important predictors of cardiovascular disease, particularly in hypertensive individuals. OBJECTIVE:Identify genetic predictors of echocardiographic phenotypes in hypertensive families. METHODS AND RESULTS:A multistage genome-wide association study (GWAS) was conducted in hypertensive-ascertained black families (HyperGEN, stage I; GENOA, stage II); findings were replicated in HyperGEN white families (stage III). Echocardiograms were collected using a common protocol, and participants were genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. The following were analyzed using mixed models adjusted for ancestryin stages I and II, 1258 and 989 blacks, respectively; and in stage III, 1316 whites. Phenotypes included LV mass, LV internal dimension (LVID), wall thicknesses (posterior [PWT] and intraventricular septum [IVST]), and relative wall thickness (RWT). In stage I, 5 single nucleotide polymorphisms (SNPs) had P≤10. In stage II, 1 SNP (rs1436109; NCAM1 intron 1) replicated with the same phenotype (PWT, P=0.025) in addition to RWT (P=0.032). In stage III, rs1436109 was associated with RWT (P=5.47×10) and LVID (P=1.86×10). Fisher combined probability value for all stages was RWT=3.80×10, PWT=3.12×10, IVST=8.69×10, LV mass=2.52×10, and LVID=4.80×10. CONCLUSIONS:This GWAS conducted in hypertensive families identified a variant in NCAM1 associated with LV wall thickness and RWT. NCAM is upregulated during the remodeling period of hypertrophy to heart failure in Dahl salt–sensitive rats. Our initial screening in hypertensive blacks may have provided the context for this novel locus.