Genetic variation in NCAM1 contributes to left ventricular wall thickness in hypertensive families

Abstract

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 ancestry: in 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(-6). 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(-4)) and LVID (P=1.86×10(-4)). Fisher combined probability value for all stages was RWT=3.80×10(-9), PWT=3.12×10(-7), IVST=8.69×10(-7), LV mass=2.52×10(-3), and LVID=4.80×10(-4).

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.

Trial registration: ClinicalTrials.gov NCT00005267.

Figures

Figure 1

Genome-wide association findings for the log of diastolic posterior wall thickness adjusted for age, age2, sex, center, and principal components 1–30 in 1 Mb region surrounding single-nucleotide polymorphism (SNP) rs1436109 in HyperGEN African Americans. Points are colored according to the level of linkage disequilibrium of the each SNP with the rs1436109; r2 estimates generated using 1000 Genomes June 2010 Yoruban data. Hack marks at the top reflect SNP density. The bottom panel indicates gene location; exons are indicated with a wider band. This figure is based on output generated by LocusZoom.

Figure 2

Interactions of NCAM1 generated with Ingenuity Pathways Analysis (Ingenuity® Systems, www.ingenuity.com). Blue lines are protein-protein interactions. Gray line interactions coded with letter. Red genes are expressed in cardiac tissue.