Novel genetic variants contributing to left ventricular hypertrophy: The HyperGEN study

OBJECTIVES: To identify genes contributing to variation in echocardiographic left ventricular mass and related traits using linkage and linkage disequilibrium analysis in sibships ascertained on hypertension. METHODS: The Hypertension Genetic Epidemiology Network (HyperGEN) Study of left ventricular hypertrophy characterized left ventricular mass, relative wall thickness (RWT), and aortic root diameter (ARD) with echocardiograms collected using a standardized protocol at four HyperGEN field centers. A high-throughput scanning fluorescence detector system genotyped 387 polymorphisms distributed throughout the genome. Linkage analyses were conducted once genotyping results became available for 885 siblings from 382 sibships. RESULTS: Although single logarithm of the odds (LOD) score peaks of 1.2 or more were found on chromosomes 1, 4, 5, 6, 7, 8, 9, 10, 12, 14, 17, and 21, we observed a broad band of peaks in both ethnic groups (white and black) on chromosome 4 and selected candidate genes (NPY1R, NPY2R, NPY5R, SFRP2, CPE, IL15, and EDNRA) from this region. Using cases and controls from extremes of the left ventricular mass index, RWT, and ARD distributions, we assessed associations with these phenotypes and haplotype-tagging single-nucleotide polymorphisms (SNPs) in the candidates. Among blacks, SNPs in IL15, NPY2R, and NPY5R showed strong evidence for association (P < 0.005); all candidates except EDNRA showed suggestive association (P < 0.05). In whites, NPY2R, NPY5R, and SFRP2 SNPs offered suggestive evidence of association with one or more traits (P < 0.05). CONCLUSION: Genetic variation in NPY1R, NPY2R, NPY5R, CPE, IL15, and SFRP2, detected using linkage analysis in hypertensive siblings, was associated with left ventricular phenotypes in blacks and/or whites.