Abstract 2187: Genomewide Association Analysis Identifies Novel Loci for Left Ventricular Mass Index: The NHLBI Family Heart Study (FHS)
Left ventricular hypertrophy is a strong predictor of cardiovascular mortality and morbidity. We carried out genomewide association analysis on 851 Caucasians in the FHS to identify common genetic variants contributing to the variability of left ventricular mass index (LVMI) measured by MAC-PC electrocardiographs, and calculated by using end-diastolic dimensions with an anatomically validated formula indexed for body surface. Genotypes were assessed using the Illumina HumMap550 chip, and we imputed up to ~2.5 million SNPs based on HapMap Release 22 CEU phased haplotypes. SNPwise tests assumed an additive model. We found evidence of association at genomewide (GW) significance with variants in 4 genes: KCTD16 (potassium channel tetramerisation domain containing 16, 5q32), YIPF5 (Yip1 domain family, member 5, 5q32), CCNH (cyclin H, 5q13), and NOS1 (nitric oxide synthase 1 (neuronal), 12q24). The strongest associations occurred within YIPF5 (rs4505984: P=9.1E-13) and KCTD16 (rs10477238: P=5.01E-12), which explain ~3% of LVMI variability. However, because these SNPs are in complete linkage disequilibrium (LD), it is not clear if both or only one represents a true signal. KCTD16 participates in potassium ion transport and YIPF5 plays a role in transport between endoplasmic reticulum and the Golgi apparatus. GW significant hits also were found within the CCNH 3′ region within a block of strong LD; the strongest association was with rs840836 (P=2.90E-11). CCNH encodes a protein that belongs to the highly conserved cyclin family. Cyclins function as regulators of cyclin-dependent kinases and may be an important link between basal transcription control and the cell cycle machinery. Finally, rs9658574 within nitric oxide synthase 1 (NOS1) was identified (p=5.9E-08). NOS1 has diverse functions, but is implicated in neural regulation of smooth muscle as well as having a role in regulating blood pressure. The identified candidates’ functions seem plausible, and their association warrant replication and further study.