Linkage of left ventricular contractility to chromosome 11 in humans: The hyperGEN study

Impaired left ventricular (LV) contractility is a major cause of cardiovascular death, especially congestive heart failure. The identification of susceptibility genes that contribute to impaired LV contractility may uncover mechanisms underlying LV contractile impairment and the development of congestive heart failure. The Hypertension Genetic Epidemiology Network (HyperGEN) collected echocardiographic measurements of myocardial contractility in a large biethnic sample of hypertensive siblings (390 blacks and 398 whites in 179 and 165 sibships, respectively). All participants expressed hypertension before age 60 years, and the mean age of siblings was 52 years in blacks and 61 years in whites. We adjusted myocardial contractility for gender, age, and age², and we calculated standardized residuals separately for men and women in both ethnic groups. We conducted multipoint variance components linkage analysis using GENEHUNTER2 and 387 anonymous markers (CHCL8 marker set). We found evidence for significant linkage to a microsatellite marker, D11S1993 (lod, 3.93 in blacks), ≈54 cM from the tip of the short arm of chromosome 11, that accounted for 72% of the phenotypic variation in LV contractility. A chromosome 22 locus showed suggestive evidence for linkage (lod, 2.83 in whites and 1.15 in blacks). The chromosome 11 peak coincides with the region containing myosin-binding protein C. Mutations in this gene are linked to familial hypertrophic cardiomyopathy. Our results show strong evidence for linkage of a region of chromosome 11 with LV contractility in blacks and suggest that an important gene for impaired LV contractility is harbored in this region.