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Linkage of left ventricular contractility to chromosome 11 in humans: The HyperGEN Study
D K Arnett1, R B Devereux, D Kitzman
1Division of Epidemiology, University of Minnesota, Minneapolis, USA. arnett@epi.umn.edu
Insights
Researchers identified a significant gene linkage on chromosome 11 associated with impaired left ventricular (LV) contractility in Black individuals. This finding may reveal genetic factors contributing to heart failure and cardiovascular death.
Area of Science:
- Cardiovascular Genetics
- Human Genetics
- Molecular Cardiology
Background:
- Impaired left ventricular (LV) contractility is a primary driver of cardiovascular mortality, particularly congestive heart failure.
- Identifying genetic susceptibility factors is crucial for understanding the mechanisms of LV contractile dysfunction and heart failure development.
Purpose of the Study:
- To identify genes contributing to impaired left ventricular contractility using a large, biethnic sample of hypertensive siblings.
- To investigate the genetic underpinnings of left ventricular contractile function in relation to cardiovascular health.
Main Methods:
- Echocardiographic measurements of myocardial contractility were collected from hypertensive siblings within the Hypertension Genetic Epidemiology Network (HyperGEN).
- Multipoint variance components linkage analysis was performed using GENEHUNTER2 and 387 anonymous markers.
- Statistical adjustments were made for gender, age, and age squared, with standardized residuals calculated separately for men and women in both ethnic groups.
Main Results:
- Significant linkage (lod, 3.93) was detected for marker D11S1993 on chromosome 11 in Black individuals, accounting for 72% of LV contractility variation.
- Suggestive evidence for linkage (lod, 2.83) was found on chromosome 22 in White individuals.
- The chromosome 11 linkage region is near the myosin-binding protein C gene, known to be associated with familial hypertrophic cardiomyopathy.
Conclusions:
- A specific region on chromosome 11 shows strong genetic linkage with left ventricular contractility in Black populations.
- This region likely harbors a critical gene influencing impaired left ventricular contractility.
- Further research into this chromosomal region may uncover novel therapeutic targets for heart failure.
Abstract:
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 age(2), 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), approximately 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.