Abstract
BackgroundLeft ventricular mass (LVM) is an important risk factor for stroke and vascular disease. The genetic basis of LVM is unclear although a high heritability has been suggested. We sought to map quantitative trait loci (QTL) for LVM using large Dominican families.MethodsProbands were selected from Dominican subjects of the population-based Northern Manhattan Study (NOMAS). LVM was measured by transthoracic echocardiography. A set of 405 microsatellite markers was used to screen the whole genome among 1360 subjects from 100 Dominican families who had complete phenotype data and DNA available. A polygenic covariate screening was run to identify the significant covariates. Variance components analysis was used to estimate heritability and to detect evidence for linkage, after adjusting for significant risk factors. Ordered-subset Analysis (OSA) was conducted to identify a more homogeneous subset for stratification analysis.ResultsLVM had a heritability of 0.58 in the studied population (p < 0.0001). The most significant evidence for linkage was found at chromosome 12p11 (MLOD = 3.11, empirical p = 0.0003) with peak marker at D12S1042. This linkage was significantly increased in a subset of families with the high average waist circumference (MLOD = 4.45, p = 0.0045 for increase in evidence for linkage).ConclusionWe mapped a novel QTL near D12S1042 for LVM in Dominicans. Enhanced linkage evidence in families with larger waist circumference suggests that gene(s) residing within the QTL interact(s) with abdominal obesity to contribute to phenotypic variation of LVM. Suggestive evidence for linkage (LOD = 1.99) has been reported at the same peak marker for left ventricular geometry in a White population from the HyperGEN study, underscoring the importance of this QTL for left ventricular phenotype. Further fine mapping and validation studies are warranted to identify the underpinning genes.
Highlights
Left ventricular mass (LVM) is an important risk factor for stroke and vascular disease
We have demonstrated that LVM is significantly associated with an increased risk of stroke and combined vascular events in a multi-ethnic cohort comprised predominately of Hispanics [4]
All subjects provided informed consent to participate in the study and the study was approved by the Institutional Review Boards of Columbia University, University of Miami, and the National Bioethics Committee and the Independent Ethics Committee of Instituto Oncologico Regional del Cibao in the Dominican Republic (DR)
Summary
Left ventricular mass (LVM) is an important risk factor for stroke and vascular disease. Studies have shown that a positive family history is a strong predictor of stroke, even after adjustment for traditional risk factors, suggesting the existence of a substantial genetic component [2]. Given the extreme complexity of genetic and environmental contributions to stroke, evaluation of the precursor (risk) phenotypes, especially the quantitative ones, may reduce heterogeneity and increase statistical power for susceptibility gene discovery. Our Family Study of Stroke Risk and Carotid Atherosclerosis is uniquely designed to evaluate genetic contribution to cerebrovascular risk phenotypes, such as carotid intimamedia thickness and left ventricular mass (LVM). We have demonstrated that LVM is significantly associated with an increased risk of stroke and combined vascular events in a multi-ethnic cohort comprised predominately of Hispanics [4]. The adjusted hazard ratio for the combined endpoint of myocardial infarction, stroke, or vascular death was 1.34 per one standard deviation (SD) increase in LVM [95% CI 1.10 to 1.63]
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