Abstract 2320: A Genome-wide Scan Identifies Novel And Known DNA Variants Associated With Component Phenotypes Of Metabolic Syndrome
Background: The metabolic syndrome and its component phenotypes of obesity, dyslipidemia, hypertension, impaired glucose tolerance and diabetes are major risk factors for heart disease and stroke. To identify common genetic variants associated with metabolic syndrome and its component risk factors, we performed a three-stage association study, genotyping 12,344 individuals from three ethnic groups.
Methods: Stage one consisted of two genome-wide scans of >240,000 SNPs in 1006 Indian Asian and 1005 European men. Analyses of these scans were used to select 5764 SNPs for a second stage of genotyping in 4569 Europeans, Indian Asians and Mexicans. Replication of 40 SNPs was performed in a third stage in 5968 individuals of European ancestry.
Results: We observed and replicated a highly significant association between triglycerides and a non-synonymous SNP in a glucose sensitive transcriptional factor which regulates lipogenesis, triglyceride synthesis and VLDL secretion (P<10–7 in replication phase). Median triglyceride levels were 2.07, 1.96, and 1.75 mmol/l in subjects with CC, CG and GG genotypes respectively, and the SNP conferred an odds ratio (OR) for hypertriglyceridaemia of 1.29 per copy of the high risk allele. The SNP accounts for 0.43% of the variance in log triglyceride levels. We separately confirmed associations with genes previously reported to be associated with either HDL cholesterol or triglyceride levels including CETP, LPL, LIPC, ABCA1, and an apolipoprotein cluster.
Conclusion: We have identified a novel genetic variant determining plasma triglyceride levels in man. The polymorphism identified underscores the importance of pathways involved in channeling glucose into lipogenesis and fat storage.