Identification of genetic variants influencing plasma lipid levels in the population isolate of Kosrae by whole genome approaches and characterization of their functional role in metabolism

Dyslipidemia is a primary risk factor for atherosclerotic cardiovascular disease, the major cause of morbidity and mortality in the industrialized countries today. Susceptibility to common forms of dyslipidemias follows complex genetic traits and is dependent upon interactions between multiple genes and environmental influences. Our knowledge about the polygenetic background of the various forms of common dyslipidemias is still limited. Genome wide association studies represent a promising approach for gene discovery in such complex traits. The aim of this proposal is to identify genetic variants influencing lipid phenotypes in the isolate population of the island of Kosrae (Federated States of Micronesia), using a whole genome approach. Dyslipidemia, as well as other metabolic risk factors for cardiovascular disease are endemic in this population and its isolation provides an ideal setting for such genetic studies, because of reduced genetic complexity. A whole genome scan with 500k SNP arrays is currently being performed on 3212 islanders. Family based association testing will be applied to determine SNPs associated with plasma lipid and lipoprotein levels. High-density SNP mapping, haplotype analysis and resequencing will be conducted to identify the causative genes. Finally, their association with disease phenotypes in other populations, as well as their functional significance in lipid pathways both in vitro and in vivo will be tested. The expected results of the proposed project will give rise to a better understanding of the molecular basis, as well as the development of novel diagnostic and therapeutic strategies in the prevention of atherogenic dyslipidemias.