Metabolic syndrome (MetS), a constellation of risk factors associated with development of cardiovascular disease and Type 2 diabetes, has reached epidemic proportions in western industrialized nations. About 47 million Americans have MetS. Consequently, it has enormous impact on public health. The hallmark of MetS is a co-occurrence of obesity, dyslipidemia, carbohydrate intolerance and high blood pressure. Familial aggregation of the individual components and the composite MetS trait suggests involvement of genetic factors. However, our knowledge concerning the genetic factors underlying MetS remains largely incomplete. We propose to undertake a thorough investigation on epidemiology and genetics of MetS in an isolated population from the island of Hvar in the eastern Adriatic coast of Croatia. The value of isolated population in complex disease gene mapping has been widely documented. The study population has a high prevalence of MetS, is ethnically relevant to the general US population, with its distinct evolutionary history of recent founding by small number of Slavic founders, geographic isolation, environmental homogeneity, extended family sizes provides a unique opportunity to understand the genetics of MetS. We propose to (1) recruit 1200 individuals above 20 years of age from five villages of Hvar, collect demographic, environmental, life-style, phenotypic, relevant clinical data, and blood samples for analysis of biochemical traits and DNA;(2) conduct appropriate analyses to estimate the effects of genetic contribution to the variability of MetS as a composite trait and its constituent phenotypes;(3) conduct a whole genome scan using a panel of densely spaced, 10K, SNP markers for linkage analysis;(4) followed by pedigree-based association studies using a 'positional candidate'approach in the regions of significant linkage for identification of genetic variants associated with MetS. The study has enormous public health importance and its scientific merit is substantial with the potential of understanding the genetic etiology of MetS. We will study an ideal population for this research;our use of dense SNP markers for linkage and association is a state-of-the-art approach and has enormous promise for identifying loci and gene variants underlying MetS.
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