The abdominal obesity metabolic syndrome is recognized as a major risk profile for several morbidities including cardiovascular disease with major economic cost. In search for the genetic etiology of this syndrome we have identified a quantitative trait locus (QTL) on Chromosome 3 (3q27). This QTL has been replicated across several racial groups. The objective of this project is to identify the role of two novel positional genes in this QTL, APM1 and PR0227, in the pathophysiology of this syndrome, we test for two complimentary hypotheses. Hypothesis 1 states that polymorphisms of these two genes could influence expression of basic and refined phenotypes of this syndrome. To test for this hypothesis we comprehensively resequence the two genes to identify all their polymorphisms in 25 sib pairs selected to be discordant for the QTL and for obesity and insulin resistance. Identified polymorphisms are then tested in all individual members of the families that contributed to observed QTL. The Bayesian Quantitative Trait Nucleartide Analysis method is utilized to determine those functional polymorphisms associated with the basic and refined phenotypes of this syndrome. Whether these polymorphyisms adequately account for the observed QTL is also evaluated. Hypothesis 2 states that polymorphisms in APM1 and PRO2207 influence target tissues mRNA levels of the candidate and cooperatively co-expressed genes. This hypothesis is tested by obtaining adipose and skeletal muscle biopsies from the 25 discordant sibs, both basely and after induction of steady state hyperinsulinemic enuglycemia. Quantitative microarray and rt PCR procedures are used to determine the dynamics of gene expression in the target tissues. The transcriptomic search modification of the Bayesian procedure method are used to identify influences of the candidate genes Detailed description of primary biologic pathways underlying the pathogenesis of the metabolic syndrome obtained in the 25 sibs. Associations between the identified APM1 and PRO227 polymorphisms, tissue gene expression profiles and perturbation in the biologic pathways is evaluated. The strength of this application rests upon the tri-consortium of experts in human biology at the Medical College of Wisconsin, in molecular genetics at Deakin University and in genetic statistics at Southwestern Foundation for Biomedical Research. These efforts should unravel novel knowledge into the genetic basis of this syndrome.
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