FA 5 Progress Report WV-INBRE - Joan C. Edwards School of ...

Program Director/Principal Investigator (Last, First, Middle): Rankin, Gary O 59GENETIC BASIS FOR FAMILIAL COMBINED HYPERLIPIDEMIA (FCHL) (0026)TYPE: Research Subproject%IDeA $: 1.000% IDeA $: 22,500INVESTIGATOR, DEGREEPrimerano, Donald A PHDBaria, Kim RNDementieva, Yulia PHDDenvir, James PHDFan, Jun BS, PHDHenderson, Angela RNNeal, William MDOmar, Hatim FAAP, MDDEPARTMENTBiochemistry &MicrobiologyHealth Research AndEducationMathematicsBiochemistry AndMicrobiologyBiochemistry &MicrobiologyClinical TrialsPediatric CardiologyPediatricsNON-HOST INSTITUTION: STATE,COUNTRYCharleston Area Medical Center, WvUsaEmmanuel College, Ma UsaCharleston Area Medical Center, WvUsaWest Virginia University , Wv UsaUniversity Of Kentucky, Ky UsaTotal # human subjects expected for entire study: 500Total # human subjects enrolled to date: 363SUBPROJECT DESCRIPTIONFamilial Combined Hyperlipidemia (FCHL) is generally defined by elevation of LDL cholesterol andtriglycerides. FCHL affects 0.5-2% of the population of Westernized societies and is one of the mostcommon genetic lipid disorders in patients with coronary artery disease. Recent segregation analyses andlinkage studies suggest an oligogenic mode of inheritance. Our long-range goal is to gain an understandingof the molecular and cellular events that lead to disregulation of cholesterol and triglyceride levels. Theoverall objective of this project is to identify gene(s) that predispose to FCHL using family-based linkageanalysis and association methods. By studying juvenile-based families we hope to identify a form of thedisease with higher heritability. We will also study families that are based on affected adults. The centralhypotheses are that there are specific genes that confer susceptibility to FCHL and that novel gene defectscontribute to juvenile FCHL. The rationale is that once these susceptibility genes have been identified, wewill better understand the molecular pathogenesis in individuals and be able to provide rational, personalizedtreatments or preventative measures can be implemented and tailored to the actual genetic defect. We planto accomplish the objective of this application by pursuing the following two specific aims:1. Identify novel FCHL loci by linkage analysis on a genome-wide set of markers.2. Perform genetic fine mapping on the susceptibility loci in order to narrow the region of interest andidentify variants that encode defective products.The proposed work is innovative because we will analyze Appalachian families based on affected juvenilepatients. These patients have greater genetic risk of developing CVD than adult FCHL patients. It is ourexpectation that this analysis will uncover novel loci and specific genes at those loci that contribute to thedevelopment of FCHL. Our findings will be significant because they will further our understanding of thepathogenesis of vascular disease and because these susceptibility genes represent new targets forpreventative and therapeutic interventions.SUBPROJECT PROGRESSFCH Progress Report Y111. IntroductionFamilial Combined Hyperlipidemia (FCH) is a complex genetic disease in which affected familyPHS 2590 (Rev. 06/09)Continuation Format Page