Heart disease remains the major cause of death and morbidity in the US. Reduction in the risk factors for heart disease remains a priority for Healthy People 2000. One of these risk factors is cholesterol. Understanding the factors that normally regulate net dietary cholesterol intake may allow us to reduce the impact of this risk factor. One such factor may the gene that is responsible for causing the autosomal recessive disease, sitosterolemia (OMIM 210250). The purpose of this study is to identify, map, and clone and characterize the biology of this gene. This gene is hypothesized to play a key role in regulating the absorption of cholesterol from the diet and its excretion from the body via the bile. Sitosterolemia is characterized by a marked elevation of plant sterols in the blood, resulting in tendon xanthomas, premature coronary artery disease and death. Knowledge of the genetic mechanisms underlying these biological processes may allow us to explore ways to manipulate cholesterol absorption and excretion through the activities of this gene product and thus control plasma cholesterol levels. 27 well-characterized family pedigrees have been assembled, providing considerable power to map and localize of the gene defect. Following the exclusion of a number of candidate genes, a genome-wide scan has been performed. The gene has been mapped to chromosome 2p21, with a maximum lodscore of 4.6. Fine mapping and haplotype analyses has narrowed the sitosterolemia locus to within a region approximately 2 cM in size. Additional families will be recruited and analyzed for evidence of recombination within this region to help further narrow this critical region. Once a suitably narrow region has been defined, cDNAs mapping to this region will be identified and used as candidate genes to allow us to identify the defective gene. The identification of this gene defect will not only allow characterization of the mutations that cause sitosterolemia, but will also provide the basis for in vitro expression studies to define some of this gene's normal functions in sterol absorption and excretion. This knowledge will allow us to test the hypothesis that the normal function of this gene product is to tightly regulate net dietary cholesterol absorption.
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