Identification of a common variant in the lipoprotein lipase gene in a large Utah kindred ascertained for coronary heart disease: the-93G/D9N variantpredisposes to low HDL-C/high triglycerides

Defects in the lipoprotein lipase (LPL) gene are associated with dyslipidem ia in the general population. Several rare mutations in the gene, as well a s two common coding region polymorphisms, D9N and N291S, exhibit deleteriou s effects on circulating lipid levels. Using a linkage-based approach, we h ave identified a large Utah kindred segregating the D9N variant in the LPL gene. The kindred was ascertained for premature coronary heart disease and was expanded based on familial dyslipidemia. A genomic scan identified a re gion of linkage including LPL, and mutation screening identified the segreg ating variant. In the kindred, the variant shows high penetrance for a hypo alphalipoproteinemia phenotype, but is also associated with hypertriglyceri demia and elevated insulin levels. The strength of linkage was dependent on the combination of phenotype definition and model parameters, favoring the use of a MOD score approach. Most other studies of LPL have proceeded by m utation screening of randomly chosen individuals or selected affected proba nds; this is the first example identifying a segregating LPL mutation using direct linkage.