GENETIC-REGULATION OF CHOLESTEROL HOMEOSTASIS - CHROMOSOMAL ORGANIZATION OF CANDIDATE GENES

As part of an effort to dissect the genetic factors involved in choles terol homeostasis in the mouse model, we report the mapping of 12 new candidate genes using linkage analysis. The genes include: cytoplasmic HMG-CoA synthase (Hmgcs 1, Chr 13), mitochondrial synthase (Hmgcs 2, Chr 3), a synthase-related sequence (Hmgcs 1-rs, Chr 12), mevalonate k inase (Mvk, Chr 5), farnesyl diphosphate synthase (Fdps, Chr 3), squal ene synthase (Fdft 1, Chr 14), acyl-Coa:cholesterol acyltransferase (A cact, Chr 1), sterol regulatory element binding protein-1 (Srebf 1, Ch r 8) and -2 (Srebf 2, Chr 15), apolipoprotein A-I regulatory protein ( Tcfcoup 2 Chr 7), low density receptor-related protein-related sequenc e (Lrp-rs, Chr 10), and Lrp-associated protein (Lrpap 1, Chr 5). In ad dition, the map positions for several lipoprotein receptor genes were refined. These genes include: low density lipoprotein receptor (Ldlr, Chr 9), very low density lipoprotein receptor (Vldlr, Chr 19), and gly coprotein 330 (Gp 330, Cur 2). Some of these candidate genes are locat ed within previously defined chromosomal regions (quantitative trait l oci, QTLs) contributing to plasma lipoprotein levels, and Acact maps n ear a mouse mutation, ald, resulting in depletion of cholesteryl ester s in the adrenals. The combined use of QTL and candidate gene mapping provides a powerful means of dissecting complex traits such as cholest erol homeostasis.