LINKAGE ANALYSIS OF THE GENETIC-DETERMINANTS OF HIGH-DENSITY-LIPOPROTEIN CONCENTRATIONS AND COMPOSITION - EVIDENCE FOR INVOLVEMENT OF THE APOLIPOPROTEIN A-II AND CHOLESTERYL ESTER TRANSFER PROTEIN LOCI

We have tested for evidence of linkage between the genetic loci determ ining concentrations and composition of plasma high density lipoprotei ns (HDL) with the genes for the major apolipoproteins and enzymes part icipating in lipoprotein metabolism. These genes include those encodin g various apolipoproteins (ape), including apoA-I, apoA-II, apoA-IV, a poB, apoC-I, apoC-II, apoC-III, apoE, and apo(a), cholesteryl ester tr ansfer protein (CETP), HDL-binding protein, lipoprotein lipase, and th e low density lipoprotein (LDL) receptor. Polymorphisms of these genes , and nearby highly polymorphic simple sequence repeat markers, were e xamined by quantitative sib-pair linkage analysis in 30 coronary arter y disease families consisting of a total of 366 individuals. Evidence for linkage was observed between a marker locus D16S313 linked to the CETP locus and a locus determining plasma HDL-cholesterol concentratio n (P = 0.002), and the genetic locus for apoA-II and a locus determini ng the levels of the major apolipoproteins of HDL, apoA-I and apoA-II (P = 0.009 and 0.02, respectively). HDL level was also influenced by t he variation at the apo(a) locus on chromosome 6 (P = 0.02). Thus, the se data indicate the simultaneous involvement of at least two differen t genetic loci in the determination of the levels of HDL and its assoc iated lipoproteins.