MULTILOCUS GENETIC-DETERMINANTS OF LDL PARTICLE-SIZE IN CORONARY-ARTERY DISEASE FAMILIES

Recent interest in atherosclerosis has focused on the genetic determin ants of low-density lipoprotein (LDL) particle size, because of (i) th e association of small dense LDL particles with a three-fold increased risk for coronary artery disease (CAD) and (ii) the recent report of linkage of the trait to the LDL receptor (chromosome 19). By utilizing nonparametric quantitative sib-pair and relative-pair-analysis method s in CAD families, we tested for linkage of a gene or genes controllin g LDL particle sizes with the genetic loci for the major apolipoprotei ns and enzymes participating in lipoprotein metabolism. We confirmed e vidence for linkage to the LDL receptor locus (P = .008). For six cand idate gene loci, including apolipoprotein(apo)B, apoAII, apo(a), apoE- CI-CII, lipoprotein lipase, and high-density lipoprotein-binding prote in, no evidence for linkage was observed by sib-pair linkage analyses (P values ranged from .24 to .81). However, in addition, we did find t entative evidence for linkage with the apoAI-CIII-AIV locus (chromosom e 11) (P = .06) and significant evidence for linkage of the cholestery l ester transfer protein locus (chromosome 16) (P = .01) and the manga nese superoxide dismutase locus (chromosome 6) (P = .001), thus indica ting multilocus determination of this atherogenic trait.