Linkage of low-density lipoprotein size to the lipoprotein lipase gene in heterozygous lipoprotein lipase deficiency

Small low-density lipoprotein (LDL) particles area genetically influenced c oronary disease risk factor. Lipoprotein lipase (LpL) is a rate-limiting en zyme in the formation of LDL particles. The current study examined genetic linkage of LDL particle size to the LpL gene in five families with structur al mutations in the LpL gene. LDL particle size was smaller among the heter ozygous subjects, compared with controls, Among heterozygous subjects, 44% were classified as affected by LDL subclass phenotype B, compared with 8% o f normal family members. Plasma triglyceride levels were significantly high er, and high-density lipoprotein cholesterol (HDL-C) levels were lower, in heterozygous subjects, compared with normal subjects, after age and sex adj ustment. A highly significant LOD score of 6.24 at theta = 0 was obtained f or linkage of LDL particle size to the LpL gene, after adjustment of LDL pa rticle size for within-genotype variance resulting from triglyceride and HD L-C. Failure to adjust for this variance led to only a modest positive LOD score of 1.54 at theta = 0. Classifying small LDL particles as a qualitativ e trait (LDL subclass phenotype B) provided only suggestive evidence for li nkage to the LpL gene (LOD = 1.65 at theta = 0). Thus, use of the quantitat ive trait adjusted for within-genotype variance, resulting from physiologic covariates, was crucial for detection of significant evidence of linkage i n this study. These results indicate that heterozygous LpL deficiency may b e one cause of small LDL particles and may provide a potential mechanism fo r the increase in coronary disease seen in heterozygous LpL deficiency. Thi s study also demonstrates a successful strategy of genotypic specific adjus tment of complex traits in mapping a quantitative trait locus.