Joint Linkage and Association Analysis of Hepatic Lipase Promoter Polymorphism and Lipoprotein Size Phenotypes
The hepatic lipase gene (LIPC) has repeatedly been implicated as a potential regulator of HDL cholesterol concentration and HDL and LDL particle size. Association studies have centered on a C to T transition in the promoter of LIPC, 514 base-pairs upstream of the transcription initiation site. We performed a genome-wide linkage screen for several lipoprotein size phenotypes and tested for association of these traits with LIPC -514C->T in 798 individuals from 23 families in the San Antonio Family Heart Study. Median diameter was measured for HDL particles stained for apoAI (A1), apoAII (A2), unesterified (UC), and esterified (EC) cholesterol as well as for LDLs stained for EC. A subset of 479 people in 10 of the largest families was genotyped for a 10 cM genetic map, including 19 markers on chromosome 15. Variance component-based multipoint linkage analyses (using all available markers), measured genotype association analyses (with LIPC -514C->T), and joint linkage/association analyses were performed with SOLAR. Median diameter of HDL-A1 and HDL-UC exhibited significant evidence of linkage to the LIPC region (LODs = 3.79 and 3.56 respectively) whereas HDL-A2, HDL-EC, and LDL-EC sizes showed suggestive evidence of linkage (LODs of 1.78 to 2.71). Association with -514C->T was detected for HDL-A1, HDL-A2, HDL-UC, and HDL-EC median diameters (p < 0.001) but not for LDL-EC median diameter. If -514C->T is the functional site within LIPC responsible for the observed linkages and associations, the LOD score will drop to 0 when -514C->T is included in the trait model. Conversely, if -514C->T is in linkage disequilibrium with another site or is one of several functional sites, evidence for linkage will remain in the joint analyses. Linkage analyses of HDL-A1 and HDL-UC sizes conditional on -514C->T reduced the LOD scores in the LIPC region only slightly (LODs of 3.16 and 3.49 respectively). This suggests that the -514C->T polymorphism can not explain the observed linkage of lipoprotein size phenotypes to the LIPC region and, therefore, that there are one or more additional functional mutations in or near LIPC influencing HDL, and potentially LDL, size variation.