A genome-wide linkage scan identifies multiple quantitative trait loci for HDL-cholesterol levels in families with premature CAD and MI

Abstract

Plasma HDL cholesterol levels (HDL-C) are an independent predictor of coronary artery disease (CAD). We have completed a genome-wide linkage scan for HDL-C in a US cohort consisting of 388 multiplex families with premature CAD (GeneQuest). The heritability of HDL-C in GeneQuest was 0.37 with gender and age as covariates (P = 5.1 x 10(-4)). Two major quantitative trait loci (QTL) for log-transformed HDL-C adjusted for age and gender were identified onto chromosomes 7p22 and 15q25 with maximum multipoint logarithm of odds (LOD) scores of 3.76 and 6.69, respectively. Fine mapping decreased the 7p22 LOD score to a nonsignificant level of 3.09 and split the 15q25 QTL into two loci, one minor QTL on 15q22 (LOD = 2.73) that spanned the LIPC gene, and the other at 15q25 (LOD = 5.63). A family-based quantitative transmission disequilibrium test (QTDT) revealed significant association between variant rs1800588 in LIPC and HDL-C in the GeneQuest population (P = 0.0067), which may account for the minor QTL on 15q22. The 15q25 QTL is the most significant locus identified for HDL-C to date, and these results provide a framework for the ultimate identification of the underlying HDL-C variant and gene on chromosomes 15q25, which will provide insights into novel regulatory mechanisms of HDL-C metabolism.

Fig. 1.

Distribution of the HDL-C concentrations [HDL-C] (A) and log transformed HDL-C concentrations (B) in the study population. HDL-C, high density lipoprotein cholesterol.

Fig. 2.

Likelihood plots for QTLs for HDL-C adjusted for age and gender. The Y-axis of each plot is the LOD score; the X-axis is the marker map position. Solid lines represent the multipoint linkage analysis; horizontal dashed lines indicate the significance threshold which is equal to a LOD score value of 3.6. Significant linkages to chromosomes 3p25, 7p22, 13q12, 13q32, and 15q25 were detected with multipoint allele sharing LOD scores of 4.10, 4.21, 4.66, 3.95, and 7.57, respectively. HDL-C, high density lipoprotein cholesterol; LOD, logarithm of odds; QTL, quantitative trait locus.

Fig. 3.

Detailed likelihood plots for significant QTLs for HDL-C on chromosomes 3p25, 7p21, 13q12, 13q32, and 15q25. The Y-axis of each plot is the LOD score; the X-axis is the marker map position. Solid lines represent the multipoint linkage analysis; horizontal dashed lines indicate the significance threshold which is equal to a LOD score value of 3.6. HDL-C, high density lipoprotein cholesterol; LOD, logarithm of odds; QTL, quantitative trait locus.

Fig. 4.

Likelihood plots for QTLs for log-transformed HDL-C adjusted for age and gender. Horizontal dashed lines indicate the significance threshold which is equal to a LOD score value of 3.6. HDL-C, high density lipoprotein cholesterol; LOD, logarithm of odds; QTL, quantitative trait locus.

Fig. 5.

Detailed likelihood plots for significant QTLs for log transformed HDL-C on chromosomes 7p21 and 15q25 adjusted for age and gender. Horizontal dashed lines indicate the significance threshold which is equal to a LOD score value of 3.6. HDL-C, high density lipoprotein cholesterol; LOD, logarithm of odds; QTL, quantitative trait locus.

Fig. 6.

Fine mapping of the 7p22 and 15q25 QTLs for log transformed HDL-C adjusted for age and gender. Horizontal dashed lines indicate the significance threshold which is equal to a LOD score value of 3.6. HDL-C, high density lipoprotein cholesterol; LOD, logarithm of odds; QTL, quantitative trait locus.