Abstract
We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia. The most significant evidence for linkage to TG levels was found in a subset of Turkish families at 11q22 [logarithm of the odds ratio (LOD)=3.34] and at 17q12 (LOD=3.44). We performed sequential oligogenic linkage analysis to examine whether multiple QTLs jointly influence TG levels in the Turkish families. These analyses revealed loci at 20q13 that showed strong epistatic effects with 11q22 (conditional LOD=3.15) and at 7q36 that showed strong epistatic effects with 17q12 (conditional LOD=3.21). We also found linkage on the 8p21 region for TG in the entire group of families (LOD=3.08). For HDL-C levels, evidence of linkage was identified on chromosome 15 in the Turkish families (LOD=3.05) and on chromosome 5 in the entire group of families (LOD=2.83). Linkage to QTLs for TC was found at 8p23 in the entire group of families (LOD=4.05) and at 5q13 in a subset of Turkish and Mediterranean families (LOD=3.72). These QTLs provide important clues for the further investigation of genes responsible for these complex lipid phenotypes. These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci.
Highlights
We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia
Atherogenic dyslipidemia is a combination of high triglyceride (TG) and low high density lipoprotein-cholesterol (HDL-C) concentrations often concomitant with high low density lipoprotein-cholesterol (LDL-C) and high total cholesterol (TC) levels [1, 2]
Hypertriglyceridemia and decreased HDL-C levels (р40 mg/dl) are two important components of the metabolic syndrome, a condition associated with increased risk for atherosclerotic cardiovascular disease (CVD) [3,4,5,6]
Summary
The GEMS Project is a large, international, and family-based study designed to explore the genetic basis of the metabolic syndrome and its constituent phenotypes. Families containing at least one individual showing evidence of atherogenic dyslipidemia (plasma TG у 75th percentile and serum HDL-C р 25th percentile, both adjusted for age, gender, and population of origin) were ascertained from six centers in Adelaide (Australia), Ottawa (Canada), Oulu (Finland), Lausanne (Switzerland), Istanbul (Turkey), and Dallas (United States). A total of 1,222 subjects including probands were affected. To calculate and assign proper marker allele frequencies in the linkage analysis, families were classified on the basis of their ethnic background as European (presumed European ancestry for individuals living in Switzerland, Canada, Australia, and the United States), Finns (those living in Finland), and Turk/Mediterranean. The Turk/Mediterranean group included 39 families residing in Turkey and 21 other families recruited in Ottawa and Adelaide. The study protocol was approved on a yearly basis by the institutional review board at each participating institution
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