A Quantitative Trait Locus on Chromosome 16q Influences Variation in Plasma HDL-C Levels in Mexican Americans

Abstract

Objective-We conducted a whole-genome, multipoint linkage screen to localize a previously reported major locus accounting for 56% to 67% of the additive genetic effects on covariate-adjusted plasma HDL cholesterol (HDL-C) levels in Mexican Americans from the San Antonio Family Heart Study (SAFHS). Methods and Results-After using complex segregation analysis to recover the major locus in 472 SAFHS participants from 10 genotyped families, we incorporated covariates required to detect that major locus, including plasma levels of triglycerides and apolipoprotein A-I, in a maximum-likelihood-based variance-components linkage screen. Only chromosome 16 exhibited convincing evidence for a quantitative trait locus (QTL), with a peak multipoint log of the odds (LOD)ϭ3.73 (Pϭ0.000034). Subsequent penetrance model-based linkage analysis, incorporating genotypes at the marker locus nearest the multipoint peak (D16S518) into the segregation model, detected linkage with the previously detected major locus (LODϭ2.73, Pϭ0.000642). Initial estimates place this QTL within a 15-cM region of chromosome 16q near the structural loci for lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP). Key Words: HDL Ⅲ genome screen Ⅲ linkage Ⅲ heritability Ⅲ Mexican Americans W e previously reported a major locus influencing quantitative variation in plasma HDL cholesterol (HDL-C) levels in Mexican-American families from the San Antonio Family Heart Study (SAFHS). 1 This major-locus effect, accounting for 56% to 67% of the additive genetic variance in HDL-C in those families, was detected only when the effects of age and sex terms plus plasma levels of apolipoprotein A-I (apo A-I) and triglycerides (TG), exogenous sex hormone use, and menopause status were included in the complex segregation analysis model for the trait. In males and females, respectively, the major locus accounted for 11% and 4% of the total phenotypic variance in plasma total HDL-C levels and for 55% and 21% of the residual phenotypic variance, ie, the proportion of the phenotypic variance not attributable to the effects of covariates. Because genotype data were not available for a whole-genome linkage screen when this major locus first was detected, we attempted to identify a locus responsible for this effect by means of combined segregation and linkage analysis with genotype data for likely candidate loci. Results of these analyses 1 were both definitive and negative, excluding linkage between the major locus for residual HDL-C and structural loci for several proteins of lipoprotein metabolism, namely, APOA-I, APOB, LDLR, LIPC, and LPL, on chromosomes 11q, 2p, 19p, 15q, and 8p, respectively. Conclusions-A QTL influencing plasma levels of HDL-C inAlthough subsequent analyses of data from the SAFHS and other studies have mapped quantitative trait loci (QTLs) for HDL-C-related measures to chromosome 1q 2 , chromosome 13q, 3,4 and chromosome 9p 5 , other reports localize HDL-Crelated QTLs to some chromosomal regions containing candidate loci ...

Multiple genetic determinants of plasma lipid levels in Caribbean Hispanics

“…These 10 significant genes, which were previously related to the lipid variation in whites and blacks, displayed similar biological effects in this Hispanic population. Previous genetic studies in the Hispanic population mostly focused on Mexican Americans rather than Caribbean Hispanics [7,8,24]. Our study presented valuable information for this under-investigated, but rapidly growing population.…”

“…Several genes, such as the apolipoprotein A5 (APOA5), apolipoprotein B (APOB), apolipoprotein E (APOE), and cholesterol ester transfer protein (CETP) genes, have been reported to be related to the lipid profiles in whites and blacks [2][3][4][5]. However, only few of them (APOA5, APOE, and CETP) have been investigated in Hispanics [6][7][8].…”

Genetic causes of high and low serum HDL-cholesterol

“…This region is the most consistently replicated region for HDL-C (91)(92)(93)(94). Using HapMap data, we selected nonredundant tag-SNPs to explore the contribution of common variation within the 12.5 Mb-linked region to HDL-C levels.…”

“…However, these studies have been diffi cult to interpret, because there is little overlap within these fi ndings ( 87 ). Chromosomal regions implicated by more than one study ( 88 ) are more plausible, of which the chromosome 16q locus represents the most consistently replicated region (91)(92)(93)(94). Nevertheless, linkage studies suggest that many different loci contribute to HDL-C levels and that the effect of most genes is too small or content dependent (i.e., genetic heterogeneity) to be detected by independent and heterogeneous study samples.…”

Genome-wide Linkage Study for Plasma HDL Cholesterol Level in an Isolated Population of Mongolia

“…These studies focused on families with extreme HDL cholesterol levels (Shoulders, Jones, and Naoumova 2004;Aouizerat et al 1999). Our study as did some others, examined families with members having serum HDL cholesterol within the normal range (Mahaney et al 2003;Pajukanta et al 2003;Arya et al 2002). When homogenous populations are studied, environmental variations might be lower and the genetic makeup of these populations less complex (Coon et al 2001).…”