Genome-Wide Linkage Analysis of Lipids in the Hypertension Genetic Epidemiology Network (HyperGEN) Blood Pressure Study

Abstract

Abstract-Full genome scans were performed for quantitative lipid measurements in 622 African American and 649 white sibling pairs not taking lipid-lowering medications who were ascertained through the Hypertension Genetic Epidemiology Network (HyperGEN) of the National Heart, Lung, and Blood Institute (NHLBI) Family Blood Pressure Program. Genotypes for 391 markers spaced roughly equally throughout the genome were typed by the NHLBI Mammalian Genotyping Service. Each of the phenotypes was adjusted for covariates within sex and race and then subjected to variance components linkage analysis, which was performed separately within race by using race-specific marker allele frequencies from additional random samples. The highest lod score detected was 2.77 for logarithmically transformed triglyceride (TG) on chromosome 20 (at 28.6 cM) in the African American sibling pairs. The highest score detected in the white sibling pairs was 2.74 for high density lipoprotein cholesterol on chromosome 5 (at 48.2 cM). Although no scores Ͼ3.0 were obtained, positive scores were found in several regions that have been reported in other genome scans in the literature. For example, a score of 1.91 for TG was found on chromosome 15 (at 28. Key Words: genome scan Ⅲ lipids Ⅲ cholesterol Ⅲ triglyceride Ⅲ genetic linkage S erum lipoprotein-lipid levels are major risk factors for coronary heart disease, 1 and genes involved in lipoprotein metabolism have been implicated in coronary heart disease. [2][3][4] Discovery of the genetic determinants of quantitative variation in lipid levels could help to elucidate the genetics of coronary heart disease.Studies have indicated that lipid levels are significantly heritable. Point estimates of heritability for total cholesterol, HDL cholesterol (HDL-C), and plasma triglycerides (TGs) range from 42% to 65%, 45% to 83%, and 37% to 75%, respectively, with twin studies providing higher point estimates. 5,6 At least half of the normal variation in LDL cholesterol (LDL-C) concentration is due to genetic factors. 7,8 Several segregation analyses have suggested major genes for lipid traits. 9 -11 The San Antonio Heart Study reported segregation analysis evidence of a major gene for HDL-C but concluded that this locus was not any of the following major candidate loci: apoA-I/apoC-III, apoB, hepatic lipase, lipoprotein lipase, LDL receptor, or apoE. 12 Similarly, data from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study (FHS) show a major gene effect for mild elevation in LDL-C that is not attributable to the LDL receptor, apoE, or the cholesterol 7␣-hydroxylase genes. 13 These studies indicate that whole genome scans may reveal new major loci underlying quantitative lipid traits.The present report describes a genome-wide search for quantitative trait loci contributing to variations in LDL-C, HDL-C, TGs, and total cholesterol in white and African American sibling pairs ascertained for hypertension. Genes accounting for variation of lipid levels within hypertensive siblings may differ f...

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