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

Abstract

Coronary artery disease (CAD) and its principal clinical complication of acute myocardial infarction (MI) represent the most important causes of death and disability in the developed world. According to the American Heart Association's 2009 statistical update, nearly 16.8 million Americans are affected with CAD, and 7.9 million have had a myocardial infarction. On average, an American will suffer from a coronary event every 26 s, and about every minute somebody will die from one ( 1 ). The lifetime risk of developing CAD after age 40 is 49% for men and 32% for women ( 1 ).A decreased concentration of plasma HDL-cholesterol (HDL-C) is a major risk factor for CAD, and epidemiological evidence from several longitudinal studies, including the Framingham Heart Study, indicate that HDL-C is an 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 × 10 ؊ 4 ). Two major quantitative trait loci (QTL) for logtransformed HDL-C adjusted for age and gender were identifi ed 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 nonsignifi cant 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 signifi cant 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 signifi cant locus identifi ed for HDL-C to date, and these results provide a framework for the ultimate identifi cation of the underlying HDL-C variant and gene on chromosomes 15q25, which will provide insights into novel regulatory mechanisms of HDL-C metabolism.

Apolipoprotein A‐I: Insights from redox proteomics for its role in neurodegeneration

“…The RCT system comprises the metabolism of HDL and the subsequent transport of cholesterol from the periphery back to the liver, and because of this role, HDL levels have been found to have an inverse relationship with cardiovascular disease . The primary apolipoprotein component of HDL is ApoA‐I, responsible for the free cholesterol loading of HDL from cells by binding to ABCA1 as well as the secretion of apoE, which stimulates lecithin‐cholesterol acyltransferase (LCAT) activity (Fig.…”

Glucuronic Acid Epimerase is Associated with Plasma Triglyceride and High‐Density Lipoprotein Cholesterol Levels in Turks

“…In a recent scan for atherogenic dyslipidemia, the multinational Genetic Epidemiology of Metabolic Syndrome study (Wyszynski et al, 2005) found significant linkage to plasma HDL‐C levels on chromosome 15q21–23 in Turkish families (Yu et al, 2005). Previous genome‐wide scans showed significant linkage of this region not only to plasma HDL‐C (Almasy et al, 1999; Feitosa et al, 2007; Yang et al, 2010) but also to triglyceride levels (Suto et al, 1999; Austin et al, 2003; Klimes et al, 2003; Rollins et al, 2006; Burgess‐Herbert et al, 2009; Li et al, 2009). Similar linkage was found for plasma HDL‐C and triglyceride levels in the orthologous region in mice and rats (Suto et al, 1999; Klimes et al, 2003; Rollins et al, 2006; Burgess‐Herbert et al, 2009).…”

Genetic loci for blood lipid levels identified by linkage and association analyses in Caribbean Hispanics

“…Among these three regions, 19q has been linked to lipid quantitative traits with the most consistent linkage evidence in the previous reports, with LOD scores ranging from 1.9 to 5.7 in the region at 50-70 cM among various populations ( 5,13,16,(53)(54)(55)(56)(57) ( Table 3 ). Similarly, 15q has previously been implicated in several genome scans of lipid-related traits, with LOD scores from 1.8 to 4.2 in the region at 61-72 cM among various populations ( 17,(58)(59)(60)(61)(62) ( Table 3 ). For 20p12, two studies have shown evidence for linkage in this region: a LOD score of 2.8 for TG at 28 cM in an African sibling sample of the Hypertension Genetic Epidemiology Network (HyperGEN) ( 63 ), and 1.6 for LDL-C in French Canadian families ( 55 ).…”