Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia

Abstract

Small, dense LDLs and hypertriglyceridemia, two highly correlated and genetically influenced risk factors, are known to predict for risk of coronary heart disease. The objective of this study was to perform a whole-genome scan for linkage to LDL size and triglyceride (TG) levels in 26 kindreds with familial hypertriglyceridemia (FHTG). LDL size was estimated using gradient gel electrophoresis, and genotyping was performed for 355 autosomal markers with an average heterozygosity of 76% and an average spacing of 10.2 centimorgans (cMs). Using variance components linkage analysis, one possible linkage was found for LDL size [logarithm of odds (LOD) ‫؍‬ 2.1] on chromosome 6, peak at 140 cM distal to marker F13A1 (closest marker D6S2436). With adjustment for TG and/or HDL cholesterol, the LOD scores were reduced, but remained in exactly the same location. For TG, LOD scores of 2.56 and 2.44 were observed at two locations on chromosome 15, with peaks at 29 and 61 cM distal to marker D15S822 (closest markers D15S643 and D15S211, respectively). These peaks were retained with adjustment for LDL size and/or HDL cholesterol. These findings, if confirmed, suggest that LDL particle size and plasma TG levels could be caused by two different genetic loci in FHTG. The causal relationship between LDL cholesterol and risk of coronary heart disease (CHD) is definitively established (1). But growing evidence reveals that other lipoproteins, including small, dense LDL particles, as well as increased plasma triglycerides (TGs) and lower HDL cholesterol levels, all characteristics of the metabolic syndrome (2), are also convincingly associated with atherosclerosis risk. Although these risk factors are all intercorrelated (3, 4), each of them is also an independent risk factor. For example, a meta-analysis of three prospective studies in middle-aged men (4-6) showed a 60% increased risk for CHD for every 10 Å decrease in LDL size (7). Adjustment for TG and HDL cholesterol reduced this to a 30% increased risk, but the odds ratio remained statistically significant, demonstrating that small LDL is an independent risk factor. Other studies have found even higher risk associated with CHD among young women (8), but lower risks among older populations (9, 10).Elevated plasma TG is now also recognized as an important independent risk factor for CHD (11)(12)(13)(14). In familial hypertriglyceridemia (FHTG), baseline TG levels predicted increased risk of cardiovascular disease mortality among first-degree relatives of probands during 20 years of follow-up, independent of baseline cholesterol levels and other covariates (15). Even more convincing data demonstrate that increasing HDL cholesterol levels can reduce risk of CHD among men with low HDL cholesterol levels (16,17).Numerous studies have demonstrated both genetic and environmental influences on LDL size, plasma TG, and HDL cholesterol (18,19). For example, segregation analyses (20, 21) have consistently demonstrated single major gene effects on LDL size. These and other studies h...

Quantitative trait loci influencing low density lipoprotein particle size in African Americans

“…Numerous analyses have been performed to assess the heritability of LDL particle size in either twin (28,29) or family studies (30)(31)(32)(33). These studies, comprising mostly non-Hispanic whites or Hispanics, found that 30-60% of the variance in LDL particle size was attributable to genetic factors.…”

Dietary and Genetic Probes of Atherogenic Dyslipidemia

“…61 In addition, genome-wide linkage studies have reported a number of chromosomal loci linked to LDL particle size phenotypes, although none has yet been confirmed. 57,[62][63][64][65] Moreover, no specific genetic polymorphism has been firmly implicated in the cause of LDL subclass phenotype B.…”

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 ).…”