High Density Lipoprotein Cholesterol Level Quantitative Trait Locus 12

A number sign (#) is used with this entry because of evidence that variation in high density lipoprotein cholesterol levels is associated with variation in the LIPC gene (151670).

Molecular Genetics

In a metaanalysis of 25 published reports on a SNP in the promoter region of the hepatic lipase gene (-514C-T; 151670.0003), involving 24,000 individuals with measurements of gene activity and lipid profiles, Isaacs et al. (2004) found significant associations between the -514 genotype and hepatic lipase activity and HDL levels.

In 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study, Kathiresan et al. (2008) studied SNPs in 9 genes, including rs1800775 of LIPC, that had previously been associated with elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the associations with each SNP and created a genotype score on the basis of the number of unfavorable alleles. With increasing genotype scores, the level of LDL cholesterol increased, whereas the level of HDL cholesterol decreased. At 10-year follow-up, the genotype score was found to be an independent risk factor for incident cardiovascular disease (myocardial infarction, ischemic stroke, or death from coronary heart disease); the score did not improve risk discrimination but modestly improved clinical risk reclassification for individual subjects beyond standard clinical factors.

Grarup et al. (2008) investigated the effect of a -250G-A variant of the LIPC gene (rs2070895; 151670.0004) on metabolic traits and risk of type 2 diabetes (see 125853) in 5,585 middle-aged treatment-naive Danish individuals from a randomized population-based study and found significant association with fasting serum HDL cholesterol (p = 8 x 10(-10)); the association was replicated in 8,407 high-risk individuals. The authors observed no association with type 2 diabetes in a cross-sectional design in this study.

Iijima et al. (2008) analyzed alphalipoprotein (HDL) levels in 2 independent Japanese populations consisting of 2,970 and 1,638 individuals, respectively, and found significant association with a 2-SNP haplotype in intron 1 of the LIPC gene (151670.0005) in both populations (p = 0.00011 and 0.00070, respectively). The authors concluded that variation at the LIPC locus influences HDL metabolism.

Aulchenko et al. (2009) reported the first genomewide association (GWA) study of loci affecting total cholesterol (TC), LDL cholesterol, HDL cholesterol, and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. This study included a total of 17,797 to 22,562 individuals aged 18 to 104 years from geographic regions spanning from the Nordic countries to Southern Europe. Aulchenko et al. (2009) established 22 loci associated with serum lipid levels at a genomewide significance level (P less than 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The region near the LIPC gene identified by rs1532085 was significantly associated with HDL cholesterol levels (P = 9.7 x 10(-36)).

In a metaanalysis of plasma lipid concentrations in greater than 100,000 individuals of European descent, Teslovich et al. (2010) identified rs1532085 as having an effect on HDL cholesterol concentrations with an effect size of +1.45 mg per deciliter and a P value of 3 x 10(-96). This variant was also found to be an expression quantitative trait locus (eQTL) regulating the expression of the LIPC gene.