Polygenic determinants of severe hypertriglyceridemia

Abstract

Recent genome-wide association (GWA) studies have identified new genetic determinants of complex quantitative traits, including plasma triglyceride (TG). We hypothesized that common variants associated with mild TG variation identified in GWA studies would also be associated with severe hypertriglyceridemia (HTG). We studied 132 patients of European ancestry with severe HTG (fasting plasma TG > 10 mmol/l), who had no mutations found by resequencing of candidate genes, and 351 matched normolipidemic controls. We determined genotypes for: GALNT2 rs4846914, TBL2/MLXIPL rs17145738, TRIB1 rs17321515, ANGPTL3 rs12130333, GCKR rs780094, APOA5 rs3135506 (S19W), APOA5 rs662799 (-1131T > C), APOE (isoforms) and LPL rs328 (S447X). We found that: (i) genotypes, including those of APOA5 S19W, APOA5 -1131T > C, APOE, GCKR, TRIB1 and TBL2/MLXIPL, were significantly associated with severe HTG; (ii) odds ratios for these genetic variables were significant in both univariate and multivariate regression analyses, irrespective of the presence or absence of diabetes or obesity; (iii) a significant fraction-about one-quarter-of the explained variation in disease status was associated with these genotypes. Therefore, common SNPs (single nucleotide polymorphisms) that are associated with mild TG variation in GWA studies of normolipidemic subjects are also associated with severe HTG. Our findings are consistent with the emerging model of a complex genetic trait. At the extremes of a quantitative trait, such as severe HTG, are found the cumulative contributions of both multiple rare alleles with large genetic effects and common alleles with small effects.

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

“…Ectopic TBL2 overexpression reduces cholesterol and miRNA-mediated knockdown raises cholesterol. TBL2 is also considered a candidate disease gene associated with triglyceride metabolism, but its role is unknown (Wang et al, 2008a). Phosphorylation of TBL2 by ATM/ATM in response to DNA damage identifies TBL2 as a member of the cellular oxidative damage response network (Matsuoka et al, 2007).…”

“…In addition, TERE1 also binds to the TBL2 protein, which has been implicated in disease associated with triglyceride metabolism (Kathiresan et al, 2008;Wang et al, 2008a). TBL2 was originally described as a gene within a chromosomal deletion in Williams Syndrome (Perez Jurado et al, 1999).…”

Large-scale genome-wide association studies in east Asians identify new genetic loci influencing metabolic traits

“…Deletion of the genomic region comprising TBL2 and BCL7B is commonly observed in Williams-Beuren syndrome 8 . Finally, mutation of TBL2 is associated with TG level 9,10 and hypertriglyceridemia 11 . For both ALT and AST, we detected the most compelling association (P overall = 7.62 × 10 −22 , effect size = 0.0045 ± 0.0005 for ALT and P overall = 2.77 × 10 −63 , effect size = 0.0016 ± 0.0001 for AST) on chromosome 12q24.13 (rs11066280 in C12orf51).…”

Is the time right for translation research in genomics?

“…Despite the current euphoria, the predictive value of genetic profiling is still limited for most disorders, with only some promising exceptions. [4,[6][7][8][9] The major limitation to date is that only a fraction of the genetic factors involved have been identified, for most disorders less than 20 [1], explaining not more than a few percentages of the heritability.…”

“…In most studies, the per allele effects of the risk genotypes typically ranged from 1.1 tot 1.4, except for AMD and hypertriglyceridemia [4,6,8]. From an epidemiological perspective, investigating the predictive value of a limited number of susceptibility genes with weak effects seems somewhat overoptimistic as a priori high predictive value is not expected [18].…”