Anti-TRIB1 (aa 125-139) polyclonal antibody

Purpose of review Recent genome-wide association studies (GWAS) have identified approximately 100 genomic loci that are associated with plasma lipid traits, two-thirds of which had never been previously associated with lipoprotein metabolism. Identification of the causal genes and variants, functional validation of these genes and biological pathways, and elucidation of molecular mechanisms is required and poses a daunting task. Recent findings Human genetics have been used to recently 'validate' genes, such as LIPG, SCARB1 and ANGPTL3, which were previously implicated in lipoprotein metabolism through classical wet bench approaches. Additionally, many novel genes have been identified as associated with plasma lipid traits by GWAS, though only relatively few have been functionally validated through targeted sequencing and genetic manipulation in cells and animals. These types of studies have defined new roles in lipid metabolism for the novel lipid genes SORT1 and TRIB1. These examples demonstrate the ways in which human genetics can validate candidate genes, as well as provide a novel discovery that requires functional validation at the bench, and point towards a more complete understanding of the molecular physiology of lipoprotein metabolism. Summary This review summarizes recent developments in the use of human genetics to validate candidate genes in lipoprotein metabolism as well as in the functional validation of novel GWAS loci associated with plasma lipid traits.

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.