Abstract
ANGPTL3 is an important regulator of lipid metabolism. Its inhibition in people with hypercholesteremia reduces plasma lipid levels dramatically. Genome-wide association studies have associated ANGPTL3 variants with lipid traits. Irisin, an exercise-modulated protein, has been associated with lipid metabolism. Intracellular accumulation of lipids impairs insulin action and contributes to metabolic disorders. In this study, we evaluate the impact of ANGPTL3 variants on levels of irisin and markers associated with lipid metabolism and insulin resistance. ANGPTL3 rs1748197 and rs12130333 variants were genotyped in a cohort of 278 Arab individuals from Kuwait. Levels of irisin and other metabolic markers were measured by ELISA. Significance of association signals was assessed using Bonferroni-corrected p-values and empirical p-values. The study variants were significantly associated with low levels of c-peptide and irisin. Levels of c-peptide and irisin were mediated by interaction between carrier genotypes (GA + AA) at rs1748197 and measures of IL13 and TG, respectively. While levels of c-peptide and IL13 were directly correlated in individuals with the reference genotype, they were inversely correlated in individuals with the carrier genotype. Irisin correlated positively with TG and was strong in individuals with carrier genotypes. These observations illustrate ANGPTL3 as a potential link connecting lipid metabolism, insulin resistance and cardioprotection.
Highlights
IntroductionNHGRI-EBI GWAS Catalog [6], which is a curated collection of all published genome-wide association studies, revealed two more SNPs, rs1748197 and rs12130333 from ANGTPL3, having strong effects on lipid metabolism
The results revealed that (i) measures of c-peptide was mediated by interaction between carrier genotypes (GA + AA) at rs1748197 and measures of IL13; and (ii) measures of irisin were mediated by interaction between carrier genotypes (GA + AA) at rs1748197 and measures of TG
When we tested the effect of type 2 diabetes (T2 D) disease status in the study cohort, we found that the levels of irisin as well as other clinical traits, such as TG, FPG, HbA1c, body mass index (BMI) and waist circumference, were significantly higher in individuals with type 2 diabetic (T2 D) when compared to non-diabetic individuals
Summary
NHGRI-EBI GWAS Catalog [6], which is a curated collection of all published genome-wide association studies, revealed two more SNPs, rs1748197 and rs12130333 from ANGTPL3, having strong effects on lipid metabolism Both these two variants are in strong linkagedisequilibrium (LD) with the lead SNP, the first one at r2 = 0.995 and the second one at r2 = 0.5. Given the above reported link between the ANGPTL3 SNP variants and lipid metabolism, our aim in this study was to identify associations between these vari-. Irisin is a novel myokine product produced from cleaving a transmembrane protein named fibronectin type III domain-containing protein 5 (FNDC5) This cleaved form of FNDC5 is released into blood circulation and has been shown to play an important role in modulating browning of white adipose tissue during exercise [11]. Based on its involvement in various metabolic pathways, including lipid metabolism, we were interested in investigating the interaction between ANGPTL3 variants and plasma levels of irisin
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