Gene-nutrient interactions with dietary fat modulate the association between genetic variation of the ACSL1 gene and metabolic syndrome

Abstract

Long-chain acyl CoA synthetase 1 (ACSL1) plays an important role in fatty acid metabolism and triacylglycerol (TAG) synthesis. Disturbance of these pathways may result in dyslipidemia and insulin resistance, hallmarks of the metabolic syndrome (MetS). Dietary fat is a key environmental factor that may interact with genetic determinants of lipid metabolism to affect MetS risk. We investigated the relationship between ACSL1 polymorphisms (rs4862417, rs6552828, rs13120078, rs9997745, and rs12503643) and MetS risk and determined potential interactions with dietary fat in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1,754). GG homozygotes for rs9997745 had increased MetS risk {odds ratio (OR) 1.90 [confidence interval (CI) 1.15, 3.13]; P = 0.01}, displayed elevated fasting glucose (P = 0.001) and insulin concentrations (P = 0.002) and increased insulin resistance (P = 0.03) relative to the A allele carriers. MetS risk was modulated by dietary fat, whereby the risk conferred by GG homozygosity was abolished among individuals consuming either a low-fat (<35% energy) or a high-PUFA diet (>5.5% energy). In conclusion, ACSL1 rs9997745 influences MetS risk, most likely via disturbances in fatty acid metabolism, which was modulated by dietary fat consumption, particularly PUFA intake, suggesting novel gene-nutrient interactions.

Trial registration: ClinicalTrials.gov NCT00272428.

Figures

Fig. 1.

Influence of ACSL1 rs9997745 genotype and dietary PUFA status on insulin resistance as assessed by HOMA (A), fasting insulin (B), and glucose (C) concentrations. Values are means ± SEM. P-values for linear regression adjusted for potential confounding factors. When dietary PUFA intake was low (<5.5% energy), GG homozygotes (n = 848) displayed greater insulin resistance (A) and higher fasting insulin (B) and glucose (C) concentrations compared with the A allele carriers (n = 327). Furthermore, fasting glucose levels were significantly higher in the GG homozygotes with a low-PUFA intake compared with both GG homozygotes (n = 418) and A allele carriers (n = 161) with a high-PUFA intake. The detrimental effects conferred by GG homozygosity on insulin resistance and insulin concentrations were abolished against a high-PUFA background (>5.5% energy).