ACC2 gene polymorphisms,metabolic syndrome,and gene-nutrient interactions with dietary fat

Acetyl-CoA carboxylase β (ACC2) plays a key role in fatty acid synthesis and oxidation pathways. Disturbance of these pathways is associated with impaired insulin responsiveness and metabolic syndrome (MetS). Gene-nutrient interactions may affect MetS risk. This study determined the relationship between ACC2 polymorphisms (rs2075263, rs2268387, rs2284685, rs2284689, rs2300453, rs3742023, rs3742026, rs4766587, and rs6606697) and MetS risk, and whether dietary fatty acids modulate this in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). Minor A allele carriers of rs4766587 had increased MetS risk (OR 1.29 [CI 1.08, 1.58], P = 0.0064) compared with the GG homozygotes, which may in part be explained by their increased body mass index (BMI), abdominal obesity, and impaired insulin sensitivity (P < 0.05). MetS risk was modulated by dietary fat intake (P = 0.04 for gene-nutrient interaction), where risk conferred by the A allele was exacerbated among individuals with a high-fat intake (>35% energy) (OR 1.62 [CI 1.05, 2.50], P = 0.027), particularly a high intake (>5.5% energy) of n-6 polyunsaturated fat (PUFA) (OR 1.82 [CI 1.14, 2.94], P = 0.01; P = 0.05 for gene-nutrient interaction). Saturated and monounsaturated fat intake did not modulate MetS risk. Importantly, we replicated some of these findings in an independent cohort. In conclusion, the ACC2 rs4766587 polymorphism influences MetS risk, which was modulated by dietary fat, suggesting novel gene-nutrient interactions.     

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

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.     

Effects of rs7903146 Variation in the Tcf7l2 Gene in the Lipid Metabolism of Three Different Populations

Background

TCF7L2 rs7903146 is an important genetic factor predicting type 2 diabetes (T2DM) which has also been linked to higher cardiovascular risk. To date, there is little information about the additional impact of this single nucleotide polymorphism (SNP) beyond glucose metabolism.

Methodology/Principal Findings

We studied whether rs7903146 influenced postprandial lipid metabolism in three different populations (healthy young men, metabolic syndrome (MetS) patients and elderly persons). Eighty-eight healthy males were submitted to a single saturated fatty acid-rich test meal. Additionally, 110 middle-aged MetS patients and 20 healthy elderly persons (≥65 years) were submitted to three different dietary models followed by test meals. Minor allele homozygotes for rs7903146 showed a worse postprandial lipemia profile in young males, as seen by a lower HDL-cholesterol and Apo A1 concentration during the postprandial lipemia and a trend towards higher triglycerides (TG), than the other genotypes. In healthy elderly persons, carriers of the minor allele showed higher total cholesterol, LDL-cholesterol, Apo B and TG in the fasting state, and a higher postprandial area under the curve for total cholesterol, Apo B, small-triglyceride rich lipoprotein (TRL) cholesterol and small-(TRL) triglycerides. These results were accompanied by differential changes in adipokines. We did not observe any influence of rs7903146 on the postprandium of MetS patients.

Conclusions/Significance

Healthy young males and elderly persons who are carriers of the mutant allele for rs7903146 have an impaired postprandial lipid metabolism that may be mediated by an alteration in adipokine regulation, and may be related to the higher cardiovascular risk observed in these persons.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00429195","term_id":"NCT00429195"}}NCT00429195     

Differential effects of the C1431T and Pro12Ala PPARgamma gene variants on plasma lipids and diabetes risk in an Asian population

We investigated the association of C1431T and Pro12Ala polymorphisms at the peroxisome proliferator-activated receptor gamma (PPARgamma) locus with plasma lipids and insulin resistance-related variables, according to diabetes status, in a large and representative Asian population from Singapore consisting of 2,730 Chinese, 740 Malays, and 568 Indians. Moreover, we estimated the diabetes risk and examined gene-nutrient interactions between these variants and the ratio of polyunsaturated fatty acid to saturated fat (SFA) in determining body mass index (BMI) and fasting insulin. We found differential effects of these gene variants. The Pro12Ala polymorphism was more associated with plasma lipids and fasting glucose concentrations, whereas the C1431T polymorphism was related to the risk of diabetes. Carriers of the 12Ala allele had higher HDL-cholesterol than did Pro12Pro homozygotes (P < 0.05), and the effect of the 12Ala allele on fasting glucose was modified by diabetes status (P < 0.001). After controlling for confounders, carriers of the T allele had decreased risk of diabetes compared with CC homozygotes [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.58-0.93; P = 0.011]; this effect was stronger in Indians (OR 0.38, 95% CI 0.15-0.92; P = 0.032). For both polymorphisms, normal subjects carrying the less prevalent allele had higher BMI (P < 0.05). The PUFA/SFA did not modify the effect of these polymorphisms on BMI or insulin.     

Association of MAOA and COMT gene polymorphisms with palatable food intake in children

Several studies have implicated dopamine (DA) in appetite regulation. The enzymes catechol-o-methyltransferase (COMT) and monoamine oxidase A (MAOA) control DA availability and their genes have well-characterized functional variants. In this study, we examined three polymorphisms in these genes, T941G and MAOAu-VNTR in the MAOA gene and Val158Met in the COMT gene, to investigate how heritable variations in enzymes that determine DA levels might influence food intake and nutritional status. This investigation was a cross-sectional examination of 354 Brazilian children of three to four years old. Polymorphisms were analyzed by PCR-based methods. Means of dietary and anthropometric data were compared among genotypes by one-way analyses of variance or Kruskal Wallis tests. The MAOAu-VNTR and COMT Val158Met polymorphisms were associated with the amount of palatable food intake in boys. Presence of the MAOAu-VNTR*long allele was associated with higher intake of lipid-dense foods (LDF) when compared with the *short allele (P=.009); the amount of sugar-dense foods (SDF) intake was also higher in males carriers of the MAOAu-VNTR *long allele than in carriers of the *short allele (P=.034). In the girls' sample, MAOAu-VNTR polymorphism was not associated with food intake and nutritional status. Carriers of the COMT Val158Met*Val allele presented higher intake of LDF when compared with Met/Met homozygotes (P=.008). This study provides the first indication that genetic variants of enzymes that control DA availability might be involved in determination of the amount of palatable food intake in children.     

Association of TCF7L2 Gene Polymorphisms with T2DM in the Population of Hyderabad,India

We attempt to evaluate the nature of association of TCF7L2 gene variants with T2DM, for the first time in the population of Hyderabad, which is considered to be diabetic capital of India. It is a case-control study of the three SNPs of TCF7L2, rs7903146, rs12255372 and rs11196205, genotyped on Sequenom Massarray platform, in a sample of 758 patients and 621 controls. The risk allele frequency of the three SNPs was found to be significantly higher in the T2DM cases than controls, implicating susceptibility for diabetes (p<0.01). The greatest risk of developing the disease was conferred by rs7903146. Further, the logistic regression of genotypes of each SNP under log additive model, and the haplotypes constituted by at least one of the three risk alleles also show significantly greater risk of developing T2DM when compared to the wild type haplotype. Further, BMI and WHR emerge as significant covariates with confounding effects. The strong association of the TCF7L2 SNPs with T2DM is consistent with the findings among other Indian and Non-Indian populations, suggesting universal phenomena of its association across ethnic groups globally, both within and outside the Indian subcontinent, albeit the functional relevance of these SNPs needs yet to be established.