👤 D Cottel

Blood polyunsaturated fatty acid (PUFA) levels are determined by diet and by endogenous synthesis via Δ5- and Δ6-desaturases (encoded by the FADS1 and FADS2 genes, respectively). Genome-wide association studies have reported associations between FADS1-FADS2 polymorphisms and the plasma concentrations of PUFAs, HDL- and LDL-cholesterol, and triglycerides. However, much remains unknown regarding the molecular mechanisms explaining how variants affect the function of FADS1-FADS2 genes. Here, we sought to identify the functional variant(s) within the FADS gene cluster. To address this question, we (1) genotyped individuals (n = 540) for the rs174547 polymorphism to confirm associations with PUFA levels used as surrogate estimates of desaturase activities and (2) examined the functionality of variants in linkage disequilibrium with rs174547 using bioinformatics and luciferase reporter assays. The rs174547 minor allele was associated with higher erythrocyte levels of dihomo-γ-linolenic acid and lower levels of arachidonic acid, suggesting a lower Δ5-desaturase activity. In silico analyses suggested that rs174545 and rs174546, in perfect linkage disequilibrium with rs174547, might alter miRNA binding sites in the FADS1 3'UTR. In HuH7 and HepG2 cells transfected with FADS1 3'UTR luciferase vectors, the haplotype constructs bearing the rs174546T minor allele showed 30% less luciferase activity. This relative decrease reached 60% in the presence of miR-149-5p and was partly abolished by cotransfection with an miR-149-5p inhibitor. This study identifies FADS1 rs174546 as a functional variant that may explain the associations between FADS1-FADS2 polymorphisms and lipid-related phenotypes. Show less

Blood levels of polyunsaturated fatty acids (PUFAs) are under control of endogenous synthesis via Δ5- and Δ6-desaturases, encoded by the FADS1 and FADS2 genes, respectively and of diet. Genome-wide associations studies (GWAS) reported associations between polymorphisms in FADS1-FADS2 and variations in plasma concentrations of PUFAs, HDL- and LDL-cholesterol and triglycerides. However, it is not established whether dietary PUFAs intake modulates these associations. We assessed whether dietary linoleic acid (LA) or α-linolenic acid (ALA) modulate the association between the FADS1 rs174547 polymorphism (a GWAS hit) and lipid and anthropometric phenotypes. Dietary intakes of LA and ALA, FADS1 rs174547 genotypes, lipid and anthropometric variables were determined in three French population-based samples (n = 3069). These samples were stratified according to the median dietary LA (<9.5 and ≥9.5 g/d) and ALA (<0.80 and ≥0.80 g/d) intakes. The meta-analysis was performed using a random-effect. Our meta-analysis confirmed the association between rs174547 and plasma lipid levels and revealed an association with waist circumference and body mass index. These associations were not modified by dietary ALA intake (all p-interaction > 0.05). In contrast, the associations with HDL-cholesterol levels, waist circumference and BMI were modulated by the dietary intake of LA (p interaction < 0.05). In high LA consumers only, the rs174547 minor allele was significantly associated with lower HDL-cholesterol levels (β = -0.05 mmol/L, p = 0.0002). Furthermore, each copy of the rs174547 minor allele was associated with a 1.58 cm lower waist circumference (p = 0.0005) and a 0.46 kg m The present study suggests that dietary LA intake may modulate the association between the FADS gene variants and HDL-cholesterol concentration, waist circumference and BMI. These gene-nutrient interactions, if confirmed, suggest that subjects carrying the rs174547 minor allele might benefit from low dietary LA intakes. Show less

The goal of the present study was to assess the effect of genetic variability at the APOA5/A4/C3/A1 cluster locus on the risk of metabolic syndrome. The APOA5 Ser19Trp, APOA5 -12,238T>C, APOA4 Thr347Ser, APOC3 -482C>T and APOC3 3238C>G (SstI) polymorphisms were analyzed in a representative population sample of 3138 men and women from France, including 932 individuals with metabolic syndrome and 2206 without metabolic syndrome, as defined by the NCEP criteria. Compared with homozygotes for the common allele, the odds ratio (OR) [95% CI] for metabolic syndrome was 1.30 [1.03-1.66] (p = 0.03) for APOA5 Trp19 carriers, 0.81 [0.69-0.95] (p = 0.01) for APOA5 -12,238C carriers and 0.84 [0.70-0.99] (p = 0.04) for APOA4 Ser347 carriers. Adjustment for plasma triglycerides, (but not for waist girth, HDL, blood pressure or glycemia - the other components of metabolic syndrome) abolished these associations and suggests that triglyceride levels explain the association with metabolic syndrome. There was no association between the APOC3 -482C>T or APOC3 3238C>G polymorphisms and metabolic syndrome. The decreased risk of metabolic syndrome observed in APOA5 -12,238C and APOA4 Ser347 carriers merely reflected the fact that the APOA5 Trp19 allele was in negative linkage disequilibrium with the common alleles of APOA5 -12,238T>C and APOA4 Thr347Ser polymorphisms. The APOA5 Trp19 allele increased susceptibility to metabolic syndrome via its impact on plasma triglyceride levels. Show less

The metabolic syndrome is a complex and multifactorial disorder often associated with type 2 diabetes mellitus and cardiovascular diseases. The liver X receptor alpha (NR1H3) plays numerous roles in metabolic pathways involved in metabolic syndrome. In the search for susceptibility genes to metabolic syndrome, we hypothesized that common genetic variation in NR1H3 gene influences metabolic syndrome susceptibility. Two large French population-based studies (n=1130 and 1160) including overall 664 individuals with and 1626 individuals without metabolic syndrome were genotyped for three polymorphisms (rs12221497, rs11039155 and rs2279239) of NR1H3. We found that the -6A allele of rs11039155 was consistently associated with a 30% reduction in risk of metabolic syndrome in the two independent population samples (adjusted OR (95% CI)=0.68 (0.53-0.86), P=0.001 for the combined sample). Moreover, it was associated with an increase in plasma HDL-cholesterol concentrations (P=0.02 for the combined sample). Neither rs12221497 nor rs11039155, both polymorphisms located in the 5' region of NR1H3, had significant influence on NR1H3 and ATP-binding cassette transporter A1 (ABCA1) gene expression in primary human macrophages. These results suggest that NR1H3 plays an important role in the HDL-cholesterol metabolism and in the genetic susceptibility to metabolic syndrome. Show less

The goal of the present study was to assess the impact of 4 single nucleotide polymorphisms (SNPs) of APOA5/A4/C3 gene cluster on lipid levels and coronary heart disease (CHD) risk in French men. A total of 442 men with CHD were recruited from the university hospital and compared to 475 men free of CHD from the population of the same geographical area. The APOA5 S19W, APOA5 -l2,238T>C, APOA4 T347S and APOC3 -482C>T SNPs were examined. The APOA5 S19W polymorphism was associated with plasma triglyceride levels. In multivariate logistic regression analyses the odds ratio (OR [95% Cl]) of hypertriglyceridemia (3rd vs. 1st tertile of triglyceride distribution) was 3.60 [1.38-9.42] in control subjects bearing at least one APOA5 19W variant. Haplotype analyses revealed a significant association between the 2111 haplotype and high triglyceride levels (+1.94 +/- 0.63 vs. 0.74 +/- 0.36 mmol/l for the 1111 haplotype p < 0.002). There was, in contrast, no significant difference in SNP distribution between CHD patients and controls. The age-adjusted OR of CHD were 1.46 [0.96-2.23], 0.79 [0.60-1.05], 0.91 [0.69-1.21] and 0.91 [0.69-l.22] in carriers of the APOA5 19W, APOA5 -12,238C, APOA4 347S and APOC3 -482T variants, respectively. There was also no significant difference in APOA5/A4/C3 haplotype distribution in patients and controls. The APOA5 19W variant is associated with increased plasma triglycerides. However, there is no evidence that APOA5 S19W, -12,238T > C, APOA4 T347S and APCC3 -482C > T SNPs are major risk factors of CHD in French men. Show less