Alain Houde

Association between the PPARα-L162V polymorphism and components of the metabolic syndrome

AbstractGenetic factors, alone or in interaction with components of the diet, are thought to be involved in the development of the metabolic syndrome. The objective of our study was first to compare the frequency of the peroxisome proliferator-activated receptor (PPAR)α-L162V polymorphism in a sample of men with and without the metabolic syndrome as defined by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) guidelines, and secondly, to evaluate gene-diet interaction effects on features of the metabolic syndrome. The PPARα-L162V genotype was determined in a sample of 632 men by a polymerase chain reaction-restriction length polymorphism (PCR-RFLP)-based method; fat as well as saturated fat intakes were evaluated by a dietitian-administered food frequency questionnaire. The frequency of the V162 allele was similar in men with (n=281) and without (n=351) the metabolic syndrome (χ2=0.03, p=0.84) but was higher in subjects having simultaneously abdominal obesity, hypertriglyceridemia, and low high-density lipoprotein cholesterol (HDL-C) levels (χ2=3.73, p=0.05). Carriers of the V162 were characterized by higher plasma apolipoprotein B and triglyceride (TG) levels (p=0.10, p=0.004). In a model including the PPARα-L162V polymorphism, fat or saturated fat, its interaction, and covariates (smoking habits, and energy and alcohol intake), the interaction explained a significant percentage of the variance observed in waist circumference (p<0.05). In conclusion, the PPARα-L162V polymorphism alone or in interaction with dietary fat intake is associated with components of the metabolic syndrome.

Caffeine reduces spontaneous energy intake in men but not in women

Abstract The present study was conducted to determine whether a sex difference exists in the short-term adaptation of energy intake following caffeine consumption. To investigate this phenomenon, spontaneous food intake was measured on two occasions in young men (n=10) and women (n=10). At the beginning of the sessions, subjects randomly consumed 300 mg caffeine or a placebo 30 min before they had free access to various foods. Following the ingestion of caffeine, energy intake was reduced by 21.7% in men in comparison to their control situation (816±221 vs 1043±209 kcal, p 0.10). This demonstration of a sex dimorphism in the short-term adaptation of energy intake in response to caffeine is consistent with the concept that women tend to preserve their body energy stores more than men when they are exposed to factors activating the sympathetic nervous system.

Variants within the muscle and liver isoforms of the carnitine palmitoyltransferase I (CPT1) gene interact with fat intake to modulate indices of obesity in French-Canadians

Obesity is under the influence of genetic and nutritional factors. The objective was to verify whether variants in the gene encoding the carnitine palmitoyltransferase I (CPT1), a key enzyme in β-oxidation of fatty acids, are associated with obesity phenotypes, alone or in interaction with fat intake. Sequencing of CPT1 was performed in 40 overweight subjects and 4 controls. Genotypes were determined in 351 French-Canadians. Fat intake was evaluated by a food frequency questionnaire. We identified 14 genetic variations in CPT1A and 26 in CPT1B. Nine variants within CPT1B and one variant within CPT1A were selected for further analyses based on the minor allele frequency (>10%) or on potential functional impact. A significant association between obesity phenotypes (BMI, weight, and waist girth) and CPT1B c.282-18C > T and p.E531K variants was observed (p < 0.05) No other association was found with variants in CPT1A and CPT1B. When subjects were divided into six groups according to p.E531K genotypes and further on the basis of fat using the median value as a cutoff point (34.4% of energy), BMI, weight, and waist girth were higher in E531/K531 on a high-fat diet compared to E531/K531 subjects under a low-fat diet (p = 0.004, p = 0.006, p = 0.003, respectively). There was no difference among E531/E531 and K531/K531. Similar results were obtained with the CPT1A p.A275T variant as BMI and waist girth were higher in A275/A275 on a high fat compared to A275/A275 subjects on a low-fat diet. Among carriers of the T275 allele, obesity indices were not affected by fat intake (p = 0.05 and p = 0.008 for BMI and waist girth, respectively). Among variants within the CPT1B gene, 13 haplotypes were inferred and the two most frequent haplotypes, H7 (38.0%) and H5 (27.7%), were kept for diplotype analysis. These haplotypes were not associated with indices of obesity, but as observed with the CPT1B E531K variant fat intake modulated this association. In conclusion, this finding suggests that indices of obesity might be modulated by an interaction between CPT1 variants and fat intake.

The lipoprotein/lipid profile is modulated by a gene–diet interaction effect between polymorphisms in the liver X receptor-α and dietary cholesterol intake in French-Canadians

Genetic and nutritional factors interact together and modulate the plasma lipid profile. We identified variations in the gene encoding the liver X receptor alpha (LXRalpha) and investigated their effects on the plasma lipoprotein/lipid profile. We also examined whether the association between cholesterol intake and plasma lipid profile was modulated by LXRalpha variants. The LXRalpha gene was sequenced in thirty-five French-Canadian men with high plasma total cholesterol (>5.0 mmol/l) and LDL-cholesterol (>3.5 mmol/l) concentrations. dietary cholesterol was obtained from a food-frequency questionnaire. The LXRalpha c.-115G>A, c.-840C>A and c.-1830T>C genotypes were determined by direct sequencing in 732 subjects. Molecular screening of the LXRalpha gene revealed sixteen variants. Genotypes c.-115G>A, c.-840C>A and c.-1830T>C (rare allele frequency of 14.3%, 14.2% and 11.0%, respectively) were analysed further. Plasma total cholesterol concentrations were higher in carriers of the -115A, -840A and -1830C allele, compared with the -115G/G, -840C/C and -1830T/T homozygotes (P< or =0.05). In a model including the c.-115G>A polymorphism, cholesterol intake, the interaction term c.-115G>A x cholesterol intake (mg/d) and covariates, LXRalpha-115G>A explained 1.8% and 2.1% of the variance in total cholesterol and LDL-cholesterol concentrations (P=0.02 and P=0.01), whereas the interaction term explained 2.9% (P=0.002) and 2.8% (P=0.005), respectively. When subjects were divided into four groups according to the median of cholesterol (290.8 mg) and -115G>A genotypes, high cholesterol intake was associated with higher cholesterol levels in -115A carriers. Similar results were observed for c.-840C>A and c.-1830T>C. These results suggest that cholesterol intake interacts with LXRalpha variants to modulate the plasma lipid profile.

Molecular screening of the microsomal triglyceride transfer protein : association between polymorphisms and both abdominal obesity and plasma apolipoprotein B concentration

AbstractMicrosomal triglyceride transfer protein (MTP) plays a critical role in the assembly of lipoproteins. The aim of this study was first to seek new MTP gene variants and then to verify whether MTP gene polymorphisms were associated with plasma lipoprotein/lipid levels in men with visceral obesity. Molecular screening of the MTP gene revealed 11 polymorphisms. The carriers of the c.933A allele and c.1151C allele or –400A/A homozygotes were characterized by increased levels of abdominal visceral adipose tissue (AT) measured by computed tomography (P=0.02, P=0.04, P=0.03, respectively). After dividing each genotype group into subgroups using 130 cm2 as a cutoff point for visceral AT, significantly higher low-density lipoprotein (LDL)-apolipoprotein B (apoB) concentrations were found in obese men bearing the c.891G allele, the –400 T allele, as well as for 282G/G homozygotes, 933C/C homozygotes, and 1151A/A homozygotes when compared to their lean counterparts. Haplotypes were not associated with phenotypes under study. In conclusion, some MTP gene polymorphisms in the French Canadian population are associated with the amount of abdominal visceral AT and plasma LDL-apoB concentrations.

Association of LIPA Gene Polymorphisms With Obesity-Related Metabolic Complications Among Severely Obese Patients

The lipase A, lysosomal acid, cholesterol esterase enzyme (LIPA) is involved in the hydrolysis of triglycerides (TGs) and cholesteryl esters (CEs) delivered to lysosomes. LIPA deficiency in human causes two distinct phenotypes characterized by intracellular storage of CE and derangements in the control of cholesterol production, namely the Wolman disease (WD) and the CE storage disease (CESD). To test the potential association of LIPA gene polymorphisms with obesity‐related metabolic complications, promoter, exons, and intronic flanking regions of the LIPA gene were first sequenced in 25 individuals. From the 14 common polymorphisms identified, 12 tagging single‐nucleotide polymorphisms (tSNPs) were genotyped in a cohort of 1,751 obese individuals. After adjustments for the effect of age, sex, diabetes, and medication, the C allele of SNP rs1051338 was associated with lower blood pressure (BP; systolic (SBP) P = 0.004; diastolic (DBP) P = 0.006). Three of the tested SNPs were associated with modifications of the plasma lipid profile. The G/G genotype of rs2071509 was associated with higher high‐density lipoprotein cholesterol (HDL‐C) levels (P = 0.009) and minor allele of rs1131706 was also associated with higher HDL‐C (P = 0.004) and an association between rs3802656 and total cholesterol (total‐C)/HDL‐C ratio was identified (P = 0.04). These results thus suggest that LIPA polymorphisms contribute to the interindividual variability observed in obesity‐related metabolic complications.

Genetic contribution to C-reactive protein levels in severe obesity

Obese individuals are characterized by a chronic, low-grade inflammatory state. Increased levels of C-reactive protein (CRP), a marker of inflammation, have been observed in subjects with the metabolic syndrome. We have previously reported that genes encoding proteins involved in the anti-inflammatory and immune response are differentially expressed in visceral adipose tissue of obese men with or without the metabolic syndrome. Among these genes, the interferon-gamma-inducible protein 30 (IFI30), CD163 molecule (CD163), chemokine (C-X-C motif) ligand 9 (CXCL9) and thymic stromal lymphopoietin (TSLP), were selected for further genetic analyses. The aim of the study was to verify whether IFI30, CD163, CXCL9 and TSLP gene polymorphisms contribute to explain the inter-individual variability of the inflammatory profile of obesity assessed by plasma high-sensitivity CRP concentrations. A total of 1185 severely obese individuals were genotyped for single nucleotide polymorphisms (SNPs) covering most of the sequence-derived genetic variability at the IFI30, CD163, CXCL9 and TSLP gene loci (total of 27 SNPs). Following measurement of plasma CRP levels, subjects were divided into two groups, low vs. high using the median value of plasma CRP levels (8.31 mg/L) as a cutoff point. Genotype frequencies were compared between groups. Associations between genotypes and plasma CRP levels (continuous variable) were also tested after adjustments for age, sex, smoking and BMI. The rs11554159 and rs7125 IFI30 SNPs showed a significant difference in genotype frequencies (p<0.05) between subgroups of low vs. high plasma CRP levels (wild type homozygotes: rs11554159=47% vs. 55%, rs7125=31% vs. 24%, for low vs. high CRP groups, respectively). The association between rs11554159 and CRP levels as a continuous variable remained significant (p=0.004). Both carriers of the GA and AA genotypes demonstrated, on average, a 13% lower CRP levels in comparison with GG homozygotes. No association was observed between SNPs in the CD163, CXCL9 and TSLP genes and CRP levels. The IFI30 rs11554159 polymorphism could partially explain the inter-individual variability observed in the inflammatory profile associated with obesity.

Effect of the factor VII R353Q missense mutation on plasma apolipoprotein B levels: impact of visceral obesity

AbstractAn atherogenic dyslipidemia, characterized by increased plasma triglyceride and apolipoprotein (apo) B levels, low HDL-cholesterol concentrations and the development of small, dense LDL particles has been associated with the presence of abdominal-visceral obesity. Visceral obesity is also associated with a hypercoagulate state and elevated concentrations of procoagulant factors such as factor VII. Moreover, it is known that some genetic variants in the gene encoding factor VII alter its activity and concentration, and consequently these variants may have an impact on atherosclerosis development. The objective of this study was to verify whether the factor VII R353Q polymorphism contributes to predict the risk of an atherogenic dyslipidemia in absence and in the presence of visceral obesity. A sample of 299 French-Canadian men, selected in order to cover a wide range of body fatness values, participated in this study. We observed that the R353 allele was more commonly observed among men characterized by apo B levels below 1.09 g/l than among men with apo B levels greater or above this threshold value (allele frequency of 92.1 vs 85.4%, χ2=6.18, P=0.01). Multivariate analyses further showed that the genotype R353/R353 was associated with a lower risk to exhibit atherogenic concentrations of total-apo B (≥1.09 g/l) and LDL apo B (≥0.95 g/l) before (odds ratio: 0.47, 95%CI=0.27–0.90, P=0.02; odds ratio:0.46, 95%CI=0.25–0.85, P=0.01, respectively) and after adjustments for age and visceral AT (odds ratio:0.49, 95%CI=0.24–0.91, P=0.02; odds ratio: 0.44, 95%CI=0.23-0.85, P=0.01, respectively). When the two genotype groups were further divided on the basis of visceral adipose tissue (AT) accumulation using a cutoff point of 130 cm2, we observed that R353/R353 homozygotes with low visceral AT were characterized by a more favorable lipoprotein-lipid profile, mainly lower total-cholesterol, total-apo B, and LDL-apo B levels compared with R353/R353 homozygotes with high levels of visceral AT. In contrast, irrespective of obesity, plasma lipid levels among carriers of the Q353 allele were similar to those of viscerally obese men homozygous for the R353 allele. In conclusion, results of the present study suggest that the factor VII R353 allele is associated with lower concentrations of plasma apo B levels. However, the presence of visceral obesity abolishes this effect. Further studies will be necessary to confirm this association and the mechanism involved.