PPARα L162V Research Articles

Gene Influence in the Effectiveness of Plant Sterols Treatment in Children: Pilot Interventional Study.

Cardiovascular disease is linked to high serum low density lipoprotein (LDL)-cholesterol levels. Cardiovascular risk may be indirectly influenced by genetic load. Serum LDL-cholesterol levels may be reduced by the consumption of food enriched with plant sterols (PS). The aim was to test a plant sterol treatment on cholesterol levels according to different genetic polymorphisms. A pilot interventional trial was performed in 26 children (n = 16 girls, n = 10 boys). Seven hundred milliliters/day of commercial skimmed milk with added plant sterols delivering 2.2 g plant sterols were ingested for three weeks. Blood draws were performed at the baseline and end of the study. Significant modifications of non-high density lipoprotein (HDL)-cholesterol (p = 0.010; p = 0.013) and LDL-cholesterol (p = 0.004; p = 0.013) levels appeared in the genes LIPC C-514T and PPAR-α L162V carriers. No statistically significant differences were observed for other genes. LIPC C-514T and PPAR-alpha L162V carriers could benefit from a plant sterol supplement to ameliorate hypercholesterolemia.

PPARγ Pro12Ala and C161T polymorphisms, but not PPARα L162V, are associated with osteoporosis risk in Turkish postmenopausal women

Stimulation of peroxisome proliferator-activated receptors (PPARs) causes mesenchymal stem cells of the human bone marrow differentiate into adipocytes instead of osteoblasts leading to a decreased number of osteoblasts and a decrease in bone mineral density (BMD). Thus, PPARs may have impacts on bone metabolism. 224 postmenopausal women (171 osteoporotic and osteopenic, 53 healthy control) were included in this study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and agarose gel electrophoresis techniques were performed to detect PPARα L162V and PPARγ Pro12Ala/C161T polymorphisms. The distribution of PPARγ Pro12Ala genotype and allele frequencies was not statistically different in control and patient (osteopenic+osteoporotic) groups (p>0.05). However, in the patient group, subjects with “Pro12Pro” genotype had lower lumbar spine (L1-L4) BMD values than those with “Ala” allele (p<0.05). The frequency of PPARγ C161T “CC” genotype was higher in the patient group when compared with that in the control group (p<0.05). There were no significant associations between the genotype and allele frequencies of PPARγ C161T/ PPARα L162V and BMD values (p>0.05). We suggested that PPARγ Pro12Ala and C161T gene variants might be contributing factors in the development of osteoporosis. 

Improvement of cardiometabolic markers after fish oil intervention in young Mexican adults and the role of PPARα L162V and PPARγ2 P12A

Polyunsaturated fatty acids (PUFA) contained in fish oil (FO) are ligands for peroxisome proliferator-activated receptors (PPAR) that may induce changes in cardiometabolic markers. Variation in PPAR genes may influence the beneficial responses linked to FO supplementation in young adults. The study aimed to analyze the effect of FO supplementation on glucose metabolism, circulating lipids and inflammation according to PPARα L162V and PPARγ2 P12A genotypes in young Mexican adults. 191 young, non-smoking subjects between 18 and 40 years were included in a one-arm study. Participants were supplemented with 2.7 g/day of EPA+DHA, during six weeks. Dietary analysis, body composition measurements and indicators for glucose metabolism, circulating lipids, and markers for inflammation were analyzed before and after intervention. An overall decrease in triglycerides (TG) and an increase in HS-ω3 index were observed in all subjects [−4.1 mg/dL, (SD:±51.7), P=.02 and 2.6%, (SD:±1.2), P<.001 respectively]. Mean fasting insulin and glycated hemoglobin (HbA1c%) were significantly decreased in all subjects [−0.547mlU/L, (SD:±10.29), P=.034 and−0.07%, (SD:±0.3), P<.001 respectively], whereas there was no change in body composition, fasting glucose, adiponectin and inflammatory markers. Subjects carrying the minor alleles of PPARα L162V and PPARγ2 P12A had higher responses in reduction of TG and fasting insulin respectively. Interestingly, doses below 2.7 g/day (1.8 g/day) were sufficient to induce a significant reduction in fasting insulin and HbA1c% from baseline (P=.019 and P<.001). The observed responses in triglycerides and fasting insulin in the Mexican population give further evidence of the importance of FO supplementation in young people as an early step towards the prevention of cardiometabolic disease.

Screening of Peroxisome Proliferator-Activated Receptors (PPARs) α, γ and α Gene Polymorphisms for Obesity and Metabolic Syndrome Association in the Multi-Ethnic Malaysian Population.

This study aimed to investigate the association of peroxisome proliferator-activated receptor (PPAR) genes PPARα L162V, PPARγ2 C161T and PPARδ T294C single nucleotide polymorphisms (SNPs) with obesity and metabolic syndrome (Met-S) in a multi-ethnic population in Kampar, Malaysia. Socio-demographic data, anthropometric and biochemical measurements (plasma lipid profile, adiponectin and interleukin-6 [IL-6] levels) were taken from 307 participants (124 males; 180 obese; 249 Met-S; 97 Malays, 85 ethnic Chinese, 55 ethnic Indians). The overall minor allele frequencies were .08, .22 and .30 for PPAR α L162V, γ C161T, δ T294C, respectively. All SNPs were not associated with obesity, Met-S and obesity with/without Met-S by χ(2) analysis, ethnicity-stratified and logistic regression analyses. Nevertheless, participants with V162 allele of PPARα had significantly higher IL-6, while those with T161 allele of PPARγ2 had significantly lower HOMA-IR. All PPAR SNPs were not associated with obesity and Met-S in the suburban population of Kampar, Malaysia, where only PPARα V162 and PPARγ2 T161 alleles were associated with plasma IL-6 and HOMA-IR, respectively.

Effects of Plasma Phospholipid Fatty Acid Composition and PPAR‐alpha L162V Polymorphism on C‐reactive Protein Levels in Response to an n‐3 Fatty Acid Supplementation

Background Fish-oil derived fatty acids (FAs) of the n-3 family including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce inflammation through several underlying mechanisms including altered phospholipids FA composition. The L162V polymorphism of the PPAR-α gene is associated with a deteriorated metabolic profile and with obesity indices in numerous studies. Objective: To study whether the PPAR-α L162V polymorphism and changes in plasma phospholipid FA composition influence plasma C-reactive protein (CRP) levels in healthy adults following the n-3 FA supplementation. Method: 189 subjects were supplemented daily with 3g of n-3 FAs (1.9-2.2g EPA and 1.1g DHA) during six weeks. Changes in CRP levels are defined by Δ CRP and changes in plasma phospholipids n-3 (EPA+DHA) by Δ n-3. Results: In univariate analyses, Δ n-3 was negatively correlated with Δ CRP (r=-0.17 p=0.02). After stratification for sex, correlations were stronger in men (r=-0.24 p=0.02) and no longer significant in women (r=-0.11 p=0.31). In multiple linear regression analyses including age, sex, BMI, and hormonal contraceptives as independent variables, Δ n-3 (3.65% p= 0.01) and PPAR-α L162V (2.10% p= 0.04) were the strongest correlates of Δ CRP. Conclusions These results suggest that the incorporation of n-3 FAs in plasma phospholipids and PPAR-α L162V polymorphism may contribute to changes in plasma CRP levels in response to an n-3 FA supplementation. Funding provided by CIHR Operating Grant.

Effects of Peroxisome Proliferator-Activated Receptors, Dietary Fat Intakes and Gene–Diet Interactions on Peak Particle Diameters of Low-Density Lipoproteins

The risk of cardiovascular diseases (CVDs) is modulated by gene–diet interactions. The objective of this study was to examine whether gene–diet interactions affect peak particle diameters (PPD) of low-density lipoprotein (LDL). Methods: The study included 674 participants. A food frequency questionnaire was administered to obtain dietary information. LDL-PPD was determined by non-denaturing 2–16% polyacrylamide gradient gel electrophoresis. Peroxisome proliferator-activated receptor (PPAR) gene polymorphisms PPARα L162V (rs1800206), PPARγ P12A (rs1801282) and PPARδ –87T→C (rs2016520) were determined by PCR-RFLP. Results: Among carriers of thePPARα L162V polymorphism, gene–diet interaction effects on LDL-PPD were observed with saturated fat (p = 0.0005) and total dietary fat (p = 0.006). Among PPARα V162 carriers, subjects with higher saturated fat intakes had smaller LDL-PPD than those with lower intakes (254.23 ± 2.74 vs. 256.21 ± 2.61 Å, respectively, p = 0.007). Among subjects homozygous for the PPARα L162 allele, those with higher saturated fat intakes had larger LDL-PPD than those with lower saturated fat intakes (255.86 ± 2.66 vs. 255.05 ± 2.65 Å, respectively, p = 0.01). Gene–diet interactions were also found for PPARγ P12A polymorphism with saturated fat intake (p = 0.04) and for PPARδ –87T→C with the polyunsaturated/saturated fat ratio (p = 0.0013). Conclusions: These results stress that dietary factors should be included in studies determining the effect of different polymorphisms on CVD risk factors.

No association between peroxisome proliferator-activated receptor and uncoupling protein gene polymorphisms and obesity in Malaysian university students

Peroxisome proliferator-activated receptors (PPARs) and uncoupling proteins (UCPs) are expressed in adipose tissue, where PPARs are nuclear receptors that function as transcription regulators of the expression of UCPs, mitochondria proteins which uncouple protons in exchange of heat released. The PPARα L162V; PPARγ2 C161T; UCP1 -3826A/G; UCP2 45 bp Ins/Del and -866G/A; and UCP3 -55C/T gene polymorphisms have been previously associated with obesity in different populations, but with inconclusive findings. This study was to investigate the prevalence of these gene polymorphisms and their possible association with obesity in a cohort of Malaysian university students in Kuala Lumpur. Random convenience sampling was performed with informed consents and anthropometric measurements were taken. Mouthwash samples were obtained for genomic DNA extraction and genotyping was performed using Polymerase Chain Reaction - Restriction Fragment Length Polymorphism. Out of the 256 subjects (140 males and 116 females), 170 were lean and 86 were overweight/obese. The mutated PPARα L162V; PPARγ2 C161T; UCP1 -3826A/G; UCP2 45 bp Ins/Del and -866G/A; and UCP3 -55C/T allele frequencies were 0.006, 0.36, 0.58, 0.12, 0.56 and 0.34, respectively. This study failed to find significant differences in the anthropometric indicators of obesity (Body Mass Index, Waist-Hip Ratio and Total Body Fat) between the genotypes of all the PPAR and UCP gene variants. Overall, the genotype and allele distributions were also not significantly different between genders and BMI status. In conclusion, overweight/obesity is not prevalent among the Malaysian university students and the PPAR and UCP gene polymorphisms are not associated with obesity.:

Omega-3 fatty acids regulate gene expression levels differently in subjects carrying the PPARα L162V polymorphism

Omega-3 fatty acids (FAs) are natural ligands of the peroxisome proliferator-activated receptor-alpha (PPARalpha), a nuclear receptor that modulates expression levels of genes involved in lipid metabolism. The L162V polymorphism of the PPARalpha gene is associated with a deteriorated metabolic profile. We postulate that subjects carrying the PPARalpha-V162 allele exhibit differences in the expression of PPARalpha and its target genes after incubation with omega-3 FAs compared with L162 homozygotes. Peripheral blood monocytes from six men carrying the PPARalpha-V162 allele paired for age and for body mass index with six L162 homozygotes were differentiated into macrophages and activated with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or mixtures of EPA:DHA. Data demonstrates that gene expression levels of PPARalpha and apolipoprotein AI (APOA1) were significantly lower for carriers of the PPARalpha-V162 allele compared to L162 homozygotes after the addition of DHA and a mixture of EPA:DHA. Additionally, lipoprotein lipase (LPL) gene expression displayed a tendency to be lower in the PPARalpha L162V polymorphism subgroup after the addition of a mixture of EPA:DHA. Consequently, individuals carrying the PPARalpha-V162 allele may demonstrate inferior improvements in their lipid profile due to alterations in gene expression rates in response to omega-3 FA supplementation.

Plasman-3 fatty acid response to ann-3 fatty acid supplement is modulated by apoE ɛ4 but not by the common PPAR-α L162V polymorphism in men

The risk of Alzheimer's disease is increased for carriers of apoE4 (E4) or the PPAR-alpha L162V polymorphism (L162V), but it is decreased in fish and seafood consumers. The link between high fish intake and reduced risk of cognitive decline in the elderly appears not to hold in carriers of E4, possibly because better cognition is linked to EPA+DHA in the blood, but only in non-carriers of E4. As yet, no such studies exist in carriers of L162V. Our objective was to determine whether the plasma fatty acid response to a dietary supplement of EPA+DHA was altered in carriers of L162V and/or E4. This was an add-on project; in the original study, men were selected based on whether or not they were carriers of L162V (n 14 per group). E4 status was determined afterwards. All subjects received an EPA+DHA supplement for 6 weeks. L162V polymorphism did not interact with the supplement in a way to alter EPA and DHA incorporation into plasma lipids. However, when the groups were separated based on the presence of E4, baseline EPA and DHA in plasma TAG were 67 and 60 % higher, respectively, in E4 carriers. After the supplementation, there were significant gene x diet interactions in which only non-carriers had increased EPA and DHA in plasma NEFA and TAG, respectively.

PPAR-α L162V and PGC-1 G482S gene polymorphisms, but not PPAR-γ P12A, are associated with alcohol consumption in a Spanish Mediterranean population

Background Peroxisome Proliferator-Activated Receptors (PPARs) and its co-activators are regulatory elements of the cellular lipid homeostasis and have been associated with feeding behavior modulation. Animal models suggest that these genes may be involved in alcohol consumption regulation. However, no studies in humans exist. Our aim is to estimate the possible association between polymorphisms in the PPAR-α, PPAR-γ and PPAR-γ co-activator 1A ( PGC-1A) genes and alcohol consumption in humans. Methods We have conducted a cross-sectional study between the PPAR-α L162V, PPAR-γ P12A and PGC-1A G482S polymorphisms, and alcohol consumption in a general Mediterranean Spanish population (303 men and 443 women). Results We have found an association between the L162V polymorphism and alcohol consumption in which, carriers of the V allele were more prevalent among alcohol consumers (19.4% vs. 9.8%; OR 2.69; 95% CI: 1.31–5.54, p = 0.007). The G482S polymorphism showed a significantly higher frequency in the group of high alcohol drinkers than in non-high alcohol drinkers (33.4% vs. 20.6%; OR 2.28; 95% CI: 1.07–4.88, p = 0.034). Mean alcohol consumption was higher as the number of G alleles increased (GG 8.6 ± 12.8 g/day, GS 6.6 ± 9.2 g/day, SS 5.6 ± 7.8 g/day, p = 0.003). These results remained statistically significant after covariate adjustment. Conclusions PPAR-α L162V and PGC-1A G482S polymorphisms are associated with alcohol consumption in the Mediterranean population.

Effect of the PPAR-Alpha L162V Polymorphism on the Cardiovascular Disease Risk Factor in Response to n–3 Polyunsaturated Fatty Acids

Background: Dietary n–3 polyunsaturated fatty acids (PUFAs) decrease the risk of cardiovascular disease (CVD). Yet, genetic variations of the gene encoding the peroxisome proliferator-activated receptor-α (PPARα) can also modulate CVD risk factors. Since fatty acids, including n–3 PUFAs, are natural ligands of PPARα, a gene-diet interaction effect could be observed. Aims: To examine whether n–3 PUFA- induced changes in CVD risk factors are influenced by the PPARα L162V polymorphism. Methods: Fourteen men, carriers of the V162 allele and 14 L162 homozygotes, were matched according to age and body mass index. Subjects followed, for 8 weeks, a low-fat diet and then were supplemented daily with 5 g of fish oil for 6 weeks. Results: Baseline characteristics were similar for both genotype groups. Independently of the genotype, the supplementation was associated with a significant decrease in plasma triacylglycerol and fasting glucose concentrations, diastolic blood pressure, and with an increase in total apolipoprotein B concentrations. The extent of the decrease in plasma triacylglycerol concentrations was comparable for both genotype groups (p < 0.03). A significant genotype-by-diet interaction effect was observed for plasma C-reactive protein concentrations (p = 0.01). Conclusions: The PPARα L162V polymorphism may contribute to the interindividual variability in the CVD risk factor response to n–3 PUFAs.

PPARα L162V underlies variation in serum triglycerides and subcutaneous fat volume in young males

BackgroundOf the five sub-phenotypes defining metabolic syndrome, all are known to have strong genetic components (typically 50–80% of population variation). Studies defining genetic predispositions have typically focused on older populations with metabolic syndrome and/or type 2 diabetes. We hypothesized that the study of younger populations would mitigate many confounding variables, and allow us to better define genetic predisposition loci for metabolic syndrome.MethodsWe studied 610 young adult volunteers (average age 24 yrs) for metabolic syndrome markers, and volumetric MRI of upper arm muscle, bone, and fat pre- and post-unilateral resistance training.ResultsWe found the PPARα L162V polymorphism to be a strong determinant of serum triglyceride levels in young White males, where carriers of the V allele showed 78% increase in triglycerides relative to L homozygotes (LL = 116 ± 11 mg/dL, LV = 208 ± 30 mg/dL; p = 0.004). Men with the V allele showed lower HDL (LL = 42 ± 1 mg/dL, LV = 34 ± 2 mg/dL; p = 0.001), but women did not. Subcutaneous fat volume was higher in males carrying the V allele, however, exercise training increased fat volume of the untrained arm in V carriers, while LL genotypes significantly decreased in fat volume (LL = -1,707 ± 21 mm3, LV = 17,617 ± 58 mm3 ; p = 0.002), indicating a systemic effect of the V allele on adiposity after unilateral training. Our study suggests that the primary effect of PPARα L162V is on serum triglycerides, with downstream effects on adiposity and response to training.ConclusionOur results on association of PPARα and triglycerides in males showed a much larger effect of the V allele than previously reported in older and less healthy populations. Specifically, we showed the V allele to increase triglycerides by 78% (p = 0.004), and this single polymorphism accounted for 3.8% of all variation in serum triglycerides in males (p = 0.0037).

PPARα L162V Shows Strong Sex-Specific Effects on Subcutaneous Arm Fat Volume

PURPOSE: To identify genetic associations with regional subcutaneous fat volume in 440 normal young adult volunteers. METHODS: Magnetic resonance imaging (MRI) was done for both upper arms before and after 12 wk unilateral supervised resistance training, with subcutaneous fat volume calculated using semi-automated analysis from an anatomical landmark. We tested 13 polymorphisms from 9 genes for association with baseline fat volume and also for changes in fat volume after training. Each of these candidate loci had been previously shown to be associated with some other measure of adiposity. RESULTS: We found a strong correlation between BMI and regional arm subcutaneous fat in our young adult population (women R2 = 0.757; P<0.001; men R2 = 0.661; P<0.001). Eight of the nine genes tested showed no strong association with regional subcutaneous fat volume in young adults in either sex (ACE, AGRP, ADRß1, ADRß2, ADRß3, LEPR, and TNFα). We found strong statistical support for one gene as a quantitative trait locus (QTL) for subcutaneous fat: PPARα?(L162V). PPARα?was associated with baseline subcutaneous fat in Caucasian men (p= 0.002; n=113; ancestral 162L allele lower fat), but not women. Male heterozygotes for this polymorphism showed a 48.5% to 58% greater baseline subcutaneous fat relative to wild-type homozygotes and explained 7.0–9.3% of all population variation in subcutaneous fat volume in Caucasian male young adults. The Valine allele was associated with greater BMI in Caucasian men (p= 0.002) (CC genotype = 24.6, CG genotype = 28.0). CONCLUSION: A PPARα polymorphism, L162V, was found to be strongly associated with subcutaneous fat and BMI in Caucasian men, but not women. This polymorphism did not contribute to adiposity in African-Americans or Asians due to very low allele frequency. We present a model explaining differing effects of PPARα polymorphism dependent on age, sex, hormonal status, and circulating fatty acid levels that is consistent with all biochemical and genetic studies to date.

Peroxisome Proliferator-Activated Receptor α L162V Polymorphism in Nonalcoholic Steatohepatitis and Genotype 1 Hepatitis C Virus-Related Liver Steatosis

BackgroundPeroxisome proliferator-activated receptor α (PPARα) plays important roles in lipid metabolism. A recently discovered L162V polymorphism of the PPARα gene is associated with enhanced transcriptional activity. In this study, the...

The peroxisome proliferator-activated receptor delta +294T/C polymorphism in relation to lipoprotein metabolism in patients with diabetes mellitus type 2 and in non-diabetic controls

Objective Peroxisome proliferator-activated receptor δ (PPARδ) is an ubiquitously expressed transcription factor that has been implicated in the regulation of genes related to cholesterol metabolism. Conflicting results exist regarding the association of the recently described +294T/C polymorphism in the 5′-untranslated region (5′-UTR) in exon 4 of the PPARδ gene and plasma lipoprotein concentrations. Purpose of the present study was to examine for the first time in a German population and for the first time also in women the presence of a potential association between the aforementioned polymorphism and lipoprotein concentrations in patients with diabetes mellitus type 2 (DM-2) and in non-diabetic controls. Furthermore, a possible gene–gene interaction between the PPARδ +294T/C polymorphism and the PPARα L162V polymorphism was examined. Design and methods We determined by PCR the polymorphism in a total of 402 patients with DM-2 (230 men and 172 women) and in 436 healthy controls (248 men and 188 women) from the LIANCO study (lipid analytic cologne). Results The genotype distribution was not different between DM-2 and controls (+294TT 65.6% versus 66.7%, +294TC 30.5% versus 29.4%, +294CC 3.9 versus 4.0%, respectively). There was no difference in the low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) or triglyceride (TG) concentrations between carriers and non-carriers of the rare C allele in the DM-2 population. In specific, the heterozygotes for the C allele had LDL-C concentrations of 157 ± 80 mg/dl, HDL-C of 54 ± 17 mg/dl and TG of 273 ± 507 mg/dl, while the C allele homozygotes had concentrations of LDL-C 149 ± 44 mg/dl, HDL-C of 59 ± 21 mg/dl and TG of 197 ± 110 mg/dl. The LDL-C, HDL-C and TG concentrations of TT homozygotes were 156 ± 49 mg/dl, 56 ± 18 mg/dl and TG 225 ± 242 mg/dl, respectively. The same lack of association was present in the non-diabetic controls, both in men and in women. There was no association between the genotypes and body mass index. Furthermore, no gene–gene interaction between the PPARδ +294TC and the PPARα L162V polymorphism was observed regarding lipoprotein concentrations and atherosclerotic disease. Conclusions The data suggest that the PPARδ +294T/C polymorphism has no influence on plasma lipoprotein concentrations, body mass index or atherosclerotic disease either in healthy subjects or in patients with DM-2, both in males and females.

Association between the PPARα L162V polymorphism, plasma lipoprotein levels, and atherosclerotic disease in patients with diabetes mellitus type 2 and in nondiabetic controls

Background Peroxisome proliferator activated receptor alpha (PPARα) regulates genes involved in lipoprotein metabolism, hemostasis, and inflammation. It thus represents a candidate gene for the risk of dyslipidemia, atherosclerosis, and coronary heart disease (CHD). Nonesterified fatty acids are PPARα ligands and their levels are increased in patients with diabetes mellitus type 2 (DM-2). The effects of the polymorphism of PPARα on plasma lipids and atherosclerosis development have been until now contradictory. The present study was performed to evaluate the association between the PPARα polymorphism L162V and the presence of dyslipidemia and/or atherosclerotic disease in patients with DM-2 in comparison with nondiabetic controls. Methods and results We determined this polymorphism in 404 subjects with DM-2 and in 438 age and sex-matched nondiabetic controls. The V allele was present in 9.4% of patients with DM-2 and in 11.4% of the control group ( P = .34). There was no significant association between the presence of the polymorphism and body mass index. There was no association between the polymorphism and lipoprotein concentrations in either group, independent of lipid-lowering therapy. In patients with DM-2, there was a trend towards a lower prevalence of atherosclerosis in carriers versus noncarriers of the V allele ( P = .0837). In the control group, the presence of the V allele was not associated with an altered prevalence of atherosclerotic disease ( P = .45). Likewise, there was a trend towards lower CHD prevalence in carriers versus noncarriers of the V allele ( P = .0622). The presence of the polymorphism was not associated with CHD in the control group ( P = .80). Conclusions The data suggest that the PPARα polymorphism L162V might protect against the development of atherosclerosis or CHD in patients with DM-2. The absence of an association between the polymorphism and plasma lipoprotein concentrations may suggest that these protective effects are exerted directly on the arterial wall.

Combined effects of PPARγ2 P12A and PPARα L162V polymorphisms on glucose and insulin homeostasis: the Québec Family Study

Peroxisome proliferator-activated receptors gamma2 and alpha are nuclear factors known to be important regulators of lipid and glucose metabolism. Two polymorphisms, namely PPARgamma2 P12A and PPARalpha L162V, were investigated for their individual and interaction effects on glucose and insulin homeostasis. Genotypes were determined in 663 nondiabetic adults participating in the Québec Family Study and who underwent an oral glucose tolerance test (OGTT). The insulin and C-peptide areas under the curve (AUC) following the OGTT were higher in subjects carrying the PPARalpha V162 allele compared to homozygous for the L162 allele. When subjects were grouped according to both polymorphisms, higher levels of insulin and C-peptide during the OGTT were observed for those carrying the PPARalpha V162 allele except when they carry at the same time the PPARgamma2 A12 allele. Thus, the PPARgamma2 A12 allele seems protective against the deleterious effect of the PPARalpha V162 allele. Furthermore, a significant gene-gene interaction was observed for the acute (0-30 min) (p<0.001) and the total (p=0.05) C-peptide AUC following the OGTT. These results provide evidence of a gene-gene interaction in the regulation of plasma glucose-insulin homeostasis, and emphasize that these interactions need to be taken into account when dissecting the genetic etiology of complex disorders.