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.     

PPAR-gamma2 Pro12Ala polymorphism in the population of obese and non-obese men of the city of Wroclaw

INTRODUCTION: The aim of this study was to examine the association of Pro12Ala PPARgamma2 polymorphism with anthropometric and biochemical parameters defining the risk for the development of metabolic syndrome in a healthy population of men. MATERIAL AND METHODS: The study group consisted of 176 healthy men, aged 25-65 years (average 54.16 years). Polymorphisms of the PPAR-g gene (Pro12Ala, Ala12Ala, Pro12Pro) were explored using the PCR-RFLP method. Plasma glucose, insulin, total cholesterol, LDL, HDL and TG were measured using commercially available kits. RESULTS: The genotypic distribution of the Pro12Ala polymorphism was as follows: Pro/Ala 69.8% (n = 123), Ala/Ala 28.4% (n = 50) and Pro/Pro 1.8% (n = 3). The Pro12Ala and Ala12Ala subjects did not differ in any of the measured variables. The non-obese (BMI < 30 kg/m(2), n = 117) and obese subpopulations (BMI > 30 kg/m(2), n = 56) did not significantly differ in the distribution of the genotypes. In the nonobese subpopulation, the homozygous Ala12 carriers (n = 38, 32.4%) had higher systolic blood pressure, plasma triglycerides, insulin levels and HOMA-IR. CONCLUSIONS: We conclude that despite the high frequency of the Ala allele at the PPAR-gamma2 gene in our population of Polish men, the Ala12 allele does not appear to improve insulin sensitivity or have an influence on the occurrence of obesity. It remains to be explained by larger studies if this polymorphism carries any risk of the development of metabolic abnormalities in non-obese men.     

Evidence for greater oxidative substrate flexibility in male carriers of the Pro 12 Ala polymorphism in PPARgamma2.

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) gene is associated with reduced type 2 diabetes risk and increased insulin sensitivity. It is possible that the oxidative shift from lipid to glucose as a fuel is more efficient in Ala allele carriers. To test this hypothesis, we examined carbohydrate and lipid oxidation by indirect calorimetry in lean, glucose tolerant subjects with (X/Ala, n = 25) and without the Pro12Ala polymorphism (Pro/Pro, n = 73) basally and after insulin stimulation during a 2-hour eugylcaemic hyperinsulinaemic clamp. Insulin sensitivity was non-significantly greater in X/Ala (0.13 +/- 0.01 micromol/kg/min/pM) than in Pro/Pro (0.12 +/- 0.01 micromol/kg/min/pM, p = 0.27). Basally, there were no lipid nor carbohydrate oxidation differences between the groups. Interestingly, the decrease in lipid oxidation during insulin stimulation was significantly greater in male X/Ala (- 0.51 +/- 0.06 mg/kg/min) than in male Pro/Pro (- 0.35 +/- 0.04 mg/kg/min, p = 0.03). No difference was observed in females. Analogously, the change in carbohydrate oxidation in male X/Ala (1.34 +/- 0.2 mg/kg/min) was significantly greater than in male Pro/Pro (1.03 +/- 0.12 mg/kg/min, p = 0.05). The respiratory quotient increased more, but not significantly more, in male X/Ala (0.11 +/- 0.01) than in male Pro/Pro subjects (0.08 +/- 0.01, p = 0.08) but similarly in females. These results indicate that the mechanism by which the Ala allele improves insulin sensitivity might involve enhanced suppression of lipid oxidation permitting more efficient (predominantly non-oxidative) glucose disposal. It is unclear why this could be demonstrated only in males, although gender differences in substrate oxidation are well documented.     

Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma is associated with increased leptin levels in women with type-2 diabetes mellitus

OBJECTIVE: To analyze the relationship between the peroxisome proliferator-activated receptor-gamma (PPARgamma2) Pro12Ala variant and type-2 diabetes mellitus and its correlation with some cytokine determinants of insulin resistance such as tumor necrosis factor (TNF)-alpha and leptin. METHODS: The PPARgamma2 Pro12Ala genetic polymorphism was studied in 167 type-2 diabetic patients and 63 healthy controls. Serum leptin and plasma-soluble TNF-R2 were measured. RESULTS: Women carriers of the Pro12Ala mutation exhibited higher leptin levels than women non-carriers (median 31.4 vs. 17.5 ng/ml; p < 0.005). sTNF-R2 levels did not show differences between the two genotypes. Analysis by the multiple linear regression model of leptin-body mass index controlled by the PPARgamma2 genotype showed that leptin levels were determined by the Pro12Ala mutation in type-2 diabetic women but not in men. CONCLUSIONS: PPARgamma2 seems to be implicated in leptin homeostasis in type-2 diabetic women.     

Impact of the <Emphasis Type="Italic">PPAR gamma-2</Emphasis> gene polymorphisms on the metabolic state of postmenopausal women

The relationship Pro12Ala (rs1801282) and C1431T (rs3856806) polymorphisms of PPAR gamma-2 with glucose and lipid metabolism is not clear after menopause. We investigated the impact of the Pro12Ala and C1431T silent substitution in the 6th exon in PPAR gamma-2 gene on nutritional and metabolic status in 271 postmenopausal women (122 lean and 149 obese). The general linear model (GLM) approach to the two-way analysis of variance (ANOVA) was used to infer the interactions between the analysed genotypes. The frequency of the Pro-T haplotype was higher in obese than in lean women (p<0.0349). In the analysed GLM models according to obesity status, the C1431C genotype was related to a lower glucose concentration (β=?0.2103) in lean women, and to higher folliculotropic hormone FSH levels (β=0.1985) and lower waist circumferences (β=?0.1511) in obese women. The influence of C1431C was present regardless of the occurrence of the Pro12Ala polymorphism. The co-existence of the C1431C and Pro12Pro genotypes was related to lower values for triceps skinfold thickness compared those for the T1241/X and Ala12/X polymorphisms (β=?0.1425). The presence of C1431C decreased the differences between triceps values that were determined by Pro or Ala allele. In conclusion, C1431T polymorphism seems to have a more essential influence on anthropometric and biochemical parameters than is the case with Pro12Ala polymorphism.     

PPARgamma2 Pro12Ala polymorphism in relation to free fatty acids concentration and composition in lean healthy Czech individuals with and without family history of diabetes type 2

Free fatty acids (FFAs) are natural ligands of the PPARgamma2 receptor. FFA plasma concentration and composition may represent one of the factors accounting for high heterogeneity of conclusions concerning the effect of the Pro12Ala on BMI, insulin sensitivity or diabetes type 2 (DM2) susceptibility. Our objective was to investigate the relation and possible interactions between the Pro12Ala polymorphism and FFA status, metabolic markers, and body composition in 324 lean nondiabetic subjects (M/F: 99/225; age 32+/-11 years; BMI 23.9+/-4.0 kg/m(2)) with and without family history of DM2. Family history of DM2 was associated with lower % PUFA and slightly higher % MUFA. The presence of Pro12Ala polymorphism was not associated with fasting plasma FFA concentration or composition, anthropometric or metabolic markers of glucose and lipid metabolism in tested population. However, the interaction of carriership status with FFA levels influenced the basal glucose levels, insulin sensitivity and disposition indices, triglycerides, HDL-cholesterol and leptin levels, especially in women. The metabolic effects of 12Ala carriership were influenced by FFA levels - the beneficial role of 12Ala was seen only in the presence of low concentration of plasma FFA. Surprisingly, a high PUFA/SFA ratio was associated with lower insulin sensitivity, the protective effect of 12Ala allele was apparent in subjects with family history of DM2. On the basis of our findings and published data we recommend the genotyping of diabetic patients for Pro12Ala polymorphism of the PPARgamma2 gene before treatment with thiazolidinediones and education of subjects regarding diet and physical activity, which modulate metabolic outcomes.     

Alcohol intake modulates the genetic association between HDL cholesterol and the PPARgamma2 Pro12Ala polymorphism

The peroxisome proliferator-activated receptor gamma (PPARgamma) Pro12Ala polymorphism affects plasma lipids, but to what extent alcohol intake interferes with this association remains unknown. We randomly recruited 251 nuclear families (433 parents and 493 offspring) in the framework of the European Project on Genes in Hypertension study and genotyped 926 participants in whom all serum lipid variables and information on alcohol consumption were available for PPARgamma2 Pro12Ala. Genotype-phenotype relations were assessed using generalized estimating equations (GEE) and a quantitative transmission disequilibrium test (QTDT). The Ala12 allele was more frequent in Novosibirsk (0.17) than in Cracow (0.12) and Mirano (0.11) (P < 0.01). Using GEE (P = 0.03) or QTDT (P = 0.007), Italian offspring carrying the Ala12 allele had higher serum HDL cholesterol than noncarriers. HDL cholesterol levels were on average 0.086 mmol/l (P = 0.001) higher in drinkers than in nondrinkers. Compared with Pro12 homozygotes, Ala12 allele carriers consuming alcohol had higher serum total and HDL cholesterol, with the opposite trend occurring in nondrinkers. This genotype-alcohol interaction was independent of the type of alcoholic beverage and more pronounced in moderate than in heavy drinkers. We conclude that alcohol intake modulates the relation between the PPARgamma2 Pro12Ala and HDL cholesterol level and that, therefore, the Pro12Ala polymorphism, pending confirmation of our findings, might affect cardiovascular prognosis.     

Impact of peroxisome proliferator-activated receptors gamma and delta on adiposity in toddlers and preschoolers in the GENESIS Study

Peroxisome proliferator-activated receptor gamma (PPAR gamma) and peroxisome proliferator-activated receptor delta (PPAR delta) are promising candidate genes for obesity. Associations between adiposity-related phenotypes and genetic variation in PPAR gamma (Pro12Ala and C1431T), as well as PPAR delta (T+294C) were assessed in 2,102 Greek children aged 1-6 years, as part of a large-scale epidemiological study (Growth, Exercise and Nutrition Epidemiological Study In preSchoolers). In girls aged 3-4 years, the Ala12 allele was associated with higher mid-upper arm (P = 0.010) and hip (P = 0.005) circumferences, as well as subscapular (P = 0.008) and total skinfolds (P = 0.011) that explained 2.0, 3.7, 2.1, and 1.9% of the phenotypic variance, respectively, while the T1431 allele was associated with higher mean values for waist circumference (P = 0.018) and suprailiac skinfold (P = 0.017), genotype accounting for 1.6% of the variance in both phenotypes. No significant effects of PPAR delta T+294C polymorphism or the interaction of the PPAR delta and PPAR gamma variants on adiposity-related phenotypes were observed in any age group or gender. Haplotype-based analysis including both PPAR gamma polymorphisms revealed that in girls aged 3-4 years, the Ala-T haplotype was associated with higher waist (P = 0.014) and hip (P = 0.007) circumferences compared to the common Pro-C haplotype. The PPAR gamma Pro12Ala and C1431T polymorphisms are associated with increased adiposity during early childhood in a gender- and age-specific manner and independently of the PPAR delta T+294C polymorphism.     

Peroxisome proliferator-activated receptor gamma 2 and acyl-CoA synthetase 5 polymorphisms influence diet response

Peroxisome proliferator-activated receptor gamma (PPARgamma) and its response gene, Acyl CoA synthetase 5 (ACSL5), which has an important role in fatty acid metabolism, may affect weight loss in response to caloric restriction. Therefore, we aimed to determine whether these genes were involved in the interindividual response to dietary treatment. Genotypic/phenotypic comparisons were made between selected obese women from the quintiles losing the most (diet responsive, n = 74) and the quintiles losing the least (diet-resistant, n = 67) weight in the first 6 weeks of a 900-kcal formula diet. Two common PPARgamma single nucleotide polymorphisms, Pro(12)Ala and C1431T, and eight polymorphisms across the ACSL5 gene were selected for single locus and haplotypic association analyses. The PPARgamma Pro(12)Ala single nucleotide polymorphism was associated with diet resistance (odds ratio = 3.48, 95% confidence interval = 1.41 to 8.56, p = 0.03), and the rs2419621, located in the 5'untranslated region of the ACSL5 gene, displayed the strongest association with diet response (odds ratio = 3.45, 95% confidence interval = 1.61 to 7.69, p = 0.001). Skeletal muscle ACSL5 mRNA expression was significantly lower in carriers of the wildtype compared with the variant rs2419621 allele (p = 0.03). Our results suggest a link between PPARgamma2 and ACSL5 genotype and diet responsiveness.     

Influence of the PPAR-gamma2 Pro12Ala and ACE I/D polymorphisms on insulin sensitivity and training effects in healthy offspring of type 2 diabetic subjects.

Aerobic endurance training improves insulin sensitivity, and is of great importance in the prevention and treatment of type 2 diabetes. The improvement in insulin sensitivity and cardiovascular function through exercise is highly variable among individuals, and is probably partly determined by genetic components. This study evaluated the peroxisome proliferation-activated receptor-gamma2 ( PPAR-gamma2) Pro12Ala polymorphism and the angiotensin converting enzyme ( ACE) I/D polymorphism with respect to any potential influence that these highly prevalent polymorphisms may impose on changes in insulin sensitivity and maximal aerobic capacity induced by exercise. Seventy-nine healthy first-degree relatives of type 2 diabetic patients were compared to a control group consisting of 54 subjects without any family history of type 2 diabetes. All subjects had a normal OGTT. The groups were comparable with respect to age (34 +/- 7 vs. 33 +/- 7 years), gender ((m/f) 43/36 vs. 30/24) and BMI (25.7 +/- 2.6 vs. 25.3 +/- 2.5 kg/m (2)); p (all) = NS. Furthermore, a subgroup of 29 offspring and 17 control subjects were engaged in a standardized training program lasting ten weeks. Insulin sensitivity (hyperinsulinemic euglycemic clamp technique) and VO (2)max (exhaustive exercise test) was assessed before and after the training period. We will demonstrate the allelic frequency of the Ala-allele of the Pro12Ala polymorphism to be lower in offspring to type 2 diabetic patients (13.3 %) compared to control subjects (21.3 %); p < 0.05. In offspring only, the Pro12Ala polymorphism of the PPAR-gamma2 gene appeared to enhance weight changes brought about by exercise (Deltaweight = - 0.3 +/- 1.4 kg vs. - 1.8 +/- 1.8 kg; p < 0.05; (Pro/Pro vs. Pro/Ala + Ala/Ala) - suggesting possible gene-environment or gene-gene interactions. The ACE I/D polymorphism was not of significant importance in determining the capability of responding to exercise in terms of improvement in insulin sensitivity or maximal aerobic capacity.     

Gene–diet-related factors of hyperglycaemia in postmenopausal women

As ageing and increased body fat are the signs of insulin resistance, we have studied whether the presence of Pro12Ala and C1431T of peroxisome proliferator-activated receptor gamma 2 gene and Trp64Arg of beta 3-adrenergic receptor gene may predispose to the hyperglycaemia development in postmenopausal women, who have never undergone hypoglycaemic treatment. The distributions of selected allele and genotype frequencies were determined by the PCR–RFLP method in normo- and hyperglycaemic, who have never been diagnosed and treated for diabetes mellitus were measured. The amount of body fat and lean body mass (LBM) were assessed by the bioimpedance method and nutritional habits by 7-day dietary recall. There were no differences between the distribution of genotypes and the allele frequencies of the Pro12Ala, C1431T and Trp64Arg polymorphisms in normo- and hyperglycaemic women. Hyperglycaemic women were characterized by visceral obesity, hypertension, higher serum insulin and triglycerides, higher intake of fat and lower consumption of complex carbohydrates and B vitamins. Normoglycaemic women with Pro12Pro polymorphism acquired higher energy from dietary fat (p?<?0.0276) and lower energy from carbohydrates (p?<?0.0480) than normoglycaemic Ala12 carriers. Subjects with Pro12Pro polymorphism and LBM >?58% of total body mass or with Trp64Trp and normal triglycerides have higher chance of normoglycaemia. Genotyping for Pro12Ala and Trp64Arg polymorphism in postmenopausal women may have the clinical benefit of predicting hyperglycaemia, thereby contributing to the prevention of diabetes mellitus development in the future. However, not only the genetic background but also the dietary habits (intake of fat, carbohydrates and B vitamins) determine the risk of hyperglycaemia.     

Fetal and maternal peroxisome proliferator-activated receptor gamma2 Pro12Ala does not influence birth weight

The association between the peroxisome proliferator-activated receptor (PPAR)gamma2 Pro12Ala polymorphism and insulin resistance is reported to depend on low birth weight. Low birth weight itself has been linked to type 2 diabetes and cardiovascular diseases in adulthood. We assessed whether the PPARgamma2 Pro12Ala polymorphism determines body size at birth and whether metabolic differences between the genotypes are already detectable in the newborn. This study was conducted at the obstetrics department of the Charité, Berlin, Germany. One thousand nine hundred thirty white woman/child pairs were consecutively included and genotyped. The newborn's weight, length, and head circumference were measured. Total glycated hemoglobin in blood served as a surrogate of fetal insulin resistance and glucose use. We found that neither the fetal nor the maternal Pro12Ala genotype determined body size or total glycated hemoglobin at birth. The results suggest that the PPARgamma2 Pro12Ala polymorphism is not relevant for intrauterine growth. Previously reported effects of PPARgamma2 Pro12Ala on insulin resistance seem to arise later in life.     

Conservation of the COP9/signalosome in budding yeast

Background

Variation at the PPARG locus may influence susceptibility to type 2 diabetes and related traits. The Pro12Ala polymorphism may modulate receptor activity and is associated with protection from type 2 diabetes. However, there have been inconsistent reports of its association with obesity. The silent C1431T polymorphism has not been as extensively studied, but the rare T allele has also been inconsistently linked to increases in weight. Both rare alleles are in linkage disequilibrium and the independent associations of these two polymorphisms have not been addressed.

Results

We have genotyped a large population with type 2 diabetes (n = 1107), two populations of non-diabetics from Glasgow (n = 186) and Dundee (n = 254) and also a healthy group undergoing physical training (n = 148) and investigated the association of genotype with body mass index. This analysis has demonstrated that the Ala12 and T1431 alleles are present together in approximately 70% of the carriers. By considering the other 30% of individuals with haplotypes that only carry one of these polymorphisms, we have demonstrated that the Ala12 allele is consistently associated with a lower BMI, whilst the T1431 allele is consistently associated with higher BMI.

Conclusion

This study has therefore revealed an opposing interaction of these polymorphisms, which may help to explain previous inconsistencies in the association of PPARG polymorphisms and body weight.     

Heterogeneous effect of peroxisome proliferator-activated receptor gamma2 Ala12 variant on type 2 diabetes risk

Conflicting results have been reported regarding whether the PPARgamma2 Pro12Ala polymorphism plays a role in the risk of type 2 diabetes (T2D), suggesting genetic heterogeneity. To investigate this issue, a meta-analysis of 41 published and 2 unpublished studies (a total of 42,910 subjects) was conducted. Ala12 carriers had a 19% T2D risk reduction, but this association was highly heterogeneous (p = 0.005). A great proportion (48%) of heterogeneity was explained by the controls' BMI, with risk reduction being greater when BMI was lower. Risk reduction of Ala12 carriers in Asia (35%) was higher than in Europe (15%, p = 0.02) and tended to be higher than in North America (18%, p = 0.10). Difference between Asians and Europeans was no longer significant (p = 0.15) after adjusting for the controls' BMI. Studies from Europe were still heterogeneous (p = 0.02) with risk reduction in Ala12 carriers being progressively smaller (test for trend in the odds ratios, p = 0.02) from Northern (26% reduction, p < 0.0001) to Central (10%, p = 0.04) and Southern (0%, p = 0.94) Europe. In conclusion, in our meta-analysis, the reduced risk of T2D in Ala12 carriers is not homogeneous. It is greater in Asia than in Europe and, among Europeans, it is higher in Northern Europe, barely significant in Central Europe, and nonexistent in Southern Europe.     

Respiratory control stability and upper airway collapsibility in men and women with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is two to three times more common in men as in women. The mechanisms leading to this difference are currently unclear but could include gender differences in respiratory stability [loop gain (LG)] or upper airway collapsibility [pharyngeal critical closing pressure (Pcrit)]. The aim of this study was to compare LG and Pcrit between men and women with OSA to determine whether the factors contributing to apnea are similar between genders. The first group of 11 men and 11 women were matched for OSA severity (mean +/- SE apnea-hypopnea index = 43.8 +/- 6.1 and 44.1 +/- 6.6 events/h). The second group of 12 men and 12 women were matched for body mass index (BMI; 31.6 +/- 1.9 and 31.3 +/- 1.8 kg/m2, respectively). All measurements were made during stable supine non-rapid eye movement sleep. LG was determined using a proportional assist ventilator. Pcrit was measured by progressively dropping the continuous positive airway pressure level for three to five breaths until airway collapse. Apnea-hypopnea index-matched women had a higher BMI than men (38.0 +/- 2.4 vs. 30.0 +/- 1.9 kg/m2; P = 0.03), but LG and Pcrit were similar between men and women (LG: 0.37 +/- 0.02 and 0.37 +/- 0.02, respectively, P = 0.92; Pcrit: 0.35 +/- 0.62 and -0.18 +/- 0.87, respectively, P = 0.63). In the BMI-matched subgroup, women had less severe OSA during non-rapid eye movement sleep (30.9 +/- 7.4 vs. 52.5 +/- 8.1 events/h; P = 0.04) and lower Pcrit (-2.01 +/- 0.62 vs. 1.16 +/- 0.83 cmH2O; P = 0.005). However, LG was not significantly different between genders (0.38 +/- 0.02 vs. 0.33 +/- 0.03; P = 0.14). These results suggest that women may be protected from developing OSA by having a less collapsible upper airway for any given degree of obesity.     

D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms interact in the modulation of insulin resistance in type 2 diabetic patients

Type 2 deiodinase (D2) converts T4 into its active metabolite T3, an essential step in thyroid metabolism. A Thr92Ala polymorphism in the gene encoding D2 has been inconsistently associated with insulin resistance (IR). Recently, it was reported that the D2 Thr92Ala (rs225014) and the peroxisome proliferator-activated receptor (PPAR) γ2 Pro12Ala (rs1801282) polymorphisms interact in the modulation of metabolic syndrome in nondiabetic subjects. Here, we investigated the effect of both polymorphisms, isolated or in combination, on IR in patients with type 2 diabetes mellitus (DM2). The D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms were genotyped in 721 DM2 patients. IR was evaluated using the homeostasis model assessment-IR (HOMA(IR)) index in a subgroup of 246 DM2 subjects. The frequencies of D2 Ala92 and PPARγ2 Ala12 variants were 0.390 and 0.074, respectively. Patients carrying D2 Ala/Ala genotype had a higher fasting plasma insulin and HOMA(IR) index as compared to patients carrying Thr/Ala or Thr/Thr genotypes (P = 0.022 and P = 0.001, respectively). A significant synergistic effect was observed between D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms on HOMA(IR) index, with carriers of both D2 Ala/Ala genotype and PPARγ2 Ala12 allele showing the highest HOMA(IR) values, after adjusting for age, gender, BMI, and use of medication for DM2 (P = 0.010). In conclusion, DM2 patients harboring both D2 Ala/Ala genotype and PPARγ2 Ala12 allele seem to present more severe IR than those with other D2/PPARγ2 genotype combinations. These findings suggest that these polymorphisms interact in the IR modulation, which may constitute a potential therapeutic target.     

Association between the Pro12Ala polymorphism of PPAR-γ gene and the polycystic ovary syndrome: a meta-analysis of case-control studies

Several studies have been conducted to examine the association between PPAR-γ2 Pro12Ala polymorphism and polycystic ovary syndrome (PCOS), but the results remain inconsistent. To make a more precise estimation of the relationship, a meta-analysis was performed. In the current meta-analysis, a total of 17 case-control studies, including 2176 cases and 2373 controls, were selected. Odds ratios (ORs) and 95% confidence intervals (CIs) for Pro/Ala+Ala/Ala versus Pro/Pro genotype in all population and different nationality groups, and homeostasis model assessment-insulin resistance (HOMA-IR) of different genotype were evaluated. In the overall analysis, significant association between PPAR-γ2 Pro12Ala polymorphism and reduced risk of PCOS was observed (OR=0.75; 95%CI, 0.62-0.91; p=0.003). Stratified analysis showed that significantly strong association was presented only in Europeans (OR=0.74; 95%CI, 0.60-0.90; p=0.003), but not in Asians (OR=0.86; 95%CI, 0.51-1.43; p=0.56). Additionally, carrying the Ala12 allele was not associated with HOMA-IR in PCOS patients (OR=-0.29; 95%CI, -0.82-0.24; p=0.29). This meta-analysis supported that PPAR-γ2 Pro12Ala polymorphism was capable of reducing polycystic ovary syndrome risk in Europeans, but not in Asians.     

The Pro12Ala Polymorphism of the PPARγ2 Gene Regulates Weight from Birth to Adulthood

Objective: The Pro12Ala polymorphism in exon B of peroxisome proliferator‐activated receptor γ 2 (PPARγ2) gene has been related to obesity, insulin resistance, and risk of type 2 diabetes. In this study, the effect of the Pro12Ala polymorphism on long‐term changes in weight and body composition was investigated. Research Methods and Procedures: The Pro12Ala polymorphism was genotyped in 311 subjects who participated in our previous population‐based study. In that study, weight at birth, 7 years, 20 years, and 41 years, and ponderal index at birth and BMI and waist circumference at 41 years were recorded. Results: The Ala12 allele of the PPARγ2 gene was associated with high ponderal index at birth (2.77 ± 0.27 kg/m³ in subjects with the Ala12Ala genotype, 2.79 ± 0.29 kg/m³ in subjects with the Pro12Ala genotype, and 2.63 ± 0.25 kg/m³ in subjects with the Pro12Pro genotype, p = 0.007, adjusted for gender) and weight at 7 years (p = 0.045) and tended to be associated with high birth weight (p = 0.094). Subjects with this allele gained less weight between 7 and 20 years (p = 0.043) and more weight between 20 and 41 years (p = 0.001) and ended up having higher waist circumference (p = 0.040) in adulthood than did subjects with the Pro12Pro genotype. Discussion: We conclude that the Pro12Ala polymorphism of the PPARγ2 gene regulates weight and body composition from utero to adulthood.