PPAR-gamma Pro12Ala Polymorphism Research Articles

Pro12Ala polymorphism in PPAR-γ gene of impaired glucose tolerance subjects in Bangladeshi population

Pro12Ala polymorphism in PPAR-gamma (PPAR-γ) gene is associated obesity and hyperglycemia in some races, but controversy exists for other races. In this study, 113 impaired glucose tolerance (IGT) and 113 healthy control subjects were recruited. Wild type (CC), heterozygous (CG), and homozygous (GG) variants of Pro16Ala polymorphism of PPAR-γ (rs1801282) were analyzed using Chi-square test, and the polymorphism was found significantly (p=0.05, Χ2=5.875) associated with IGT subjects. Allele frequency also shows significant association with IGT subjects in the Chi-square test (p=0.026, Χ2=2.248). When the waist-hip ratio was reanalyzed according to genotype variation, the waist-hip ratio was found significantly higher among subjects with heterozygous and homozygous variants of pro16Ala polymorphism. Therefore, our study concluded that PPAR-γ P12A variants might be associated with impaired glucose tolerance. It is also documented that higher waist to hip ratio in IGT subjects may associate with heterozygous (CG) and homozygous (GG) variants of Pro12Ala mutation in the PPAR-γ gene.
 Journal of Bangladesh Academy of Sciences, Vol. 44, No. 2, 179-189, 2020

Peroxisome proliferator activated receptor gamma polymorphism Pro12Ala in polycystic ovary syndrome (PCOS) of South Indian Population

Abstract Objective To investigate the frequency of Pro12Ala polymorphism in PPAR gamma gene among PCOS of South Indian Population. Understanding this polymorphism may help us in better diagnosis prevention and therapeutic approaches towards management of PCOS. Method A total of 75 women with the diagnosis of PCOS and 75 healthy controls were included in this study. The Pro12Ala variant in the PPAR gamma gene was analysed by PCR-RFLP. Results Genotypic frequencies for PPAR gamma gene Pro12Ala polymorphism showed the frequency of Pro/Pro genotypes was 77% in PCOS and 81% in controls. The odds ratio was 0.71 (95% CI 0.31–1.63) and 2.66 (95% CI 0.21–32.9) and alleles expressed 0.87 (95% CI 0.42–1.79). Regarding hormone levels, there were significant differences between PCOS and non PCOS. Conclusion PPARγ2 gene Pro12Ala polymorphism was supposed to be susceptible genes in PCOS. The present study demonstrated that there is a statistical difference between the distributions of PPAR gamma Pro12Ala polymorphism in South Indian Population.

PPAR-Gamma Pro12Ala Polymorphism and Gastric Cancer Risk in a Turkish Population

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand dependent transcription factor involved in various processes, including carcinogenesis. We aimed to investigate any possible association of the PPARγPro12Ala (rs1801282) polymorphism with risk of developing gastric cancer (GC). A hospital based case control study was designed covering 50 patients with GC and 120 healthy controls. The frequencies of PPARγPro12Ala (rs1801282) were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The Ala12 allele of the PPARγPro12Ala G gene was associated with a 1.95 fold increased risk of GC development (p: 0.022; 95% CI: 1.58-2.40). Subgroup analyses showed that the same allele was also associated with metastasis (p: 0.000; OR:4.09; 95%CI:2.273-7.368) and differentiation (p: 0.004; OR:1.95; 95%CI:1.335-2.875) in patients with GC. This study suggests that the PPARγPro12Ala G (Ala12) allele might be associated with development, differentiation and metastatic process of GC in the Turkish population. Further studies conducted in larger study groups and in different ethnic populations will be needed to clarify the exact role of the PPARγPro12Ala polymorphism in GC.

Peroxisome Proliferator‐Activated Receptor Gamma Polymorphism and Periodontitis in Pregnant Japanese Women

Recent studies suggest an association between maternal periodontitis and preterm birth, although the association remains controversial. It was suggested that mechanisms such as a genetic predisposition for a hyperinflammatory response cause periodontitis and preterm births. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor and ligand-dependent transcription factor. PPARgamma inhibits the transcriptional activity of the genes that produce proinflammatory mediators and repress periodontitis. Recently, a common polymorphism, proline(PRO)-to-alanine(ALA) mutation at codon12 in exonB (Pro12Ala: rs 1801282) PPARgamma, was reported to reduce the ability to transactivate responsive promoters. In this study, we tested whether the PPARgammaPro12Ala polymorphism was associated with maternal periodontitis and/or preterm birth. Genomic DNA was isolated from the venous blood of pregnant Japanese women (term birth: n = 72; preterm birth: n = 58). The PPARgammaPro12Ala genotype was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Within 5 days after labor, clinical periodontal parameters were evaluated, and periodontopathic bacteria from the subgingival plaque were detected by species-specific PCR. The mean clinical attachment level (P = 0.012), mean probing depth (P = 0.031), mean gingival index (P = 0.037), and percentages of sites with bleeding on probing (P = 0.041) in women with the PPARgammaPro12Ala genotype were significantly higher than in women with the PPARgammaPro12Pro genotype. However, there was no association between preterm birth and periodontitis. We suggest that the PPARgammaPro12Ala polymorphism may represent a genetic susceptibility factor for the clinical measurements of periodontitis in a limited number of pregnant Japanese women, but it probably cannot influence the relationship between periodontitis and preterm birth.

PPARγ Pro12Ala Pro/Pro and resistin SNP‐420 G/G genotypes are synergistically associated with plasma resistin in the Japanese general population

The Ala allele of the Pro12Ala polymorphism (rs1801282) of peroxisome proliferator-activated receptor gamma (PPARgamma) is protective against type 2 diabetes (T2DM). Resistin, secreted from adipocytes, causes insulin resistance in rodents. Resistin gene expression is reduced by the PPARgamma ligand. We previously reported that subjects with the G/G genotype of a resistin gene single nucleotide polymorphism (SNP) at -420 (rs1862513) had the highest circulating resistin levels, followed by C/G and C/C. The aim of this study was to determine the relationship among PPARgamma Pro12Ala polymorphism, resistin SNP-420, and plasma resistin. We cross-sectionally analysed 2077 community-dwelling subjects attending an annual medical check-up. Genotypes were determined by TaqMan analysis. Fasting plasma resistin was measured using ELISA. Plasma resistin appeared to be higher in subjects with the Pro/Pro genotype of PPARgamma than those with Pro/Ala and Ala/Ala genotypes (mean +/- SE, 11.6 +/- 0.2 vs. 10.4 +/- 0.5 microg/l). Multiple regression analysis, adjusted for age, gender, BMI, and resistin SNP-420, revealed that the Pro/Pro genotype was a positive predictor of plasma resistin (PPARgamma , Pro/Pro vs. Pro/Ala + Ala/Ala, unstandardized regression coefficient (beta) = 1.03, P = 0.0384). The effects of the Pro/Pro genotype of PPARgamma (Pro/Pro vs. Pro/Ala + Ala/Ala) and the G/G genotype of resistin SNP-420 (G/G vs. C/C) on plasma resistin were synergistic (beta = 4.76, P = 0.011). The PPARgamma Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes were synergistically associated with plasma resistin, when adjusted for age, gender, and BMI, in the Japanese general population.

Association of peroxisome proliferator-activated receptor-gamma gene polymorphisms with the development of asthma

The peroxisome proliferator-activated receptors (PPAR) are the nuclear hormone receptor superfamily of ligand-activated transcriptional factors. PPAR-gamma (PPARG) activation downregulates production of Th2 type cytokines and eosinophil function. Additionally, treatment with a synthetic PPARG ligand can reduce lung inflammation and IFN-gamma, IL-4, and IL-2 production in experimental allergic asthma. In patients with asthma, PPARG gene expression is known to be associated with the airway inflammatory and remodeling responses. Thus, genetic variants of PPARG may be associated with the development of asthma. We genotyped two single nucleotide polymorphisms on the PPARG gene, +34C>G (Pro12Ala) and +82466C>T (His449His), in Korean subjects (839 subjects with asthma and 449 normal controls). Association analysis using logistic regression analysis showed that +82466C>T and haplotypes 1(CC) and 2(CT) were associated with the development of asthma (p=0.01-0.04). The frequency of PPARG-ht2 was significantly lower in the patients with asthma compared to the normal controls in codominant and dominant models (p=0.01, p(corr)=0.03 and p=0.02, p(corr)=0.03, respectively). Conversely, the frequency of PPARG-ht1 was significantly higher in the patients with asthma compared to the normal controls in the codominant model [p=0.04, OR: 1.27 (1.01-1.6)]. In addition, the rare allele frequency of +82466C>T was significantly lower in patients with asthma in comparison to normal controls in the codominant model (OR: 0.78, p=0.04). Thus, polymorphism of the PPARG gene may be linked to an increased risk of asthma development.

Peroxisome proliferator-activated receptor-gammaPro12Ala polymorphism and the association with blood pressure in type 2 diabetes: skaraborg hypertension and diabetes project.

This study explored whether the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPARgamma) is associated with blood pressure in subjects with type 2 diabetes. A community-based, cross-sectional observation study. Primary care. One hundred and ninety-two men and 192 women with type 2 diabetes who consecutively underwent annual follow-up. The PPARgammaPro12Ala genotype was determined by polymerase chain reaction-based techniques. Associations between genotype and blood pressure were analysed by linear regression and expressed as differences in blood pressure (delta) with 95% confidence interval (CI). The mean systolic blood pressure and the diastolic blood pressure were 160 mmHg (standard deviation = 22.8) and 84 mmHg (standard deviation = 9.6), respectively. Subjects with Pro/Ala (24%) or Ala/Ala (2%) had lower diastolic blood pressure (delta = 2.8; 95% CI, 0.6-5.0) when adjusted for age and gender compared with Pro/Pro subjects (74%). This association was restricted to men (delta = 4.4; 95% CI, 1.3-7.4), who also had a borderline significant difference in systolic blood pressure (delta = 6.9; 95% CI, -0.8 to 13.8). In men the difference in diastolic blood pressure remained after adjustment for age, body mass index, serum triglycerides, serum insulin and haemoglobin A(1c) (delta = 4.6; 95% CI, 1.1-8.1). A subanalysis of normotensive men (n = 100) confirmed the difference associated with the Pro12Ala polymorphism in diastolic blood pressure (delta = 5.2; 95% CI, 0.6-10.0). The common Pro12Ala polymorphism in PPARgamma is associated with lower diastolic blood pressure in male subjects with type 2 diabetes.

The PPAR-gamma Pro12Ala polymorphism and risk of cognitive impairment in a longitudinal study

The Pro12Ala polymorphism in the PPAR-γ gene has been associated with reduced incidence of type 2 diabetes. Although diabetes has been implicated as a risk factor for dementia, the association of Pro12Ala with cognitive impairment is unclear. Dementia and cognitive impairment without dementia (CIND) were determined during six annual follow-up evaluations in a cohort of 929 older Latinos. Among those with diabetes at baseline, there was an increased rate of dementia/CIND for Ala carriers compared to non-carriers (adjusted hazard ratio (HR)=2.5, 95% confidence interval (CI): 1.3–4.9) but not among non-diabetic participants (adjusted HR=0.94; 95% CI: 0.49–1.8). Among males, there was also an increased rate for Ala carriers (adjusted HR=2.7, 95% CI: 1.4–5.2) but not among female carriers (adjusted HR=0.88; 95% CI: 0.47–1.6). The rate of dementia/CIND was highest in diabetic male Ala carriers (adjusted HR=4.2; 95% CI: 1.5–11) compared to non-diabetic male carriers (adjusted HR=2.9; 95% CI: 1.1–7.4), diabetic female carriers (HR=1.6; 95% CI: 0.66–4.1), and non-diabetic female carriers (HR=0.52; 95% CI: 0.21–1.3). These data suggest that although the Ala variant is associated with a reduced risk of type 2 diabetes, it may increase the risk of cognitive impairment in individuals once diabetes has developed. Male Ala carriers may also have a greater risk of dementia/CIND.

Lack of association between the Pro12Ala polymorphism of the PPAR-γ2 gene and type 2 diabetes mellitus in the Qatari consanguineous population

Peroxisome proliferators-activated receptor gamma (PPAR gamma) is a nuclear hormone receptor that serves as a master regulator for adipocytes-specific genes contributing to adipocytes differentiation, insulin sensitivity and lipid metabolism. The substitution of proline to alanine at codon 12 of the PPAR gamma 2 gene (Pro12Ala polymorphism) is most widely studied, and the associations with diabetes, obesity, and other clinical parameters have been reported and discussed in several ethnic groups. Among native Qatar ethnicity, however, there is no report about this polymorphism. The aim of this study was to estimate the allele frequency of the Pro12Ala polymorphism of PPAR gamma 2 gene among Qatari population and investigate the association between this polymorphism and obesity or type 2 diabetes. This is a matched case-control study. It was carried out among diabetic patients and healthy subjects at the Primary Healthcare Clinics, and the survey was conducted from February 2003 to March 2006 in Qatari male and female nationals aged 35 to 60 years. The study was based on matched age, sex, and ethnicity of 400 cases (with diabetes) and 450 controls (without diabetes). Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI), and obesity. Their health status was assessed by medical conditions, family history, and blood pressure measurements. The allele frequency of Pro12Ala polymorphism in PPAR gamma 2 gene among Qataris is lower than that in many Caucasian ethnic groups. No association is seen between the Pro12Ala and type 2 Diabetes (0.055 vs 0.059, OR = 1.1311, P = 0.669). Nearly half of the diabetic type 2 patients (48.5%) were obese (BMI > 30) compared to nondiabetic subjects (29.8%) (P < 0.001). In this study, no association is seen between the Pro12Ala polymorphism in PPAR gamma 2 gene and the type 2 diabetes in Qatar.

Influence of Peroxisome Proliferator-activated Receptor (PPAR)γ Plo12Ala Polymorphism as a Shared Risk Marker for Both Gastric Cancer and Impaired Fasting Glucose (IFG) in Japanese

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to inhibit the proliferation of gastric cancer cells. A common polymorphism at codon 12 of this gene (Pro12Ala) has been shown to confer protection against diabetes and colorectal cancer. We investigated the influence of PPARgamma gene Plo12Ala polymorphism on the risk of gastric cancer and on the severity of Helicobacter pylori-induced gastritis as well as impaired fasting glucose (IFG) in Japanese. About 215 patients with gastric cancer (GC) and 201 patients without GC enrolled in this study. Plo12Ala polymorphism of PPARgamma was investigated by PCR-RFLP in all of the subjects. The gastritis score of noncancerous antral mucosa was calculated by the updated Sydney system. The diagnosis of IFG was based on repeated evidence of serum fasting glucose (SFG) concentration of greater than or equal to 110 mg/dl. The Plo12Ala genotype of PPARgamma showed a significantly higher frequency in GC patients than in controls (OR = 2.43; 95%CI = 1.04-5.67). In contrast, the Plo12Ala genotype held a lower risk of IFG (OR = 0.33; 95%CI = 0.13-0.83). The same genotype was associated with an increased risk of non-cardiac gastric cancer (OR = 2.39; 95%CI = 1.02-5.65), lower third gastric cancer (OR = 3.56; 95%CI = 1.31-9.71), advanced cancer (OR = 2.93; 95%CI = 1.13-7.58), and Lauren's intestinal cancer (OR = 2.94; 95%CI = 1.13-7.66). Among 151 gastric cancer subjects, the atrophy and metaplasia scores of the antral mucosa adjacent to cancer showed a tendency to be higher in those with the 12Ala allele. Our study suggests that the PPARgamma Pro12Ala polymorphism may be a shared risk marker of both IFG and gastric cancer in Japanese.

Association between Pro12Ala polymorphism of peroxisome proliferator‐activated receptor‐gamma 2 and myocardial infarction in the Chinese Han population

Peroxisome proliferator-activated receptor-gamma 2 (PPAR-gamma 2) is a nuclear receptor that plays an important role in adipocyte differentiation, energy metabolism, and homeostasis. The Pro12Ala polymorphism of PPAR-gamma 2 is associated with decreased risk of diabetes mellitus. Presumably, it may have a protective effect on myocardial infarction (MI). The purpose of the study was to explore the association between the Pro12Ala polymorphism and the risk of MI in the Chinese population. The Pro12Ala polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism among 844 subjects, including 218 patients with MI and 626 controls. Clinical parameters such as fasting serum total cholesterol, triglycerides, and plasma glucose were detected by autoanalyzer assay. Waist circumference, weight, height, and blood pressure (BP) were measured and body mass index (BMI) was calculated. The frequencies of the Ala allele in the MI and control groups were 0.053 and 0.032, respectively. There was a significant difference in genotype and allele frequency distribution between the two groups (after adjustment for age, gender, BP, fasting plasma glucose, total cholesterol, triglycerides, and smoking, odds ratio [OR] = 2.51, 95% confidence interval [CI]: 1.26-5.00, p = 0.009). In the group with MI, the difference in frequency of the Ala allele in women (0.241) compared with that of men (0.056) was significant (OR = 4.29, 95% CI: 1.96-9.37, p < 0.001). There was no relationship between the Pro12Ala polymorphism and waist circumference, weight, BMI, BP, or triglycerides (p > 0.05). Our study suggests that Pro12Ala polymorphism is associated with increased risk of MI.

Association of Two Polymorphisms in the Peroxisome Proliferator-Acativated Receptor-γ Gene With Adenomyosis, Endometriosis, and Leiomyomata in Japanese Women

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear hormone receptor that plays an important role in many diseases. This study investigated whether two polymorphisms (Pro12Ala in exon B and C161T in exon 6) of the PPAR-gamma2 gene are related to adenomyosis, endometriosis, or leiomyomata. A total of 390 patients with adenomyosis, endometriosis, and/or leiomyomata were classified into four groups: 103 patients with adenomyosis (21 adenomyosis only and 82 adenomyosis with endometriosis and/or leiomyomata), 95 patients with endometriosis only, 100 patients with leiomyomata only, and 92 patients with endometriosis and leiomyomata. There was no association between distribution of genotype or allele frequencies for the PPAR-gamma Pro12Ala polymorphism and the presence of adenomyosis, endometriosis, and/or leiomyomata. However, compared with results for controls, the PPAR-gamma 161CC genotype and 161C allele frequencies were significantly increased in patients with adenomyosis (genotype: chi2 = 8.185, corrected P value [Pc] = .0169; allele: chi2 = 8.337, Pc = .0155) and in patients with endometriosis (genotype: chi2 = 6.748, Pc = .0375; allele: chi2 = 6.413, Pc = .0453). The results suggest that the PPAR-gamma 161CC genotype could be a genetic risk factor for adenomyosis and endometriosis, whereas the Pro12Ala polymorphism was not associated with these estrogen-dependent benign uterine diseases in a Japanese population.

Role of Genetic Polymorphism Peroxisome Proliferator-Activated Receptor- 2 Pro12Ala on Ethnic Susceptibility to Diabetes in South-Asian and Caucasian Subjects: Evidence for heterogeneity

To determine whether the peroxisome proliferator-activated receptor (PPAR)-gamma Pro12ala polymorphism modulates susceptibility to diabetes in South Asians. South Asians (n = 697) and Caucasians (n = 457) living in Dallas/Forth Worth, Texas, and South Asians living in Chennai, India (n = 1,619), were enrolled for this study. PPAR-gamma Pro12Ala was determined using restriction fragment-length polymorphism. Insulin responsiveness to an oral glucose tolerance test (OGTT) was measured in nondiabetic subjects. The Caucasian diabetic subjects had significantly lower prevalence of PPAR-gamma 12Ala when compared with the Caucasian nondiabetic subjects (20 vs. 9%, P = 0.006). However, there were no significant differences between diabetic and nondiabetic subjects with reference to the Pro12Ala polymorphism among the South Asians living in Dallas (20 vs. 23%) and in India (19 vs. 19.3%). Although Caucasians carrying PPAR-gamma Pro12Ala had lower plasma insulin levels at 2 h of OGTT than the wild-type (Pro/Pro) carriers (76 +/- 68 and 54 +/- 33 microU/ml, respectively, P = 0.01), no differences in either fasting or 2-h plasma insulin concentrations were found between South Asians carrying the PPAR-gamma Pro12Ala polymorphism and those with the wild-type genotype at either Chennai or Dallas. Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that the PPAR-gamma Pro12Ala polymorphism is protective against diabetes in Caucasians but not in South Asians.

ACDC/Adiponectin and PPAR‐γ Gene Polymorphisms: Implications for Features of Obesity

The main purpose of this study was to investigate associations of single-nucleotide polymorphisms (SNPs) in the adipocyte C1q and collagen domain-containing (ACDC) gene and its regulator, the nuclear peroxisome proliferator-activated receptor (PPAR)-gamma gene, with body fat mass and its topographical distribution in postmenopausal women. Participants were 1501 healthy women, 60 to 85 years old, who were genotyped for four SNPs in the ACDC gene (-11391G/A, -11377C/G, +45T/G, +276G/T) and the Pro12Ala SNP in the PPAR-gamma gene. Total body fat mass and the central to peripheral fat mass ratio (CFM/PFM ratio) were measured using DXA. Adiponectin and homeostasis model assessment of insulin resistance were measured in 287 subjects. The -11377C/G SNP was associated with adiponectin (p < 0.001) and the CFM/PFM ratio (p = 0.005); the G allele being associated with low adiponectin and high CFM/PFM ratio. Similar associations of adiponectin (p = 0.0001) and the CFM/PFM ratio (p = 0.002) characterized the 1_2 (G_G) promoter haplotype (11391G/A_-11377C/G). Genotype variation of SNP Pro12Ala was associated with total body fat mass (p = 0.04); women with GG being the most obese (p = 0.01). The Ala/Ala (GG) genotype of Pro12Ala SNP interacted with the CC genotype of SNP-11377C/G in the determination of BMI (p = 0.001), when analyzed using a codominant model. Polymorphisms in the ACDC gene are associated with body fat distribution, whereas the Pro12Ala polymorphism in PPAR-gamma is associated with overall adiposity, apparently in interaction with an ACDC promoter SNP.

Influence of peroxisome proliferator-activated receptor γ gene polymorphism on 24S-hydroxycholesterol levels in Alzheimer’s patients

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor, that is involved in lipid and glucose metabolism, which both seem to influence the risk of Alzheimer's disease (AD). 24S-Hydroxycholesterol is the major cholesterol elimination product of the brain and plasma and CSF 24S-hydroxycholesterol levels are altered in patients with neurodegenerative diseases. We investigated the effect of the common Pro12Ala variant of the PPARgamma gene on plasma cholesterol levels and 24S-hydroxycholesterol/ cholesterol ratios in 124 AD patients and 77 healthy controls. Furthermore, the influence of PPARgamma polymorphism on the risk of AD in 247 AD patients and 324 healthy controls was investigated. We found that PPARgamma Pro12Ala polymorphism influenced plasma 24S-hydroxycholesterol/ cholesterol ratios in AD patients in that carriers of the Ala allele presented with higher ratios than homozygote carriers of the Pro-allele. PPARgamma polymorphism did not influence the risk of AD. These results might point to an influence of PPARgamma Pro12Ala polymorphism on the elimination of 24S-hydroxycholesterol.

O0091 PRO12ALA POLYMORPHISM OF PPARGAMMA 2 IN HEALTHY AND OBESE CHILDREN

O0091 PRO12ALA POLYMORPHISM OF PPARGAMMA 2 IN HEALTHY AND OBESE CHILDREN

O0091 PRO12ALA POLYMORPHISM OF PPARGAMMA 2 IN HEALTHY AND OBESE CHILDREN

O0091 PRO12ALA POLYMORPHISM OF PPARGAMMA 2 IN HEALTHY AND OBESE CHILDREN

Lack of association of the codon 12 polymorphism of the peroxisome proliferator-activated receptor gamma gene with breast cancer and body mass.

A principal hypothesized mechanism underlying breast carcinogenesis involves oestrogen-induced cell proliferation. In addition to its well-established role in the transcriptional regulation of genes required for adipocyte differentiation, the peroxisome proliferator-activated receptor gamma (PPARgamma) may be involved in transcriptional down-regulation of aromatase, a key enzyme in oestrogen biosynthesis. Furthermore, specific agonists for PPARgamma induce differentiation and suppress markers of malignancy in breast cancer cells in vitro. We investigated the association of the Pro12Ala PPARgamma polymorphism with breast cancer in a case-control study nested within the prospective Nurses' Health Study. Included were 725 incident cases of breast cancer diagnosed after blood collection through 1996 and 953 matched controls. In addition to breast cancer, the association of the PPARgamma Pro12Ala polymorphism with breast cancer risk factors, body mass index (BMI), weight gain since age 18 years, plasma hormones [oestrone sulphate, oestrone, oestradiol, androstenedione, testosterone, dehydroepiandrosterone (DHEA) and DHEA sulphate] and plasma lipids (total cholesterol and high density lipoprotein) was analysed. No significant association was observed between PPARgamma Pro12Ala polymorphism and either incident breast cancer (odds ratio = 1.08, 95% confidence interval = 0.85-1.38 for Ala allele carriers compared to non-carriers), plasma hormones, plasma cholesterol, BMI, weight gain since age 18 years or waist-to-hip ratio. To our knowledge, this is the first study to investigate the role of the Pro12Ala PPARgamma polymorphism in cancer. We did not find evidence to support a role for this polymorphism in breast cancer susceptibility. Furthermore, similar to others, we did not find evidence to suggest that Pro12Ala PPARgamma polymorphism is directly associated with body mass or weight gain.

Comment: studies of the Pro12Ala polymorphism of the PPAR-gamma gene in the Danish MONICA cohort: homozygosity of the Ala allele confers a decreased risk of the insulin resistance syndrome.

The Pro12Ala polymorphism of PPAR-gamma 2 has been shown to influence insulin sensitivity and the risk of type 2 diabetes in various ethnic populations. We examined whether the polymorphism was related to the insulin resistance syndrome (IRS) among nondiabetic Danish subjects. The Pro12Ala variant was examined using PCR-restriction fragment length polymorphism in a phenotypically well characterized population-based sample of 2245 nondiabetic subjects. The study participants were characterized by a number of anthropometric and biochemical measurements and the European Group for the Study of Insulin Resistance criteria enabling a classification of the study population in an IRS group and a non-IRS group. The allelic frequency of the Pro12Ala polymorphism in the total study sample was 14% (95% confidence interval, 13-15%). Two hundred ninety-four subjects fulfilled the European Group for the Study of Insulin Resistance criteria defining the IRS. The frequency of the Ala allele was 12.6% in the IRS group and 14.2% among subjects classified as not having the IRS (P = 0.15). However, the frequency of the variant in the homozygous form was significantly lower in the IRS group [0.7% (0-1.6%)] compared with the frequency in the non-IRS group [2.8% (2.1-3.5%); P = 0.02; odds ratio, 0.24 (0.06-0.99)]. Moreover, in the total study population, homozygous carriers of the variant had lower levels of fasting serum triglyceride [1.1 +/- 0.4 mmol/liter (means +/- SD) vs. 1.4 +/- 0.9 mmol/liter; P = 0.04] and a lower diastolic blood pressure (79 +/- 8 mm Hg vs. 82 +/- 11 mm Hg; P = 0.01) compared with wild-type carriers. The same tendency was observed with regard to the homeostasis model assessment estimate of insulin resistance (P = 0.16). There were no differences between genotype groups with respect to measures of body composition (BMI and waist circumference). In conclusion, homozygosity of the codon 12 variant of PPAR-gamma 2 confers a reduced risk of the IRS among Danish Caucasian subjects.

Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes.

PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARgamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARgamma activity observed in heterozygous PPARgamma-deficient mice or the Pro12Ala polymorphism in human PPARgamma, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARgamma antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARgamma-deficient mice with an RXR antagonist or a PPARgamma antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.