Proliferator-activated Receptor Gamma Gene Research Articles

Rescue of a peroxisome proliferator activated receptor gamma gene network in muscle after growth of human breast tumour xenografts

AbstractBackgroundFatigue is common in patents with breast cancer (BC), and can occur in patients with early stage disease and in the absence of muscle wasting (i.e. cachexia). We have reported transcriptional and proteomic alterations in muscles from BC patients, which are associated with fatigue. Mice implanted with human BC xenografts recapitulate the muscle molecular composition changes seen in patients, coupled with a greater rate of contraction‐induced fatigue. Multiple bioinformatics platforms in both human and mouse muscles have identified peroxisome proliferator activated receptor gamma (PPARG) as central to this phenotype, with several PPARG target genes downregulated in muscle in response to tumour growth. The current study tested the hypothesis that the PPARG agonist pioglitazone (pio), a commonly prescribed diabetes drug, would rescue the transcriptional alterations observed in muscles of tumour‐bearing mice.MethodsSixteen female NSG mice were implanted with breast cancer patient‐derived orthotopic xenografts (BC‐PDOX) via transplantation of Her2/neu+ human tumour fragments. BC‐PDOX mice were randomly assigned to a treatment group that received daily oral pio at 30 mg/kg (n = 8), or a control group that received a similar volume of vehicle (n = 8). Treatment was initiated when tumours reached a volume of 600 mm3, and lasted for 2 weeks. Hindlimb muscles were isolated from BC‐PDOX and non‐tumour bearing mice for RNA‐sequencing, gene expression validation, and ATP quantification. Differentially expressed genes (DEGs) in muscles from BC‐PDOX mice relative to non‐tumour bearing controls were identified using DESeq2, and multiple bioinformatics platforms were employed to contextualize the DEGs.ResultsWe found that the administration of pio restored the muscle gene expression patterns of BC‐PDOX mice to a profile resembling muscles of non‐tumour bearing NSG control mice. Validation of skeletal muscle gene expression by qPCR confirmed pio increased the expression of PPARG target genes (P < 0.05 in all genes but PPARG P = 0.684) in skeletal muscles. Isolated mitochondria from muscles of BC‐PDOX mice treated with pio contained greater levels of ATP (mean luminescence 33770 ± 4057 in BC‐PDOX vs. 62780 ± 11510 in BC‐PDOX PIO, P = 0.045). There were no differences in body weights (P = 0.560), muscle weights (Gas P = 0.295, Sol P = 0.365, EDL P = 0.182, TA P = 0.415) or tumour volumes (P = 0.885) in pio versus vehicle treated BC‐PDOX mice.ConclusionsThese data demonstrate that oral pio supplementation rescues the BC‐associated downregulation of PPARG target genes in skeletal muscle. Additionally, muscles from BC‐PDOX mice treated with pio had greater levels of ATP, which would be associated a more fatigue‐resistant muscle phenotype. Therefore, we propose that the FDA‐approved and generic diabetes drug, pio, be considered as a supportive therapy for the treatment of BC‐associated muscle fatigue.

Association of Single Nucleotide Polymorphisms in LEP, LEPR, and PPARG With Humoral Immune Response to Influenza Vaccine.

Background: Although previous studies have proposed leptin plays an important role in energy metabolism as well as in immune response, the effects of leptin-related genes on influenza vaccine-induced immune response remain unexplored. In this study, we aimed to investigate the potential association of leptin gene (LEP), leptin receptor gene (LEPR), and peroxisome proliferator activated receptor gamma gene (PPARG) polymorphisms with humoral immune response to influenza vaccine. Methods: Based on the seroconversion to influenza vaccine, 227 low-responders and 365 responders were selected in this study, and 11 candidate single nucleotide polymorphisms (SNPs) were genotyped using the MassARRAY technology platform. Univariate and multivariate logistic regression analyses were used to explore the association of SNPs in LEP, LEPR, and PPARG with humoral immune response to influenza vaccine. We also conducted a stratified analysis by gender to further clarify this association. The haplotypes analysis was performed using SNPStats. Results: Significant differences were observed in the genotypic distribution of PPARG rs17793951 between the two groups (p = 0.001), and the PPARG rs17793951 AG + GG genotype was associated with a higher risk of low responsiveness to influenza vaccine adjusted for gender and age (additive genetic model: OR = 2.94, 95% CI = 1.67–5.19, dominant genetic model: OR = 2.81, 95% CI = 1.61–4.92). No significant association of other SNPs in LEP and LEPR with immune response to influenza vaccine was found. The stratified analysis found the gender difference in the association of LEPR and PPARG variants with immune response to influenza vaccine. We found that LEPR rs6673591 GA + AA genotype was correlated with low responsiveness to influenza vaccine only in males (OR = 1.96, 95% CI = 1.05–3.67), and PPARG rs17793951 AG + GG genotype was associated with low responsiveness to influenza vaccine in females (OR = 3.28, 95% CI = 1.61–6.67). Compared with the CGGAGGC haplotype composed of LEPR rs1327118, rs7602, rs1137101, rs1938489, rs6673591, rs1137100, and rs13306523, the CAAAAAC haplotype was positively correlated with immune response of influenza vaccine (OR = 0.34, 95% CI = 0.15–0.77). Haplotype TG comprised of PPARG rs796313 and rs17793951 was associated with a 2.85-fold increased risk of low responsiveness to influenza vaccine. Conclusion: Our study identified that PPARG rs17793951 variants were significantly associated with the immune response to influenza vaccine.

Клинико-генетические особенности пациентов с ожирением и неалкогольной жировой болезнью печени

Актуальность. В настоящее время важное значение в патогенезе ожирения и неалкогольной жировой болезни печени (НАЖБП) придается полиморфизму rs1801282 (Pro12Ala) гена PPAR-γ2 (гамма-рецептор, активируемый пролифераторами пероксисом). Однако в украинской популяции больных с сочетанной патологией не изучены клинико-лабораторные особенности пациентов с этим полиморфизмом. Цель — исследовать клинико-лабораторные особенности больных с ожирением и НАЖБП в зависимости от rs1801282 полиморфизма гена PPAR-γ2. Материалы и методы. В исследовании приняли участие 123 пациента с 1–3 степенью ожирения и НАЖБП. Всем пациентам проведено молекулярно-генетическое исследование rs1801282 полиморфизма гена PPAR-γ2, а также антропометрические измерения, лабораторное и инструментальное обследование (в том числе ультразвуковая стеатометрия). Результаты. У больных с ожирением и НАЖБП с генотипами CG и GG rs1801282 полиморфизма гена PPAR-γ2 выявлены достоверно более высокие показатели индекса массы тела (p = 0,03), глюкозы (p = 0,02), инсулина (p < 0,0001) и С-пептида натощак (p = 0,02), АЛТ (p = 0,04), гамма-глутамилтранспептидазы (p < 0,0001), общего холестерина (p = 0,03), триглицеридов (p = 0,002), холестерина липопротеидов низкой плотности (p = 0,004), холестерина липопротеидов очень низкой плотности (p = 0,001), коэффициента атерогенности (p < 0,0001), а показатели контролируемого параметра затухания (p = 0,002), стимулированного инсулина (p < 0,0001), мочевой кислоты (p = 0,008) и холестерина липопротеидов высокой плотности (p < 0,0001) оказались достоверно ниже по сравнению с CC-генотипом. Выводы. В украинской популяции больных с сочетанием ожирения и НАЖБП у носителей аллели G rs1801282 полиморфизма гена PPAR-γ2 обнаружены достоверные метаболические различия, которые могут быть связаны с защитой от развития стеатоза и сахарного диабета 2 типа, но в то же время повышают сердечно-сосудистый риск.

The novel loss of function Ile354Val mutation in PPARG causes familial partial lipodystrophy.

Familial partial lipodystrophy (FPLD) is a rare autosomal dominant disorder, mostly due to mutations in lamin A (LMNA) or in peroxisome proliferator-activated receptor gamma (PPARG) genes. In the present study, we aimed to identify and functionally characterize the genetic defect underlying FPLD in an Italian family presenting with several affected individuals in three consecutive generations. Mutational screening by direct Sanger sequencing has been carried out on both LMNA and PPARG genes. In silico analyses and functional in vitro studies on transfected cell lines have been also performed to evaluate the biological impact of the identified mutation. We identified a novel PPARG missense mutation (i.e., PPARγ2 Ile354Val) segregating with FPLD in the study family. In silico analyses and in vitro experiments showed that probably altering the PPARγ2 ligand binding domain conformation, the Ile354Val aminoacid change leads to a significant reduction (i.e., ~ 30-35%) of transcriptional activity in the mutant receptor, with no evidences of a dominant negative effect on the wild-type receptor. Our present data extend the spectrum of PPARG mutations responsible for FPLD3 and reinforce the notion that even loss of function mutations affecting transcriptional activity to an extent lower than that observed in the case of haploinsufficiency are able to cause a severe FPLD3 phenotype.

Study on the polymorphism of PPAR-γ gene and preeclampsia susceptibility

Objective To investigate the correlation between peroxisome proliferator-activated receptor-gamma (PPAR-γ) gene polymorphism and preeclampsia (PE). Methods 110 PE patients and 110 normal pregnants who delivered in our hospital from May 2016 to October 2018 were selected as the study subjects. Detection of two loci of PPAR-γ gene by SNaPshot technique: rs10865710 and rs4684847. Results ⑴ rs10865710: The genotype frequencies of CC, CG and GG in the control group were 44.55%, 42.73% and 12.73%, respectively, and those in the PE group were 31.82%, 44.55% and 23.64%, respectively. There was a critical difference in the distribution of genotype frequencies between the two groups (χ2=5.975, P=0.050); The frequencies of C and G alleles were 65.91% and 34.09% in the control group, 54.09% and 45.91% in the PE group, respectively. There was significant difference in the frequency distribution of C and G alleles between the two groups (χ2=6.402, P=0.015). ⑵ rs4684847: the genotype frequencies of CC, CT and TT in control group were 94.55%, 5.45%, 0, and those in PE group were 84.55%, 15.45% and 0, respectively, with significant difference in the distribution of genotype frequencies between the two groups (χ2=5.875, P=0.015). The frequencies of C and T alleles in control group were 97.27%, 2.73% and those in PE group were 92.27% and 7.73%, respectively, with significant difference in allele frequency distribution between the two groups (χ2=5.551, P=0.030). ⑶ The frequency of GG genotype and G allele at rs10865710 locus in PE group was significantly higher than that in control group [OR (95% CI)=2.600 (1.190-5.679), P=0.021; OR (95% CI)=1.64 (1.117-2.411), P=0.015]. The frequencies of CT genotype and T allele at rs4684847 locus in PE group were significantly higher than those in control group [OR (95% CI)=3.168 (1.199-8.374), P=0.026; OR (95% CI)=2.987 (1.155-7.726), P=0.030]. Conclusions The single nucleotide polymorphisms of PPAR-γ gene rs10865710 and rs4684847 may be related to the susceptibility to preeclampsia in Chinese population. Key words: Pre-eclampsia; PPAR gamma; Polymorphism, genetic

Meta-analysis of the Association of Prol2Ala Polymorphism of Peroxisome Proliferator Activated Receptor Gamma Gene with Diabetic Kidney Disease in Chinese Han Population

Meta-analysis of the Association of Prol2Ala Polymorphism of Peroxisome Proliferator Activated Receptor Gamma Gene with Diabetic Kidney Disease in Chinese Han Population

PRESENCE OF THE ALA ALLELE IN THE PPAR-GAMMA GENE IS NOT PROTECTIVE AGAINST RISK OF IMPAIRED GLUCOSE METABOLISM ASSOCIATED WITH POP EXPOSURE

BACKGROUND Exposure to persistent organic pollutants (POPs) is associated with type 2 diabetes. Presence of the Ala allele in the peroxisome proliferator-activated receptor-gamma (PPARG) gene has b...

Peroxisome proliferator activated receptor gamma gene variants influence susceptibility and insulin related traits in Indian women with polycystic ovary syndrome

Peroxisome proliferator activated receptor gamma (PPARγ), a transcription factor involved in glucose and lipid metabolism is one of the candidate genes associated with polycystic ovary syndrome (PCOS). We investigated individual and combined associations of Pro12Ala and His447His polymorphisms of PPARγ with PCOS susceptibility and its related traits (hyperinsulinemia, hyperandrogenemia and lipid parameters) in Indian women. Genotyping of PPARγ polymorphisms in this case-control study was performed in PCOS (n = 450) and age-matched controls (n = 300) by direct sequencing. Clinical, anthropometric, hormonal and metabolic parameters were estimated in 275 women with PCOS and 169 controls. Chi-square test was used to compare the categorical data while regression analysis was used to evaluate association of genotypes with PCOS as well as its related phenotypes. The frequencies of CC and CG + GG genotypes of Pro12Ala (χ² = 15.3, p < 0.0001) and CC and CT + TT genotypes of His447His (χ² = 12.7, p = 0.0004) polymorphisms were significantly different between PCOS and controls. Logistic regression analysis revealed a significant association of PCOS with Pro12Ala but not the His447His polymorphism. Carriers of variant genotypes at both PPARγ loci showed significantly reduced 2 h glucose levels while carriers of variant His447His genotype showed lower fasting insulin and HOMA-IR levels in PCOS women. Pro12Ala polymorphism of PPARγ showed significant association with decreased PCOS susceptibility. Both polymorphisms influenced insulin related traits (2 h glucose, fasting insulin and HOMA-IR) and improved glucose metabolism in these women. This is the first report to establish that variations in PPARγ gene influence the insulin resistance pathophysiology in Indian women with PCOS.

Genetic Variation in the Peroxisome Proliferator Activated Receptor-Gamma Gene Is Associated with Histologically Advanced NAFLD

The peroxisome proliferator activated receptor-gamma (PPARG) is a nuclear receptor that regulates adipocyte differentiation, insulin sensitivity and lipid metabolism, thus, it represents a good candidate gene for non-alcoholic fatty liver disease (NAFLD). We investigated the association of two PPARG variants (Pro12Ala and C1431T) with NAFLD and its histological features. DNA was extracted from 274 archived, formalin-fixed liver biopsy specimens from 212 patients with NAFLD and 62 controls with normal liver histology. Individual SNPs did not show significant association with NAFLD or its histological features. A haplotype comprised of both minor alleles (GT) was less enriched whereas a haplotype comprised of the two major alleles (CC) was more enriched in subjects with NAFLD compared to controls [9.3% vs. 28.1% for GT (P = 0.001, OR 0.26 (range 0.14-0.48) and 80.4% vs. 64.8% for CC (P = 0.037, OR 2.23 (range 1.30-3.81)]. Both haplotypes were significantly associated with steatosis and fibrosis. The GT haplotype was also associated with lobular inflammation. Genetic variation in PPARG is associated with NAFLD, and the GT haplotype is associated with inflammatory and fibrotic changes that denote histologically advanced NAFLD.

Alteration in the expression of inflammatory parameters as a result of oxidative stress produced by moderate zinc deficiency in rat lung

ABSTRACTSuboptimal intake of dietary zinc (Zn) is one of the most common nutritional problems worldwide. Previously, the authors have shown that zinc deficiency (ZD) produces oxidative and nitrosative stress in lung of male rats. The goal of this study is to test the effect of moderate ZD on insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-5, NADH oxidase (NOX)-2, tumor necrosis factor alpha (TNFα), as well as the effect of restoring zinc during the refeeding period. Adult male rats were divided into 3 groups: Zn-adequate control group, Zn-deficient group, and Zn-refeeding group. eNOS, metallothionein (MT) II, and NOX-2 was increased in ZD group. The authors observed an increased gene transcription of superoxide dismutase (SOD)-2 and gluthathione peroxidase (GPx)-1 in ZD group, as well as in ZD-refeeding group, but catalase (CAT) transcription did not change in the treated groups. Proinflammatory factors, such as TNFα and vascular cell adhesion molecular (VCAM)-1 increased in ZD, whereas it decreased in ZD refeeding. However, peroxisome proliferator-activated receptor gamma (PPARγ) and IGF-1 gene transcription decreased in ZD, whereas IGFBP-5 decreased in the ZD group. These parameters are associated to alterations in the lung histoarchitecture. The zinc supplementation period is brief (only 10 days), but it is enough to inhibit some proinflammatory factors. Perhaps, zinc deficiency implications must be taken into account in health interventions because inflammation and prooxidant environment are associated with ZD in lung.

Analysis of two sequence variants in peroxisome proliferator activated receptor gamma gene in Tajik population at high altitudes and Han population at low altitudes in China

The Tajik people in China have resided at high altitude for thousands of years. We analyzed the Pro12Ala (C > G) polymorphism in exon B and the 161C > T polymorphism in exon 6 of peroxisome proliferator activated receptor gamma gene (PPARG) in Chinese Tajik population living at high altitude and Chinese Han population living at low attitude. Significant higher frequencies of the CG and GG genotypes and G allele of the Pro12Ala (C > G) polymorphism were observed in the Tajik population than that in the Han population (P < 0.0001), which suggested the G allele was associated with high-altitude adaptation in the dominate model. The significant differences were remained in both of the male and female groups after stratified by gender, and the differences were more pronounced in men (G versus C, OR = 7.700) than in women (OR = 5.056). No significant difference was observed for the 161C > T polymorphism in the two populations. The frequencies of haplotypes GT (P < 0.0001) and GC (P < 0.05) were significantly higher, while the frequency of CT (P < 0.0001) was significantly lower in the Tajik population than that in the Han population. Our results suggest that PPARG is a candidate gene for high-altitude adaptation in the Chinese Tajik population.

A genetic mutation in PPAR gamma is associated with enhanced fat cell differentiation: implications for human obesity.

Human obesity may have genetic causes, but determining the specific genes involved has been difficult. The peroxisome proliferator-activated receptor gamma (PPAR gamma) gene encodes a protein that plays an important role in the differentiation of fat cells. A mutation has been discovered in this gene which leads to a receptor that cannot be inactivated. This mutation, while probably rare, is associated with extreme obesity.

The relationship of polymorphism of peroxisome proliferator activated receptor gamma gene (PPAR γ) and osteoporosis in aged male

The relationship of polymorphism of peroxisome proliferator activated receptor gamma gene (PPAR γ) and osteoporosis in aged male

Pharmacogenetics of Glucose-Lowering Drug Treatment

Intensive blood glucose lowering can significantly reduce the risk of micro- and macrovascular complications in patients with diabetes mellitus. However, 30% of all treated patients do not achieve optimal blood glucose levels. Genetic factors may influence the response to glucose-lowering medication. A search of MEDLINE-indexed literature published between January 1966 and July 2007 revealed 37 studies reporting data on genetic polymorphisms and response to glucose-lowering drugs. Most studies involving cytochrome P450 (CYP) genes had small sample sizes (21 studies <50 subjects) and were among healthy volunteers. Multiple studies indicated that the CYP2C9 *3 allele (Ile359Leu polymorphism) was associated with decreased clearance of sulfonylurea drugs. Supporting this, one study reported an increased insulin secretion in CYP2C9*3 allele carriers when using the sulfonylurea agent glyburide. The CYP2C9*3 allele was also associated with a decreased clearance of meglitinides, whereas the CYP2C8*3 (Arg139Lys; Lys399Arg) variant increased the clearance of meglitinides. Polymorphisms in genes encoding the inwardly rectifying potassium channel Kir6.2 (KCNJ11) and the insulin receptor substrate-1 (IRS1) were reported to be associated with an increased risk of (secondary) failure to respond to sulfonylurea therapy. A significant decrease in fasting plasma glucose and hemoglobin A(1c) (HbA(1c)) in response to rosiglitazone was seen in subjects carrying the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma (PPARG) gene. Conversely, carriers of this polymorphism also had a higher conversion to diabetes mellitus when treated with acarbose; this effect was also seen in adiponectin (ADIPOQ) gene polymorphism carriers. Future studies with adequate sample sizes in which several SNPs in multiple candidate genes are genotyped in patients with diabetes should provide reliable information on genetic variants and response to glucose-lowering drugs.

Genetic Variation in the Peroxisome Proliferator Activated Receptor-gamma Gene Is Associated with NAFLD and Its Histological Phenotypes

Purpose: Peroxisome proliferator activated receptor-gamma (PPAR-γ) is a nuclear receptor that regulates adipocyte differentiation, lipid metabolism and insulin sensitivity and is the molecular target for thiazolidinediones, agents that enhance sensitivity to insulin. Thus, it is a good candidate gene for NAFLD. The Ala12 variant of PPAR-γ has been associated with increased insulin sensitivity, lower body mass and protection from type 2 diabetes. A second polymorphism C1431T has been associated with increased body weight. Aim: To test the association of two PPAR-γ single nucleotide polymorphisms (SNP) with NAFLD and its histological sub-phenotypes. Methods: DNA was extracted from 158 archived, formalin-fixed liver biopsy specimens from patients with NAFLD and normal controls. Two SNPs of PPAR-γ (Pro12Ala and C1431T) were genotyped by Taqman assay using the Biotrove OpenArray system. PPAR-γ haplotypes were predicted using the program Dandelion, which employs the Expectation-Maximization (EM) algorithm to obtain maximum likelihood estimates of the haplotype frequencies and the probabilities of the observed haplo-genotypes for each individual. Results: DNA was successfully isolated and genotyped for 26 controls, 87 FL, and 45 NASH patients. For both SNPs tested, the minor allele frequencies were decreased in NAFLD compared to controls (10.8 vs 25% for C1431T, and 9.5 vs 17.3% for Pro12Ala). In subjects with NAFLD, the minor alleles were enriched in subjects with FL compared to those with NASH (12.5 vs 7.5% for C1431T and 13.3 vs 0.03% for Pro12Ala). Only variation in C1431T was associated with steatosis (P 0.03). Haplotype analysis revealed a haplotype consistent of both minor alleles (TG) that is present only in subjects with NAFLD but not in controls (2.7 vs 0%). This haplotype was also significantly associated with steatosis, fibrosis, ballooning and lobular inflammation under an additive genetic model. Conclusion: Genetic variation in PPAR-γ is associated with NAFLD and its histological phenotypes. A haplotype shows strong association with histological findings of NASH, and is more common in individuals with NAFLD than controls. This haplotype may influence the development of NASH and its characteristic inflammatory and fibrotic changes.

Polymorphisms of the peroxisome proliferator–activated receptor-γ and its coactivator-1α genes in Chinese women with polycystic ovary syndrome

The polymorphisms of the peroxisome proliferator-activated receptor-gamma (Pro12Ala) and its coactivator-1 (Gly482Ser) genes were investigated among 201 Chinese Han women with polycystic ovary syndrome (PCOS) and among 147 regularly cycling women as control subjects. We did not find statistically significant differences with peroxisome proliferator-activated receptor-gamma2 Pro12Ala and peroxisome proliferator-activated receptor-gamma-1alpha Gly482Ser polymorphism distributions between Chinese women with PCOS and controls, or with body mass index and reproductive hormones among various genotypic groups of PCOS, suggesting that these genetic mutants did not have an effect on the susceptibility to PCOS.

Colonic polyps of acromegalic patients are not associated with mutations of the peroxisome proliferator activated receptor gamma gene.

Peroxisome proliferator activated receptor (PPAR)gamma plays a pivotal role in regulating adipocyte differentiation and metabolism, but also has an antiproliferative effect in several tissues, including colonic mucosa, where it is highly expressed. Loss-of-function mutations have been reported in about 10% of sporadic primary colon cancer. Acromegalic patients have an increased prevalence of colonic neoplasms and lower PPARgamma levels in the colonic mucosa. Thus, PPARgamma may act as a tumor suppressor gene, and its reduced expression or loss-of-function mutations may contribute to tumorigenesis. In this study the expression and mutations of the PPARgamma gene in the colonic polyps and mucosa outside polyps were investigated in 10 acromegalic and 17 non-acromegalic patients. PPARgamma expression was evaluated by RT-PCR. PPARgamma was expressed in each sample, but expression appeared to be lower in polyps than in mucosa outside polyps from either acromegalic or non-acromegalic patients. All exons of the PPARgamma gene were directly sequenced after PCR amplification: no mutations were found either in acromegalic or in non-acromegalic patients. In conclusion, the results of this preliminary study suggest that the lower expression of PPARgamma rather than somatic mutations of this gene is involved in colonic tumorigenesis.

Alanine for proline substitution in the peroxisome proliferator-activated receptor gamma-2 (PPARG2) gene and the risk of incident myocardial infarction.

Recent studies have implicated the potential importance of peroxisome proliferator-activated receptors as a molecular mechanism involved in atherothrombosis. A common alanine (A) for proline (P) substitution at codon 12 in the peroxisome proliferator activated receptor gamma-2 gene (PPARG2) has been associated with reduced risk of developing type 2 diabetes mellitus. Because diabetes and atherothrombosis share common antecedents, we sought evidence that this polymorphism might also be associated with reduced risk of myocardial infarction. Using DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we evaluated a P12A polymorphism in the PPARG2 among 523 individuals who subsequently developed myocardial infarction and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. As hypothesized, presence of the A12 allele was associated with significantly reduced risk of myocardial infarction (odds ratio in an age- and smoking-adjusted dominant model of inheritance, 0.77; 95% CI, 0.60 to 0.98; P=0.034). This protective effect remained statistically significant in analyses controlling for traditional cardiovascular risk factors, was present among nondiabetic study participants, was observed to be of similar magnitude in analyses assuming codominant or dominant modes of inheritance, and was seen in fully adjusted post hoc analyses in which we limited our control group to those individuals specifically matched to myocardial infarction cases (OR, 0.71; 95% CI, 0.53 to 0.96; P=0.024). In this cohort, a common A for P substitution at codon 12 in the PPARG2 was associated with reduced incidence of myocardial infarction. If confirmed in other cohorts, these data would have implications for novel treatments of cardiovascular disease, including development of PPARG-targeted therapy.