A Pro12Ala polymorphism in the human peroxisome proliferator-activated receptor-gamma 2 is associated with combined hyperlipidaemia in obesity

OBJECTIVE: Peroxisome proliferator-activated receptor-gamma 2 (PPAR gamma 2) is an important regulator of adipose tissue metabolism and insulin sensitivity. The aim of this investigation was to determine whether a PPAR gamma 2 Pro12Ala polymorphism was associated with cardiovascular risk factors (obesity, blood pressure, diabetes and blood lipids) in Western Australian Caucasians (n=663). DESIGN: Subjects were selected from two population studies (the Carotid Ultrasound Disease Assessment Study (CUDAS) and Busselton Population Health Survey) on the basis of body mass index (BMI). 292 obese (BMI > or =30 kg/m) and 371 lean (BMI <25 kg /m) subjects were studied. METHODS: Blood pressure and anthropometric measurements were collected from all participants, as well as a fasting venous blood sample. Biochemical measurements (high-density lipoprotein (HDL)- and low-density lipoprotein-cholesterol, triglycerides) and PPAR gamma 2 Pro12Ala genotype were also determined. RESULTS: Obese Pro/Ala and Ala/Ala subjects had lower levels of HDL-cholesterol (P=0.032) and a trend towards higher levels of triglycerides (P=0.055) compared with obese Pro/Pro subjects. In the obese group, the Ala allele was significantly associated with the presence of combined hyperlipidaemia (odds ratio = 2.33, P=0.042). There was no significant difference in the frequency of the polymorphism between lean and obese groups (P=0.069). No association was observed between Pro12Ala genotype and obesity, blood pressure or diabetes in either group. CONCLUSIONS: Obese carriers of the Pro12Ala polymorphism have a greater risk of developing combined hyperlipidaemia, possibly due to impaired activation of PPAR gamma target genes. The Pro12Ala polymorphism is not directly associated with obesity, hypertension or diabetes in this population.     

A possible association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma2 gene with obesity in native Javanese in Indonesia

BACKGROUND: Peroxisome proliferators-activated receptor gamma (PPAR gamma) is a nuclear hormone receptor that serves as a master regulator of adipocytes-specific genes contributing to adipocytes differentiation, susceptibility to obesity, and insulin sensitivity. The substitution of proline to alanine at codon 12 of the PPAR gamma2 gene (Pro12Ala polymorphism) is most frequently identified and the associations with diabetes, obesity, and other clinical parameters have been reported and discussed in several ethnic groups. Among native Javanese ethnicity, however, there is no report about this polymorphism. AIMS AND METHODS: Aims of this study were to estimate the allele frequency of the Pro12Ala polymorphism of PPAR gamma2 gene among native Javanese in Indonesia and to investigate the relationship between this polymorphism and obesity or diabetes. This study included 540 native Javanese subjects consisting of 337 diabetic patients and 203 normal glucose tolerance subjects. Both groups included totally 160 obese subjects (body mass index > or = 25 kg/m(2)). PCR-restriction fragment length polymorphism was used for the genotype determination. RESULTS: The allele frequency of Pro12Ala polymorphism in PPAR gamma2 gene among native Javanese is lower than that in other ethnic groups. No association is seen between the Pro12Ala and diabetes (0.01 vs 0.017%, p = 0.404), a trend of the higher BMI was observed in Pro12Ala carriers in nondiabetic subjects, although this association is limited by small numbers. CONCLUSION: In this study, no association is seen between the Pro12Ala polymorphism in PPAR gamma2 gene and diabetes; a weak association with obesity is seen.     

Gender specific association of genetic variation in peroxisome proliferator-activated receptor (PPAR)gamma-2 with longevity

Long-lived subjects have been shown to have peculiar anthropometric features (i.e. lower body mass index (BMI)) and metabolic parameters (i.e. improved insulin sensitivity). Life style and a genetic background potentially protective against the age-related metabolic derangement might contribute to such a particular phenotype. Peroxisome proliferator-activated receptor (PPAR)gamma-2 is an important regulator of adipose tissue metabolism, insulin sensitivity and inflammatory response. Thus, the potential role of genetic variability at Pro/Ala loci of PPARG gene on longevity was studied in 222 long-lived subjects and 250 aged subjects. We found a different Pro/Ala genotype frequency distribution between long-lived and aged men subjects, long-lived men having an increased frequency of Pro/Ala genotype (20 vs 8.5%); no differences was found when allele and genotype distribution of Pro/Ala gene polymorphism were analyzed in the two age group of women. Interestingly, subjects with Pro/Ala polymorphism had significantly lower BMI than Ala/Ala and Pro/Pro polymorphism. In conclusion, our study demonstrated that paraoxonase Pro/Ala gene polyporphism is associated with human longevity. Such an effect is probably due to the effect of Pro/Ala polymorphism on body composition and appears to be gender specific.     

Influence of Pro12Ala peroxisome proliferator-activated receptor γ2 polymorphism on glucose response to exercise training in type 2 diabetes

Aims/hypothesis Exercise training improves glycaemic control in some but not all individuals and little research has been done regarding genetic impact on the exercise training response in type 2 diabetes. The purpose of this study was to investigate the influence of the Pro¹²Ala variant of the peroxisome proliferator-activated receptor (PPAR) 2 gene on changes in fasting plasma glucose in response to exercise training.Methods The study population comprised 139 sedentary type 2 diabetic patients (age: 54.4±7.2; HbA₁c: 7.7±0.9%) who completed 3 months of supervised exercise training. The primary outcome variable in our analysis was the post-intervention change in blood glucose. Other assessments included measures of body composition, insulin sensitivity indices and maximal oxygen uptake (VO_2max).Results The frequency of the Ala allele was 8.3% and the genotypes were in Hardy–Weinberg equilibrium. At baseline, neither body composition variables (weight, BMI, waist circumference), glucose homeostasis variables (glucose, insulin, HbA₁c, homeostasis model assessment method) nor VO_2max were different between genotypes (wild-type: Pro¹²Pro n=117, Ala carriers: X¹²Ala n=22). The exercise-training intervention led to similar improvements in body composition and glucose homeostasis variables in both genotype groups (p<0.05). The change in fasting plasma glucose was significantly different between PPAR2 genotypes (–1.66 mmol/l vs –0.54 mmol/l, Ala carriers and wild-type, respectively) (p=0.034 unadjusted and p=0.089 including baseline glucose) and the significant association between genotype and glucose response remained after adjusting for statistically significant predictors (age, changes in insulin and BMI [p=0.015]) and including baseline glucose, insulin and BMI (p=0.031).Conclusions/interpretation These data suggest that the Pro¹²Ala polymorphism may influence the glycaemic response to exercise in type 2 diabetes.     

Effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma-2 gene on adiposity,insulin sensitivity and lipid profile in the Spanish population

OBJECTIVE: To investigate the role of the Pro12Ala peroxisome proliferator-activated receptor (PPAR) gamma-2 polymorphism in the susceptibility to the insulin resistance syndrome and its metabolic complications in a population-based nationwide multicenter study in Spain. DESIGN: 464 unrelated adults (45.3% men and 54.7% women) aged between 35 and 64 years were randomly chosen from a nationwide population-based survey of obesity and related conditions including insulin resistance and cardiovascular risk factors. METHODS: Anthropometric determinations included: body mass index (BMI), waist-to-hip ratio, sagittal abdominal diameter; biochemical determinations included: fasting plasma glucose concentration and concentration 2 h after an oral glucose tolerance test (OGTT), total cholesterol, high and low density lipoprotein-cholesterol, triglycerides, leptin and insulin. Systolic and diastolic blood pressure were also measured. Genotyping of the PPARgamma-2 Pro12Ala polymorphism was determined by polymerase chain reaction and single strand conformation polymorphism analysis. RESULTS: The Ala12 allele frequency was higher in obese men than in lean men (0.15 vs 0.08, P=0.03). Men carriers of the Ala12 allele had a higher BMI than non-carriers (38.9% vs 21.3%; adjusted odds ratio 2.36, 95% confidence interval 1.10-5.05, P=0.03). However, despite higher BMI obese men carriers of the Ala12 allele had lower sagittal abdominal diameter than Pro12 homozygotes (24.1+/-3.2 vs 26.3+/-2.5 cm, P=0.01). The Ala12 allele was associated with lower total triglycerides levels in the overall population and it was also associated with lower fasting insulin levels and a higher insulin sensitivity by homeostasis model assessment (HOMA) in women. CONCLUSIONS: Our results suggest that the Pro12Ala polymorphism of the PPARgamma-2 gene promotes peripheral deposition of adipose tissue and increased insulin sensitivity for a given BMI. The results in women might be due to their different adipose tissue distribution.     

Pro12Ala polymorphism in PPAR-γ2 and dementia in Chinese nonagenarians/centenarians

We examined the existence of a relationship between polymorphism and dementia in subjects aged 90 years and above. The sample included 732 unrelated Chinese nonagenarians/centenarians (aged 90–108 years, mean age 93.68 years; 67.5% women). The Pro12Ala variant was examined using polymerase chain reaction restriction fragment length polymorphism. Cognitive function was measured with 30-item mini-mental state examination. The genotype frequencies of the Pro12Ala polymorphism were 0% Ala12Ala, 9.1% Pro12Ala, and 90.9% Pro12Pro. The prevalence rates of dementia were 64.9% in the whole sample (45.0% for men and 74.5% for women). In both men and women, between subjects with and without 12Ala carriers, there was no significant difference in cognitive function scores and also no significant difference in prevalence of dementia; there was no significant difference in frequency of 12Ala carriers between subjects with and without dementia. Multiple logistic regression was performed by adjusting clinical factors that are thought to be associated with cognitive function or with 12Ala carriers. We found that 12Ala is not a risk factor for dementia. We found that Pro12Ala polymorphism in PPAR-γ2 was not directly correlated with dementia among Chinese nonagenarians and centenarians.     

Pro12Ala substitution in peroxisome proliferator-activated receptor gamma 2 is associated with low adiponectin concentrations in young Japanese men

Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to play an important role in adipocyte differentiation. A Pro12Ala substitution in PPAR gamma 2 has been reported to decrease receptor activity in vitro and to be associated with a decreased risk of type 2 diabetes in the general population. Recently, a PPAR response element (PPRE) was identified in the adiponectin promoter, suggesting that decreased PPAR gamma activity may lead to lower adiponectin levels. In the present study, serum adiponectin concentrations and the PPAR gamma Pro12Ala polymorphism were analyzed to determine whether this polymorphism is associated with lower serum adiponectin concentrations in young healthy Japanese subjects. Serum adiponectin concentrations were significantly lower in men with than in those without the Ala12 allele, whereas body mass index (BMI), homeostasis model assessment (HOMA)-beta, HOMA-IR, the insulin sensitivity index during oral glucose tolerance test (ISI [composite]), and serum leptin did not differ significantly between subjects with and without the Ala12 allele. Stepwise regression demonstrated BMI and the Ala12 allele to be independent predictors of serum adiponectin concentrations in men. In conclusion, the Pro12Ala substitution in PPAR gamma 2 may reduce serum adiponectin concentrations in young Japanese men.     

Pro12Ala substitution in peroxisome proliferator-activated receptorγ2 is associated with low adiponectin concentrations in young Japanese men

Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to play an important role in adipocyte differentiation. A Pro12Ala substitution in PPAR gamma 2 has been reported to decrease receptor activity in vitro and to be associated with a decreased risk of type 2 diabetes in the general population. Recently, a PPAR response element (PPRE) was identified in the adiponectin promoter, suggesting that decreased PPAR gamma activity may lead to lower adiponectin levels. In the present study, serum adiponectin concentrations and the PPAR gamma Pro12Ala polymorphism were analyzed to determine whether this polymorphism is associated with lower serum adiponectin concentrations in young healthy Japanese subjects. Serum adiponectin concentrations were significantly lower in men with than in those without the Ala12 allele, whereas body mass index (BMI), homeostasis model assessment (HOMA)-beta, HOMA-IR, the insulin sensitivity index during oral glucose tolerance test (ISI [composite]), and serum leptin did not differ significantly between subjects with and without the Ala12 allele. Stepwise regression demonstrated BMI and the Ala12 allele to be independent predictors of serum adiponectin concentrations in men. In conclusion, the Pro12Ala substitution in PPAR gamma 2 may reduce serum adiponectin concentrations in young Japanese men.     

Inverse effects of the PPAR(gamma)2 Pro12Ala polymorphism on measures of adiposity over 15 years in African Americans and whites. The CARDIA study

Few studies have addressed the association of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma 2 (PPAR gamma 2) gene with longitudinal measures of adiposity and insulin sensitivity during young adulthood, or reported on its relationship with these outcomes in African Americans. These issues were examined in the biracial Coronary Artery Risk Development in Young Adults (CARDIA) cohort, a population-based sample of 5115 African Americans and whites followed prospectively over 15 years. Frequency of the Ala12 allele was 2.1% in African Americans and 12.8% in whites, consistent with previous reports. A generalized estimating equation method was used to simultaneously examine the cross-sectional and longitudinal relationships between the Pro12Ala polymorphism and the measures of adiposity and insulin sensitivity. The Pro12Ala polymorphism was significantly associated with mean 15-year levels of adiposity, but these associations were in opposite direction in the 2 racial groups. On average, African Americans carrying the Ala12 allele had a 1.1 kg/m2 lower body mass index (BMI) ( P = .02) and whites a 0.6 kg/m2 higher BMI ( P = .01), as compared to Pro12 homozygotes. The Ala12 allele was also significantly associated with a decreased risk of incident insulin resistance syndrome in each race (OR = 0.44, P = .04 in African Americans; OR = 0.61, P = .01 in whites) and lower mean 15-year levels of fasting insulin ( P = .02), glucose ( P = .02), and homeostasis model assessment ( P = .01) in African Americans but not in whites. Important roles of BMI and ethnic background in influencing the complex relationships among PPAR gamma gene variation, adiposity, and insulin resistance are suggested.     

Lack of association between the Pro<Subscript>12</Subscript>Ala polymorphism of the PPAR-γ2 gene and type 2 diabetes mellitus in the Qatari consanguineous population

Peroxisome proliferators-activated receptor γ (PPARγ) 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 γ2 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 γ2 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 γ2 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 γ2 gene and the type2 diabetes in Qatar.     

Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes

Aims/hypothesis The Pro12Ala polymorphism of peroxisome proliferator-activated receptor (PPAR) has been consistently associated with Type 2 diabetes. The rare Ala12 variant is estimated to reduce the risk of developing Type 2 diabetes by 20 percent. This variant is in linkage disequilibrium with another common variant, T1431. Both have opposing associations with body weight. We therefore examined the association of specific haplotypes marked by these two variants with susceptibility to Type 2 diabetes.Methods We determined the PPARG genotype of a large Scottish cohort of Type 2 diabetic patients (n=1997) and compared allele frequencies with a cohort of local children (n=2444) and a middle-aged, population-based cohort from Scotland (n=1061).Results Frequency of the Ala12 allele was slightly lower in the Type 2 diabetic cohort than in the children [odds ratio (OR)=0.91, p=0.1]. In contrast, the Ala12 variant was under-represented in the Type 2 diabetic population when compared with similarly aged non-diabetic adults (OR=0.74, p=0.0006). When the Ala12 variant was on a haplotype not bearing the 1431T variant, it conferred greater protection (OR=0.66, p=0.003). However, when it was present in haplotypes containing the 1431T variant (70% of Ala12 carriers), this protection was absent (OR=0.99, p=0.94).Conclusions/interpretation We replicated the finding that the Ala12 variant of PPAR affords protection from Type 2 diabetes, and suggest that this protection is modulated by additional common variation at the PPARG locus.Abbreviations PPAR Peroxisome proliferator-activated receptor - DARTS Diabetes Audit and Research in Tayside Scotland - APOSS Aberdeen Prospective Osteoporosis Screening Study     

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

BACKGROUND: 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). HYPOTHESIS: The purpose of the study was to explore the association between the Pro12Ala polymorphism and the risk of MI in the Chinese population. METHODS: 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. RESULTS: 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). CONCLUSIONS: Our study suggests that Pro12Ala polymorphism is associated with increased risk of MI.     

The in vivo effects of the Pro12Ala PPARγ2 polymorphism on adipose tissue NEFA metabolism: the first use of the Oxford Biobank

Aims/hypothesis To investigate the phenotypic effects of common polymorphisms on adipose tissue metabolism and cardiovascular risk factors, we set out to establish a biobank with the unique feature of allowing a prospective recruit-by-genotype approach. The first use of this biobank investigates the effects of the peroxisome proliferator-activated receptor (PPAR) Pro12Ala polymorphism on integrative tissue-specific physiology. We hypothesised that Ala12 allele carriers demonstrate greater adipose tissue metabolic flexibility and insulin sensitivity. Materials and methods From a comprehensive population register, subjects were recruited into a biobank, which was genotyped for the Pro12Ala polymorphism. Twelve healthy male Ala12 carriers and 12 matched Pro12 homozygotes underwent detailed physiological phenotyping using stable isotope techniques, and measurements of blood flow and arteriovenous differences in adipose tissue and muscle in response to a mixed meal containing [1,1,1-¹³C]tripalmitin. Results Of 6,148 invited subjects, 1,072 were suitable for inclusion in the biobank. Among Pro12 homozygotes, insulin sensitivity correlated with HDL-cholesterol concentrations, and inversely correlated with blood pressure, apolipoprotein B, triglyceride and total cholesterol concentrations. Ala12 carriers showed no such correlations. In the meal study, Ala12 carriers had lower plasma NEFA concentrations, higher adipose tissue and muscle blood flow, and greater insulin-mediated postprandial hormone-sensitive lipase suppression along with greater insulin sensitivity than Pro12 homozygotes. Conclusions/interpretation This study shows that a recruit-by-genotype approach is feasible and describes the biobank’s first application, providing tissue-specific physiological findings consistent with the epidemiological observation that the PPAR Ala12 allele protects against the development of type 2 diabetes.     

The Pro12Ala polymorphism of the PPARG gene is not associated with the metabolic syndrome in an urban population of middle‐aged Swedish individuals

Background To determine if the common Pro12Ala polymorphism (rs1801282) of the peroxisome proliferator‐activated receptor (PPARG) gene is associated with the metabolic syndrome (MetS) or with its individual components in middle‐aged Swedish individuals. Methods MetS was defined according to the National Cholesterol Education Program/Adult Panel III (NCEP/ATP III), the International Diabetes Federation (IDF) and the European Group for the Study of Insulin Resistance (EGIR) criteria in a population‐based sample of nearly 5000 subjects participating in the Malmö Diet and Cancer‐cardiovascular arm. Results Of the subjects included in the analysis, 21.8, 29.4 and 20.4% had MetS according to the NCEP/ATP III, IDF and EGIR (only in subjects without diabetes) definitions, respectively. The Pro12Ala was not associated with MetS or with its individual components. These results were similar when patients with diabetes were excluded. Hypertensive and obese ala‐carriers had lower fasting glucose and hypertensive ala‐carriers also had lower level triglycerides (P < 0.05). Conclusions Our data do not support a major role for the Pro12Ala variant of the PPARG gene in MetS and its individual components. The modest difference in triglyceride and glucose levels, restricted to hypertensive and obese subjects in our cohort, suggests that the polymorphism has a minor effect on glucose and lipid metabolism, particularly in individuals at risk for gluco‐metabolic disturbances.     

Associations of peroxisome proliferator-activated receptor-γ Pro12Ala polymorphism with non-alcoholic fatty liver disease: A meta-analysis

BackgroundPolymorphisms in peroxisome proliferator-activated receptor-γ pro12Ala (PPAR-γ Pro12Ala) have been associated with Non-alcoholic Fatty Liver Disease (NAFLD) in several studies. However, the results of these studies are not entirely consistent. Thus, we performed a meta-analysis to investigate the association between the PPAR-γ Pro12Ala polymorphisms and NAFLD.MethodsStudies were identified by searching PubMed database and manual assessment of the cited references in the retrieved articles. Study-specific relative risks (RRs) and 95 % confidence intervals (CIs) were estimated using a random-effect model. Study quality was assessed using the Newcastle–Ottawa scale.ResultsRelevant medical researches show that 11 studies have been conducted on the analysis of NAFLD for meta-analysis, with a total of 2404 cases and 3959 participating controls. Meta-analysis results show that PPAR-γ Pro12Ala polymorphism and NALAD Ala alleles[no association between dominance model (OR = 0.968, 95%CI: 0.734–1.276, P = 0.815); Pro/Ala vs. Pro/Pro (OR = 0.930, 95 % CI: 0.701–1.233, P = 0.612); Ala/Ala vs. Pro/Pro (OR = 1.220, 95 % CI: 0.668–2.230, P = 0.518); recessive model (OR = 0.907, 95 % CI: 0.516–1.596, P = 0.736)]. Moreover, stratification by ethnicity also revealed that no matter it is in Caucasian populations or in Asian populations, NAFLD has no association with the PPAR-γ Pro12Ala polymorphism.ConclusionsAccording to the meta-analysis, both in Asians and Caucasian populations, the PPAR-γ Pro12Ala polymorphism can't be demonstrated to have any link with susceptibility to NAFLD.