Peroxisome proliferator-activated receptor gamma polymorphism Pro12Ala is associated with nephropathy in type 2 diabetes

AIM: One putative determinant of diabetic nephropathy is the Pro12Ala (P12A) polymorphism in the gene encoding peroxisome proliferator-activated receptor gamma (PPARgamma). Previous research has found a "protective" role for the A12 allele in association with type 2 diabetes, atherosclerosis, and measures of kidney damage. The objective of this study was to investigate a possible role for the P12A PPARgamma gene polymorphism with diabetic nephropathy in an isolated aboriginal Canadian population at high risk for renal disease. METHODS: The P12A PPARgamma gene polymorphism was genotyped in 159 subjects (62 men and 97 women) of Oji-Cree descent. Participants were selected from a communitywide survey, which included diabetic nephropathy assessment by albumin/creatinine (A/C) ratio measurement. Genetic associations were tested by multivariate regression analysis, using a forward stepwise modeling approach. RESULTS: PPARgamma A12 allele carriers had reduced prevalence of microalbuminuria with a approximately 1.5-fold reduction in A/C ratio. Both PPARG P12A genotype [odds ratio (OR)=0.25, 95% confidence interval (95% CI)=0.076-0.85, P=.026] and systolic blood pressure (OR=1.69, 95% CI=1.15-2.48, P=.0075) were associated with microalbuminuria. CONCLUSIONS: The genetic influence of PPARG P12A genotype is modest and is overshadowed by duration of diabetes and systolic blood pressure as the major risk factors for diabetic nephropathy in the Oji-Cree population. The observed genetic association with diabetic nephropathy, however, confirms earlier findings, highlighting the importance of this polymorphism.     

Peroxisome proliferator-activated receptor-gamma2 Pro12Ala and endothelial nitric oxide synthase-4a/b gene polymorphisms are not associated with hypertension in diabetes mellitus type 2

OBJECTIVE AND DESIGN: The Pro12Ala and the 4a/b polymorphisms of the peroxisome proliferator-activated receptor gamma (PPARgamma) and the endothelial nitric oxide-synthase (eNOS) genes, respectively, have been associated with hypertension in some but not all studies. The purpose of this study was to investigate the association between these polymorphisms and hypertension in patients with diabetes mellitus type 2 (DM2). METHODS: We determined, by polymerase chain reaction (PCR), the Pro12Ala PPARgamma2 and the eNOS 4a/b gene polymorphisms in a total of 395 patients with diabetes mellitus 2 (DM2) (225 men and 170 women) from the LIANCO (Lipid-Analytic-Cologne) study. Hypertension was defined as known or newly diagnosed hypertension according to current national guidelines. Associations were determined using chi-square statistics. The influence of genotype and other parameters on blood pressure was determined by analysis of variance (ANOVA) and multivariate analyses. RESULTS: The genotype frequencies of the Pro12Ala polymorphism were 3% AlaAla, 23% ProAla and 74% ProPro and of the eNOS 4a/b polymorphism 3% a/a, 25% b/a and 72% b/b. There were 65% patients with, and 35% without hypertension. A total of 77% of the patients with hypertension were under pharmacological treatment. The mean systolic and diastolic blood pressure (SBP, DBP) was 148 +/- 22 and 84 +/- 11 mmHg in patients with, and 131 +/- 12 and 79 +/- 8 mmHg in patients without, hypertension. There was no difference in the occurrence of hypertension among ProAla and AlaAla subjects compared with ProPro subjects (P = 0.98). There was also no difference between a-allele carriers and non-carriers of the eNOS polymorphism (P = 0.42). There were no differences between men and women in the associations. Analysis of variance did neither identify an influence on systolic or diastolic blood pressure by the presence of the Ala or the a-allele of the respective genotypes nor a significant interaction of the two. CONCLUSIONS: In DM2 the Pro12Ala and 4a/b gene polymorphisms of the PPARgamma2 and eNOS genes, respectively, are not associated with systolic or diastolic blood pressure, either in men or in women. Our results in a large cohort fail to confirm reports of recent studies suggesting an association of lower blood pressure in patients with DM2 and carriers of Pro12Ala polymorphism.     

Peroxisome proliferator-activated receptor-gamma2 P12A and type 2 diabetes in Canadian Oji-Cree

Among the Oji-Cree of northern Ontario, we previously identified a novel variant in the HNF1A gene, namely G319S, that was strongly associated with type 2 diabetes. However, the majority of subjects with diabetes did not have the HNF1A S319 variant, suggesting that there might be other genetic determinants of diabetes susceptibility. In the course of sequencing candidate genes in diabetic subjects who were homozygous for HNF1A G319/G319, we found that some of them had the PPARG A12 variant. After genotyping PPARG in the entire adult Oji-Cree population, we found that: 1) PPARG A12 was strongly associated with type 2 diabetes in women, but not men; 2) among women, the odds of being affected for carriers of PPARG A12 compared with noncarriers was 2.3 (95% confidence interval, 1.4-3.8); and 3) among women, affected carriers of PPARG A12 had a significantly earlier age-of-onset and/or age-at-diagnosis compared with noncarriers. When taken together with the previously reported association of diabetes with HNF1A in both men and women, the gender-specific association with PPARG A12 confirms that type 2 diabetes is etiologically complex in the Oji-Cree and that at least two genes are involved in determining susceptibility to the disease in these people.     

Association between the Pro12Ala variant of the peroxisome proliferator-activated receptor-gamma2 gene and increased 24-h diastolic blood pressure in obese patients with type II diabetes

The aim of the study was to examine an association between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR)-gamma2 gene and blood pressure values assessed by 24-h ambulatory blood pressure monitoring (ABPM) in obese patients with long-lasting type II diabetes. Two hundred and fourteen obese patients (95 men and 119 women) with above 10-year history of type II diabetes were recruited for the study. In all the patients, ABPM was performed and other parameters, including age, body mass index (BMI), waist/hip ratio (WHR), haemoglobin A1c (HbA(1c)), serum lipids and creatinine were also evaluated. The Pro12Ala polymorphism was analysed by polymerase chain reaction-restriction fragment length polymorphism. Two subgroups of patients were compared: (a) Pro/Pro: homozygotic Pro/Pro (n=154) and (b) Ala: Ala allele carriers (Ala/Ala+Ala/Pro) (n=60). The studied groups were not different when age, BMI, WHR, HbA(1c), lipids, creatinine and frequency of hypertension were compared. A similar ratio of patients from both groups were treated with angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, beta-blockers and alpha-blockers. A difference was observed in a mean 24-h (Ala: 71.9+/-8.1 vs Pro/Pro: 69.4+/-7.8 mm Hg, P=0.034) and a mean night time (Ala: 67.1+/-7.8 vs Pro/Pro: 64.5+/-8.4 mm Hg, P=0.025) diastolic blood pressure, which was significantly higher in patients with Ala variant. There was also a trend towards a higher mean daytime diastolic blood pressure in this group. It seems that the Pro12Ala variant is associated with an increased mean 24-h diastolic blood pressure in obese diabetic patients. Different reaction for antihypertensive medication depending on a variant of the PPAR-gamma2 gene should also be considered as a possible cause of the presented results.     

Peroxisome proliferator-activated receptor-gamma2-Pro12Ala and endothelial nitric oxide synthase-4a/bgene polymorphisms are associated with essential hypertension

OBJECTIVE: Peroxisome proliferator-activated receptor-gamma2 (PPARgamma2) belongs to the family of the nuclear hormone receptors and has been recently implicated in vascular biology. PPARgamma2(Pro12Ala) gene polymorphism is associated with obesity, body mass index and diabetes mellitus. The endothelial nitric oxide synthase (eNOS) (4a/b) gene polymorphism contributes to coronary heart disease and hypertension risk. We tested whether both polymorphic variants were associated with hypertension risk, and their inter-relationship with plasma homocysteine. DESIGN: A case-control study was conducted selecting 235 subjects with arterial hypertension and 223 normotensive matched controls. METHODS: Genotyping for the PPARgamma2(Pro12Ala) and the eNOS(4a/b) were performed by mutagenically separated polymerase chain reaction and by polymerase chain reaction. Glucose, lipid profile, plasma creatinine, homocysteine and microalbuminuria were measured.RESULTS We found a significant contribution of the PPARgamma2(Pro12Ala) and eNOS(4a/b) gene polymorphisms to hypertensive risk in our population (odds ratio, 1.9 and 1.6, respectively), confirmed by multiple logistic regression analysis. Those subjects with normal plasma homocysteine values had an increased hypertensive risk with an odds ratio of 2.6 for the PP genotype of the PPARgamma2 gene and an odds ratio of 1.8 for the a allele of the eNOS gene. CONCLUSIONS: Both analyzed polymorphisms were associated in a synergistic manner with hypertension. This effect manifested only in those subjects with normal homocysteine plasma values. Our findings suggest complex genotype-environmental interactions on hypertensive risk.     

Peroxisome proliferator-activated receptor gamma 2 Pro12Ala gene variant is strongly associated with larger body mass in the Taiwanese

The peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) has been studied extensively because of its putative role in adipocyte differentiation and insulin sensitivity. The association of the Pro12Ala and Pro115Gln PPARgamma2 gene variants with type 2 diabetes mellitus, the body mass index (BMI), and other diabetes-related phenotypes was examined in the Taiwanese population. Genotypes were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Allele frequencies were compared between 280 subjects with type 2 diabetes mellitus and 310 subjects without diabetes using the chi-square test. Continuous phenotype analysis was performed by multiple logistic regression adjusting for age and BMI where appropriate. There was no significant association between the Pro12Ala gene variant and type 2 diabetes; the frequency of the Ala12 allele was 0.03 in type 2 diabetics and 0.04 in nondiabetics (P = .40). The Gln115 allele was not detected in any of the cases or controls. In multiple linear regression analysis of all cases and controls combined adjusted for age, sex, and diabetic status, carriers of the Ala12 allele had a mean BMI of 25.9+/-0.5 kg/m2 (mean +/- SE), compared with 24.2+/-0.1 kg/m2 in Pro12 homozygotes (P < .001). In addition, carriers of the Ala12 allele have a 2.9 times (95% confidence interval [CI], 1.5 to 5.5) higher odds of having a BMI of at least 25 kg/m2. These results suggest that in the Taiwanese, the Pro12Ala PPARgamma2 gene variant may contribute to fat accumulation and a higher BMI independent of type 2 diabetes. These results need to be confirmed in future studies, as a linkage disequilibrium of this variant with other mutations cannot be ruled out.     

PPARγ2基因多态性与2型糖尿病相关性研究

目的 旨在研究过氧化物酶增殖物活化受体γ2（PPARγ2）基因Pro12Ala多态性与2型糖尿病相关性。方法 选取北京地区汉族101对病例一对照配偶对，应用聚合酶链反应一长度多态性方法进行基因型测定。结果 对照组中携带Ala12等位基因组，血清载脂蛋白B明显低于Pro12Pro基因型组（P＝0.006)；但Pro12Ala多态性与2型糖尿病不相关（OR＝1．48，95％CI=0．52－4．18，P＝0．461）。结论 在北京汉族人群中，PPARγ2基因Pro12Ala多态性与脂肪代谢异常有关，PPARγ2基因多态性可能不是2型糖尿病主要的致病因素。     

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.     

Impact of the Peroxisome Proliferator Activated Receptor gamma2 Pro12Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus

OBJECTIVE: The Pro12Ala polymorphism of the Peroxisome Proliferator Activated Receptor gamma2 (PPARgamma2) gene has been inconsistently associated with body mass index variations and non-insulin-dependent diabetes mellitus (NIDDM). We investigated the impact of this polymorphism on obesity markers, lipid and glucose variables in a sample of French subjects and evaluated its possible role in the onset of NIDDM. DESIGN AND SUBJECTS: Within the framework of the WHO-MONICA project, a population study composed of 1195 subjects aged 35-64 y was randomly sampled from the electoral rolls of the urban community of Lille, in northern France. Subjects receiving medical treatment for hypercholesterolemia, hypertension or diabetes mellitus were excluded for the analyses, to avoid any interferences between medical treatment and biological variables. This resulted in a sample size of 839 subjects (421 men/418 women, age=49.4+/-8.1 y, body mass index (BMI)=25.7+/-4.4 kg/m2). To evaluate the role of the Pro12Ala polymorphism in the onset of NIDDM, we evaluated its distribution in 170 Caucasian NIDDM subjects from a clinical series (117 men/53 women, age=62.3+/-9.0 y, BMI=30.1+/-3.6 kg/m2). MEASUREMENTS: The PPARgamma2 Pro12Ala polymorphism genotyping was carried out with allele specific oligonucleotides hybridisation. Data were statistically analysed for association with various obesity markers (body weight (BW), BMI, waist-to-hip ratio (WHR), plasma leptin concentrations, lipid and glucose variables. RESULTS: In the WHO-MONICA population, the Ala allele frequency was 0.11. The presence of the Ala allele was significantly associated with higher body weight (P=0.002), BMI (P=0.02), height (P=0.02) and waist circumference (P=0.04). Increased plasma concentrations of total cholesterol (P=0.01), LDL-cholesterol (P=0.004) and apolipoprotein B (P=0.01) were also detected in Ala allele bearers. The distribution of the Pro12Ala polymorphism was similar in NIDDM subjects (Ala allele frequency: 0.10) and in the WHO-MONICA population subjects. CONCLUSION: Our results suggest that genetic variability of PPARgamma2 affects body weight control and lipid homeostasis in humans and do not support a significant role for the PPARgamma2 Pro12Ala polymorphism in the aetiology of NIDDM. International Journal of Obesity (2000) 24, 195-199     

Pulse pressure and diurnal blood pressure variation: association with micro- and macrovascular complications in type 2 diabetes

BACKGROUND: In nondiabetic subjects pulse pressure (PP) is an independent predictor of cardiovascular disease and microalbuminuria. Reduced circadian blood pressure (BP) variation is a potential risk factor for the development of diabetic complications. We investigated the association between retinopathy, nephropathy, macrovascular disease, PP, and diurnal BP variation in a group of type 2 diabetic patients. METHODS: In 80 type 2 diabetic patients we performed 24-h ambulatory BP (AMBP) and fundus photographs. Urinary albumin excretion was evaluated by urinary albumin/creatinine ratio. Presence or absence of macrovascular disease was assessed by an independent physician. RESULTS: Forty-nine patients had no detectable retinal changes (grade 1), 13 had grade 2 retinopathy, and 18 had more advanced retinopathy (grades 3-6). Compared to patients without retinopathy (grade 1), patients with grades 2 and 3-6 had higher PP and blunted diurnal BP variation: night PP 55 +/- 10 mm Hg, 64 +/- 10 mm Hg, 61 +/- 15 mm Hg, P < .05 and systolic night/day ratio 89.3% +/- 7%, 94.6% +/- 8%, and 92.0% +/- 6%, P < .05 (grade 1, 2, and 3-6, respectively). Comparing nephropathy groups (45 normo-, 19 micro-, and 15 macroalbuminuric patients) results were similar: night PP 54 +/- 9 mm Hg, 57 +/- 10 mm Hg, and 70 +/- 15 mm Hg, P < .001 and systolic night/day ratio 88.9% +/- 7%, 92.0% +/- 7%, and 94.9% +/- 7%, P < .02. Likewise, compared to patients without macrovascular disease (n = 55), patients with this complication (n = 25) had higher AMBP values: night PP 57 +/- 12 mm Hg v 63 +/- 11 mm Hg, P < .05 and systolic night/day ratio 89.2% +/- 6% v 94.1% +/- 9%, P < .01. CONCLUSIONS: Increased PP and blunted diurnal BP variation are hemodynamic abnormalities associated with micro- and macrovascular complications in type 2 diabetes.     

Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus

Type 2 diabetes mellitus, a global epidemic, is largely attributed to metabolic syndrome and its clustering of cardiovascular risk factors including abdominal obesity, dyslipidemia, hypertension and hyperglycemia. The two primary approaches to optimally control risk factors associated with metabolic syndrome are lifestyle changes and medications. Although many pharmacological targets have been identified, clinical management of cardiovascular risk factors associated with metabolic syndrome and type 2 diabetes is still dismal. Recent evidence suggests premises of the peroxisome proliferator-activated receptor (PPAR) ligands in the combat against type 2 diabetes and metabolic syndrome including obesity and insulin resistance. Three subtypes of the PPAR nuclear fatty acid receptors have been identified: alpha, beta/delta and gamma. PPARalpha is believed to participate in fatty acid uptake (beta- and omega-oxidation) mainly in the liver and heart. PPARbeta/delta is involved in fatty acid oxidation in muscle. PPARgamma is highly expressed in fat to facilitate glucose and lipid uptake, stimulate glucose oxidation, decrease free fatty acid level and ameliorate insulin resistance. Synthetic ligands for PPARalpha and gamma such as fibric acid and thiazolidinediones have been used in patients with type 2 diabetes and pre-diabetic insulin resistance with significantly improved HbA(1c) and glucose levels. In addition, nonhypoglycemic effects may be elicited by PPAR agonists or dual agonists including improved lipid metabolism, blood pressure control and endothelial function, as well as suppressed atherosclerotic plaque formation and coagulation. However, issues of safety and clinical indication remain undetermined for use of PPAR agonists for the incidence of heart disease in metabolic syndrome and type 2 diabetes.     

Association of the Pro12Ala gene polymorphism with treatment response to thiazolidinediones in patients with type 2 diabetes: a meta-analysis

International Journal of Diabetes in Developing Countries - With the conflicting results on available studies regarding the association of the Pro12Ala polymorphism with the response of patients...     

罗格列酮对2型糖尿病合并高血压患者血压的作用

目的：运用胰岛素增敏剂罗格列酮治疗2型糖尿病伴高血压患者，研究其降压作用及降压机理。方法：38例2型糖尿病伴高血压患者，口服罗格列酮（文迪雅）4～8mg／d，共12周，观察治疗前后的血压、瘦素、血糖和胰岛素水平，计算胰岛素敏感指数和胰岛素抵抗指数，并进行分析比较。结果：罗格列酮治疗后收缩压和舒张压明显下降（P〈0．05）；甘油三酯（TG）、空腹血糖（FBG）、餐后血糖（PBG）、空腹胰岛素（FINS）和餐后胰岛素（PINS）均明显降低（P均〈0．05）；瘦素水平明显升高（P〈0．01）；胰岛素敏感性指数（ISI）显著升高（P〈0．05），胰岛素抵抗指数（IR）显著下降（P〈0．05）。结论：罗格列酮在降低血糖、改善胰岛索抵抗、提高胰岛素敏感指数的同时，具有升高瘦素水平和降低血压的作用。     

合并高血压的老年2型糖尿病患者血压控制目标探讨

目的探讨老年2型糖尿病合并高血压患者降压的目标值。方法选取2008年1月至2011年1月在福建省立医院内科就诊的707例65岁以上老年2型糖尿病合并高血压患者,其中男324例,女383例,平均年龄（72±6）岁。按收缩压（SBP）高低分为收缩压严格控制组（130mm Hg≤SBP〈140mmHg,1mmHg=0．133kPa）235例,收缩压宽松控制组（140mmHg≤SBP〈160mm Hg）472例,两组患者收缩压水平均维持至少3年。所有患者进行12导联心电图检查,预估肾小球滤过率（eGFR）通过Cockcroft—Gault公式计算。将心电图aVL导联R波的电压（RaVL）作为心血管风险的替代指标,将eGFR作为评价肾功能的指标。以RaVL≥0．57mV和〈0．57mV作为二分类变量,使用logistic回归法分析心血管疾病风险。结果收缩压宽松控制组与严格控制组RaVL分别为：0,55（0．50～0．59）、0．58（0．52～0．64）mV,差异无统计学意义（F：0．235,P〉0．05）。收缩压宽松控制组eGFR为55．6（53．2～58．0）ml／min,低于收缩压严格控制组[59．6（56．2～63．1）ml／min],但差异无统计学意义（F=1．289,P〉0．05）。将RaVL≥0．57mV及RaVL〈0．57mV作为因变量进行多因素logistic回归分析发现,收缩压宽松控制组RaVL≥0．57mV的风险与收缩压严格控制组相比差异无统计学意义（OR=0．927,95％CI：0．567～1．514,P〉0．05）。结论老年2型糖尿病合并高血压患者收缩压的目标值控制在140mm Hg以下可能并不改善心血管和肾脏预后。     

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.