The TNF-alpha -308G/A polymorphism is associated with type 2 diabetes mellitus: an updated meta-analysis

The tumor necrosis factor (TNF)-alpha -308G/A polymorphism has long been suspected of being a gene variant that is associated with type 2 diabetes, but studies have reported conflicting outcomes. An updated meta-analysis was performed to investigate whether the TNF-alpha -308A variant is associated with an increased risk of type 2 diabetes. Statistical analyses were performed using Revman 5.0 and STATA 10.0 software. A total of 38 case–control studies in 38 articles were included. Statistical analyses of the results suggested that the TNF-alpha -308G/A polymorphism was associated with an increased risk of type 2 diabetes mellitus (OR = 1.21, 95 % CI 1.06–1.37, P = 0.003) in a dominant model, particularly for Asian carriers of the A mutation (GA+AA), who were shown to have a 39 % increased risk of type 2 diabetes (OR = 1.39, 95 % CI 1.11–1.74, P = 0.004) compared with wild-type (GG) subjects. However, no significant difference in diabetes risk was found between the mutant and wild-type genotypes in Caucasian subjects (OR = 1.08, 95 % CI 0.98–1.18, P = 0.12). This meta-analysis indicates that the TNF-alpha -308A variant could be a risk factor for the development of type 2 diabetes, particularly in Asian subjects. However, this association was not statistically significant in Caucasian subjects. More specified ethnical studies are required to reveal the detailed physiological characteristics of the TNF-alpha -308 G/A polymorphism.     

Meta-analysis of TNF 308 G/A polymorphism and type 2 diabetes mellitus

Background and Objectives

Many investigations have focused the association between TNF 308 G/A polymorphism and risk for type 2 diabetes mellitus (T2DM). However, the sample sizes of most of the studies were small. The aim of this study is to evaluate the precise association between this variant and risk for T2DM in a large-scale meta-analysis.

Methods

All publications were searched on the association between TNF 308 G/A polymorphism and T2DM. The key words were as follows: diabetes, tumor necrosis factor and polymorphism/variant/genotype. This meta-analysis was assessed by Review manager 5.0.

Results

There were 18 studies identified. The odd ritos (ORs) and 95% confidence intervals (CI) for GA+AA versus GG genotype of TNF 308 G/A polymorphism were 1.03 (0.95–1.12), 1.03 (0.94–1.13) and 1.03 (0.78–1.36) in overall, Caucasian and Asian populations, respectively. The sensitivity analysis further strengthened the validity of this association. No publication bias or heterogeneity was observed in this study.

Conclusion

In summary, there was no significant association detected between the TNF 308 G/A polymorphism and risk for T2DM.     

G-2548A polymorphism of the leptin gene is correlated with extreme obesity in Taiwanese aborigines

We examined the genetic associations of the G-2548A polymorphism in the promoter of the leptin (LEP) gene and the Gln223Arg (Q223R) polymorphism of the leptin receptor (LEPR) gene with obesity. Two hundred twenty-six obese aboriginal subjects (BMI > or = 27 kg/m2) and 182 aboriginal subjects with normal weight (BMI < 25 kg/m2) participated in this study. The polymorphisms of LEP G-2548A and LEPR Q223R were genotyped by polymerase chain reaction/restriction fragment length polymorphism, and their anthropometric characteristics were measured. Levels of leptin, triglycerides, and cholesterol were measured after overnight fasting. We found that the frequencies of the LEP G/G homozygote (22.6%) with Mendelian recessive (chi2 = 7.89, p = 0.005) and codominant (chi2 = 7.93, p = 0.02) models to be higher in the extremely obese subjects (BMI > or = 35 kg/m2) than in normal weight subjects (6.9%) but not in moderately obese subjects (35 > BMI > or = 27 kg/m2). There was no difference in genotypic frequency of the LEPR Q223R polymorphism between the extreme obese and control groups. We suggest that the LEP -2548 G/G homozygote plays a genetic recessive role in the development of extreme obesity in Taiwanese aborigines.     

The 223A>G polymorphism of the leptin receptor gene is associated with macroangiopathy in type 2 diabetes mellitus

To determine whether leptin receptor (LEPR) 223A>G polymorphism has an effect on the plasma leptin levels and the macroangiopathic complications in type 2 diabetes mellitus (T2DM). The genotypes and allelic frequencies of the LEPR 223A>G were examined with polymerase chain reaction and restriction fragment length polymorphism in 301 patients with T2DM and 172 unrelated healthy subjects. The plasma concentrations of leptin were determined in all subjects. The mean plasma leptin levels in the T2DM group were significantly higher than that of controls and the plasma levels of leptin were higher in diabetic patients with macroangiopathy than in patients without macroangiopathy (P < 0.05). The genotype (GG, AG and AA) distribution of 223A>G polymorphism was 58.3, 32.5, and 9.2% in diabetic patients with macroangiopathy, 75.3, 22.1, and 2.6% in patients without macroangiopathy, and 70.3, 27.5, 2.2% in controls respectively, a significant difference was found between diabetic patients with and without macroangiopathy (P < 0.05). The frequency of the allele A was higher in patients with macroangiopathy than in patients without macroangiopathy (25.6 vs. 16.3%; P < 0.05). Moreover, the plasma leptin levels were markedly higher in patients with AA genotype than those with AG or GG genotype in patients with macroangiopathy (P < 0.05). The LEPR 223A>G gene polymorphism associated with a predisposition to increased plasma leptin levels could constitute a useful predictive marker for diabetic macroangiopathy.     

Association of six single nucleotide polymorphisms with gestational diabetes mellitus in a Chinese population

Background

To investigate whether the candidate genes that confer susceptibility to type 2 diabetes mellitus are also correlated with gestational diabetes mellitus (GDM) in pregnant Chinese women.

Methodology/Principal Findings

In this study, 1764 unrelated pregnant women were recruited, of which 725 women had GDM and 1039 served as controls. Six single nucleotide polymorphisms (rs7754840 in CDKAL1, rs391300 in SRR, rs2383208 in CDKN2A/2B, rs4402960 in IGF2BP2, rs10830963 in MTNR1B, rs4607517 in GCK) were genotyped using TaqMan allelic discrimination assays. The genotype and allele distributions of each SNP between the GDM cases and controls and the combined effects of alleles for the risk of developing GDM were analyzed. We found that the rs4402960, rs2383208 and rs391300 were statistically associated with GDM (OR = 1.207, 95%CI = 1.029–1.417, p = 0.021; OR = 1.242, 95%CI = 1.077–1.432, p = 0.003; OR = 1.202, 95%CI = 1.020–1.416, P = 0.028, respectively). In addition, the effect was greater under a recessive model in rs391300 (OR = 1.820, 95%CI = 1.226–2.701, p = 0.003). Meanwhile, the joint effect of these three loci indicated an additive effect of multiple alleles on the risk of developing GDM with an OR of 1.196 per allele (p = 1.08×10⁻⁴). We also found that the risk alleles of rs2383208 (b = −0.085, p = 0.003), rs4402960 (b = −0.057, p = 0.046) and rs10830963 (b = −0.096, p = 0.001) were associated with HOMA-B, while rs7754840 was associated with decrease in insulin AUC during a 100 g OGTT given at the time of GDM diagnosis (b = −0.080, p = 0.007).

Conclusions/Significance

Several risk alleles of type 2 diabetes were associated with GDM in pregnant Chinese women. The effects of these SNPs on GDM might be through the impairment of beta cell function and these risk loci contributed additively to the disease.     

Meta-analysis: Interleukin 6 gene -174G/C polymorphism associated with type 2 diabetes mellitus and interleukin 6 changes

The gene coding interleukin 6 (IL-6) is a promising candidate in predisposition to type 2 diabetes mellitus (T2DM). This study aimed to meta-analytically examine the association of IL-6 gene −174G/C polymorphism with T2DM and circulating IL-6 changes across −174G/C genotypes. Odds ratio (OR) and standard mean difference (SMD) with 95% confidence interval (CI) were calculated. Twenty-five articles were meta-analysed, with 20 articles for T2DM risk and 9 articles for circulating IL-6 changes. Overall, there was no detectable significance for the association between −174G/C polymorphism and T2DM, and this association was relatively obvious under dominant model (OR: 0.82, 95% CI: 0.56-1.21). Improved heterogeneity was seen in some subgroups, with statistical significance found in studies involving subjects of mixed races (OR: 0.63, 95% CI: 0.46-0.86). Begg's and filled funnel plots, along with Egger's tests revealed week evidence of publication bias. In genotype-phenotype analyses, carriers of −174CC and −174CG genotypes separately had 0.10 and 0.03 lower concentrations (pg/mL) of circulating IL-6 than −174GG carriers. Albeit no detectable significance for the association of −174G/C with T2DM, our findings provided suggestive evidence on a dose-dependent relation between −174G/C mutant alleles and circulating IL-6 concentrations, indicating possible implication of this polymorphism in the pathogenesis of T2DM.     

Quantitative assessment of the influence of PPARG P12A polymorphism on gestational diabetes mellitus risk

The peroxisome proliferator-activated receptor-γ (PPARG) is a member of the nuclear hormone receptor superfamily that has attracted considerable attention as a candidate gene for gestational diabetes mellitus (GDM) based on its function as a key factor involved in the regulation of adipocyte differentiation as well as lipid and glucose metabolism and insulin sensitivity. Many studies have examined the association between P12A polymorphism (rs1801282) in the PPARG gene and risk of GDM, but the results have been inconsistent. To derive a more precise estimation of the relationship, a meta-analysis of 2,858 GDM patients and 6,890 controls from nine published case–control studies was performed. An overall random effects odds ratio of 0.89 (95 % confidence interval [CI]: 0.77–1.04, P = 0.15) was found for 12A allele. In the subgroup analysis by ethnicity, significantly decreased risks were found in East Asians, while no significant associations were detected among Caucasian and Middle Eastern populations. Similar results were also observed using dominant genetic model. This meta-analysis suggested an overall weak association between the P12A polymorphism and GDM risk among East Asians. However, additional very large-scale studies are warranted to provide conclusive evidence on the effects of the PPARG gene on risk of GDM.     

Predictive parameters of gestational diabetes mellitus

Gestational diabetes mellitus is a carbohydrate intolerance recognized in pregnancy. The objective of this study was to determine the prevalence of gestational diabetes mellitus (GDM) of all deliveries at the University Hospital Rijeka, Croatia (34 997 deliveries over 10-year period) using 2-hour 75 g oral glucose tolerant test and to evaluate the impact of GDM on neonatal outcomes and mother's health. Gestational diabetes was diagnosed in 55 of 128 pregnant women with suspected glucose intolerance. Logistic regression analysis was used to examine the relationship between fasting plasma glucose, age, family history, body mass index, maternal weight gain, neonatal weight, neonatal head diameter and Apgar score in the gestational diabetes group and in the non-diabetes group. The results indicate that fasting plasma glucose greater than 7.0 mmol/L and maternal overweight are strong predictors for GDM and macrosomia. There was no difference in the mode of delivery, and vitality and metabolic complications among the infants of all analyzed mothers. We concluded that to prevent GDM as well as to reduce the rate of macrosomic infants good glycemic control should be initiated as soon as possible. The 2-hour 75 g OGTT is worth enough to evaluate GDM. Women should be counseled and encouraged to lose weight before or at the beginning of the conception period.     

Association of cytotoxic T-lymphocyte associated antigen 4 gene polymorphism with type 1 diabetes mellitus: A meta-analysis

To evaluate the association between costimulatory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and type 1 diabetes mellitus(T1DM), sixty-three published studies before December, 2011 were included. Meta-analysis was performed for each genotype in a random/fixed effect model. The combined odds ratio (OR) with 95% confidence interval (95%CI) was calculated to estimate the strength of the association. Overall, significant correlation was noted between CTLA-4 gene polymorphism (i.e. +49A/G, CT60A/G in a per-allele model) and the risk of T1DM (for +49A/G: OR=1.47, 95%CI=1.36-1.60, P<0.001; for CT60A/G: OR=1.31, 95%CI=1.18-1.45, P<0.001). However, no significant association was noted between C(-318)T polymorphism and T1DM. In the subgroup analysis, for +49A/G and CT60A/G, the statistically significant associations were also demonstrated in diverse racial descents (Caucasian and Asian) and age of onset (<20years and >20years). In conclusion, our results suggest that CTLA-4 polymorphism contributes to the susceptibility of T1DM.     

Association of gestational diabetes mellitus and low-density lipoprotein (LDL) particle size

A predominance of small, dense low-density lipoproteins (LDL) is characteristic of the dyslipidemic state seen in type 2 diabetes. However, no study has investigated the association in gestational diabetes mellitus (GDM), which is pathophysiologically similar to type 2 diabetes. We hypothesized that LDL particle size is reduced in GDM cases compared with controls. Gradient gel electrophoresis was used to characterize LDL subclass phenotypes in non-fasting intrapartum plasma from 105 GDM cases and 96 controls. All participants were free of pre-existing diabetes or hypertension. The authors used logistic regression to estimate odds ratios (OR) and 95 % confidence intervals (CI) adjusted for confounders. Women with this phenotype had a significant 4.9-fold (95 % CI: 1.1-23.2) increased risk of GDM compared with those with the large, buoyant phenotype. The magnitude of this association was attenuated when plasma triglyceride and other confounders were included in the model (OR=4.2, 95 % CI: 0.5-39.5). Mean LDL particle size in GDM cases was smaller compared with controls (270.1 vs. 272.7A, p=0.003). The OR of GDM risk was 1.8 (95 % CI: 0.9-3.3) for every 10-A reduction in LDL particle size. Large prospective studies are needed to evaluate the association between smaller LDL particle size in early pregnancy with subsequent GDM risk.     

脂蛋白脂酶基因多态性与2 型糖尿病的相关性研究

目的：探讨脂蛋白脂酶（lipoprotein lipase,LPL）基因PvuⅡ酶切多态性与2型糖尿病的相关性。方法：采用聚合酶链反应-限制性片段长度多态性（PGR-RFLP）方法,分析了156例样本LPL基因第6内含子PvuⅡ多态性（病例组98人。对照组58。其中40个2型糖尿病同胞对,病例组40人,对照组40人）。结果：病例组与对照组的基因型和基因频率均无显著性差异。结论：湖北汉族人群脂蛋白脂酶基因PvuⅡ酶切多态性与2型糖尿病无明显关联。     

Association of the 163A/G and 1181G/C osteoprotegerin polymorphism with bone mineral density.

The aim of the study was to investigate the distribution of 163 A/G osteoprotegerin gene promoter and 1181 G/C osteoprotegerin exon 1 polymorphisms in a group of women with different hormonal status and to analyze their relationship with BMD. Osteoprotegerin polymorphisms and BMD were analyzed in 332 women (69 premenopausal and 263 postmenopausal). BMD was quantified at the lumbar spine (L 2-4), femoral neck, and total hip. Genotyping for the presence of different polymorphisms was performed using the Custom Taqman ((R)) SNP Genotyping assays. There were not significant differences in BMD according to 163 A/G genotype. However, significant differences in lumbar spine BMD were found according to 1181 G/C alleles. Thus, women with CC genotype had significant higher BMD at the lumbar spine than those with GC or GG genotype. No differences were found in femoral neck and total hip BMD. In age-adjusted models, the 1181 G/C OPG polymorphism explained 2.2% of BMD variance at the spine, 0.3% at the femoral neck, and 0.9% at the total hip in the whole group. In the subgroup of premenopausal women, the polymorphism was strongly related to spine BMD, and explained 11.5% of the variance, whereas body weight explained 7.9%. The 1181 G/C polymorphism was associated with lumbar spine BMD in Spanish women. Premenopausal women with the CC genotype had a higher BMD.     

Association between the CTGF -945C/G polymorphism and systemic sclerosis: A meta-analysis

BACKGROUND: The -945C/G polymorphism of the connective tissue growth factor (CTGF) has been associated with systemic sclerosis, however, results were conflicted. The aim of this study was to validate the evidence for the CTGF -945C/G polymorphism and systemic sclerosis risk. METHODS: Electronic search of PubMed was conducted to select studies. Case-control studies containing available genotype frequencies of -945C/G were chosen, and odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of this association. RESULTS: Six published case-control studies including 3335 cases and 3589 controls were identified. The overall results suggested that the variant genotypes were not associated with the systemic sclerosis risk (OR=0.947, 95% CI: 0.792-1.132, p=0.55). The stratified analysis in Caucasian (OR=1.002, 95% CI: 0.837-1.2, p=0.788) did not suggest an association either. However, analysis in Asian (OR=0.632, 95% CI: 0.459-0.869, p=0.005) showed that CC/CG genotype greatly decreased the susceptibility of systemic sclerosis in a dominant model. Asymmetric funnel plot, the Egger's test (p=0.292), and the Begg's test (p=0.593) were all suggestive of the lack of publication bias. CONCLUSION: This meta-analysis supports that CC/CG genotype greatly decreased the susceptibility of systemic sclerosis in Asian. Due to the limited samples in subpopulations, further prospective studies with larger number of participants worldwide are needed to examine the association between the CTGF -945C/G polymorphism and systemic sclerosis.     

Association of ghrelin Leu72Met polymorphism with type 2 diabetes mellitus in Chinese population

Background

Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to implicate the development of the type 2 diabetes mellitus (T2DM). The Leu72Met (+ 408 C > A) polymorphism of the preproghrelin, has been linked to obesity, insulin resistance and diabetes.

Objective

To investigate the distribution of ghrelin gene Leu72Met polymorphism and its association with the type 2 diabetes mellitus in Chinese population.

Methods

We conducted a case–control study on 877 patients with T2DM and 864 controls, which were genotyped by the polymerase chain reaction (PCR) technique, denaturing high performance liquid chromatography (DHPLC) and DNA sequence analysis. Laboratory analyses were carried out in the hospital laboratory.

Results

No significant difference in the Leu72Met genotype distributions and allele frequency was observed between type 2 diabetes mellitus and controls (both P > 0.05). The polymorphism was not associated with T2DM. However, among the T2DM group, the patients carrying Leu72Leu genotype had significantly increased levels of FPG and serum creatinine compared with variant genotypes (Leu72Met and Met72Met) (P < 0.05). In the control group, the subjects with variant genotypes had significantly increased levels of FINS, HOMA-IR compared with Leu72Leu genotype (P < 0.05).

Conclusion

The Leu72Met polymorphism of the preproghrelin gene was not associated with T2DM in Chinese population. However, it may have some roles in the etiology of insulin resistance.     

The interleukin-6 (-174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians

Chronic low-grade activation of the immune system may play a role in the pathogenesis of type-2 diabetes mellitus (T2DM). Interleukin-6 (IL6), a powerful inducer of hepatic acute phase response, has been implicated in the etiology of insulin resistance and T2DM. Recently, an IL6 promoter polymorphism (G/C) at position -174 was found to be associated with measures of insulin sensitivity. Because we have previously found an association between high IL6 levels and insulin resistance in both Pima Indians - a population with high rates of insulin resistance and T2DM - and Caucasians, we aimed to assess whether the IL6 promoter polymorphism is associated with T2DM in these populations. We genotyped the IL6 (-174) G/C polymorphism using pyrosequencing in 463 Native Americans and by PCR-RFLP in 329 Spanish Caucasians. Among the Spanish Caucasian subjects, there was a significant difference in genotypic distribution between diabetic and non-diabetic subjects (P=0.028); the GG genotype was more common in diabetic (0.40) than in non-diabetic (0.29) subjects. The G allele was much more frequent in the Native American sample, and among a sample of 143 cases and 145 controls, the GG genotype was significantly more common in diabetic subjects (P=0.019). When this sample population was stratified according to ethnic heritage, all 211 subjects who were of full Pima Indian heritage had the GG genotype, whereas in the 77 American Indian subjects with non-Pima admixture, T2DM was associated with IL6 genotype (P=0.001). These findings are consistent with a role for genetic determinants of inflammation in the development of T2DM in both Native Americans and Caucasians.     

N-acetyltransferase 2 polymorphism in patients with diabetes mellitus

The arylamine N-acetyltransferases (NATs) are a unique family of enzymes that catalyse the transfer of an acetyl group from acetyl-CoA to the terminal nitrogen of hydrazine and arylamine drugs and carcinogens. Human arylamine NATs are known to exist as two isoenzymes, NAT1 and NAT2. The objective of this study was to identify whether the genetic polymorphism of NAT2 plays a role in susceptibility to Diabetes Mellitus (DM). Ninety-seven patients with DM and 104 healthy controls were enrolled in the study. NAT2*5A, NAT2*6A, NAT2*7A/B and NAT2*14A polymorphisms were detected by using real time PCR with LightCycler (Roche Diagnostics GmbH, Mannheim, Germany). According to our data, the NAT2*5A and NAT2*6A mutant genotypes and NAT2*14A heterozygous genotype were associated with an increased risk of development of DM (OR = 47.06; 95%CI: 10.55-209.77 for NAT 2*5A, OR = 18.48; 95%CI: 3.83-89.11 for NAT2*6A and OR = 18.22; 95%CI: 6.29-52.76 for NAT2*14A). However, the NAT2*7A/B gene polymorphism carried no increased risk for developing DM disease. After grouping according to phenotypes as either slow or fast acetylators, NAT2*6A slow acetylator was found to be a significant risk factor for DM (OR = 6.09; 95%CI: 1.99-18.6, p = 0.02). The results indicate that NAT2 slow acetylator genotypes may be an important genetic determinant for DM in the Turkish population.     

Association of vitamin D receptor BsmI gene polymorphism with the risk of type 2 diabetes mellitus

Abstract

Relationship between vitamin D receptor (VDR) BsmI (rs1544410) gene polymorphism and the type 2 diabetes mellitus (T2DM) susceptibility is still conflicting at present. This meta-analysis was conducted to assess the association between VDR BsmI gene polymorphism and the risk of T2DM. The association studies were identified from PubMed, and Cochrane Library on 1 January 2014, and eligible investigations were included and synthesized using meta-analysis method. Eleven reports were recruited into this meta-analysis for the association of VDR BsmI gene polymorphism with T2DM susceptibility. In overall populations, B allele, BB genotype and bb genotype were not associated with T2DM risk. VDR BsmI gene polymorphism was also not associated with the T2DM risk in Asians and Caucasians. In conclusion, VDR BsmI gene polymorphism was also not associated with T2DM risk in overall populations, Asians and Caucasians. However, more studies should be conducted to confirm it.     

Association between maternal and child leptin levels 9 years after pregnancy complicated by gestational diabetes.

Obesity is a state of relative leptin resistance, and obesity in childhood is associated with an increased incidence of type 2 diabetes in later life. Offspring of mothers with gestational diabetes mellitus (GDM) are at increased risk of obesity. A cohort consisting of 64 mothers, 33 GDM and 31 controls screened for diabetes during the index pregnancy together with their 9-year-old offspring were studied. Our hypotheses were: 1) an elevated child leptin is associated with elevated maternal leptin in GDM mothers 9 years post delivery; and 2) child leptin at 9 years serves as a marker for incipient insulin resistance. By univariate analyses, child leptins were only significantly correlated with maternal leptins among the offspring of GDMs (OGDM) (r = 0.59; p = 0.001). By multivariate analyses, child leptin for the total study group was significantly associated with child body mass index (BMI) (R(2) = 0.65; p < 0.0001), child fasting insulin (R(2) = 0.08; p = 0.03), and female gender (R(2) = 0.28; p = 0.001). In addition, among OGDM child leptin was associated with maternal leptin (R(2) = 0.14; p = 0.005). Our results suggest that there is an association between maternal and child leptin levels 9 years after a pregnancy complicated by gestational diabetes.