The Association between KCNQ1 Gene Polymorphism and Type 2 Diabetes Risk: A Meta-Analysis

Background

KCNQ1 (potassium voltage-gated channel KQT-like sub-family, member 1) encodes a pore-forming subunit of a voltage-gated K⁺ channel (KvLQT1) that plays a key role for the repolarization of the cardiac action potential as well as water and salt transport in epithelial tissues. Recently, genome-wide association studies have identified KCNQ1 as a type 2 diabetes (T2D) susceptibility gene in populations of Asian descent. After that, a number of studies reported that the rs2237892 and rs2237895 polymorphism in KCNQ1 has been implicated in T2D risk. However, studies on the association between these polymorphism and T2D remain conflicting. To investigate this inconsistency, we performed this meta-analysis.

Methods

Databases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Potential sources of heterogeneity were also assessed by subgroup analysis and meta-regression.

Results

A total of 25 articles involving 70,577 T2D cases and 99,068 controls were included. Overall, the summary odds ratio of C allele for T2D was 1.32 (95% CI 1.26–1.38; P<10−5) and 1.24 (95% CI: 1.20–1.29; P<10−5) for KCNQ1 rs2237892 and rs2237895 polymorphisms, respectively. Significant results were also observed using co-dominant, dominant and recessive genetic models. After stratifying by ethnicity, sample size, and diagnostic criteria, significant associations were also obtained.

Conclusions

This meta-analysis suggests that the rs2237892 and rs2237895 polymorphisms in KCNQ1 are associated with elevated type 2 diabetes susceptibility.     

KCNQ1 and type 2 diabetes: study in Hubei Han Chinese and meta-analysis in East Asian populations

Recent genome-wide association studies in East Asian poulations reported the association of KCNQ1 variants with type 2 diabetes. In the present study, we first investigated the association between rs2237892 in KCNQ1 and type 2 diabetes in a Hubei Han Chinese population (223 type 2 diabetes patients and 201 controls). The frequencies of CC genotype and C allele in type 2 diabetes patients were significantly higher than those of controls group (CC: 51.6% vs 39.3%, P=0.001; C: 72.2% vs 61.2%, P=0.001). The odds ratio for the risk allele C was 1.65 (95%CI 1.23–2.2, P=0.001). Then, we systematically reviewed the association of SNPs (rs2237892, rs2237895, rs2237897, rs2074196) in KCNQ1 with type 2 diabetes risk in a meta-analysis. Significant heterogeneity between studies was found for SNPs rs2237892 and rs2237897. Combined odds ratios of the rs2237892 C, rs2237895 C, rs2237897 C, rs2074196 G allele were 1.35 (95% CI 1.29–1.41, P<0.0001), 1.27 (95%CI 1.23–1.32, P<0.0001), 1.32 (95%CI 1.21–1.43, P<0.0001), 1.30 (95%CI 1.25–1.35, P<0.0001) respectively. Our results and meta-analysis demonstrated that KCNQ1 polymorphisms were reproducibly associated with the risk of type 2 diabetes in Han Chinese and East Asian populations.     

Association study of four variants in <Emphasis Type="Italic">KCNQ1</Emphasis> with type 2 diabetes mellitus and premature coronary artery disease in a Chinese population

Four single nucleotide polymorphisms (SNPs, rs2237892, rs2237895, rs2237897, rs2283228) in KCNQ1 are associated with type 2 diabetes mellitus in different ancestral groups. We investigated whether these 4 genetic markers are determinants of type 2 diabetes and premature coronary artery disease (CAD) in a Chinese population. We studied 398 consecutive patients, including 180 with coronary stenosis ≥50% or previous myocardial infarction (male <55 years, female <65 years) and 218 controls without documented CAD. CAD cases and controls were genotyped for 4 SNPs by using the ligase detection reaction method. The 3 genotypes AA, AC, and CC were present in rs2283228 and rs2237895, and the 3 genotypes CC, CT, TT were present in rs2237897 and rs2237892. No differences were found in genotype distribution and allele frequencies of these 4 SNPs between subjects with and without type 2 diabetes. Logistic regression showed that the risk of premature CAD in subjects carrying the CC genotype at rs2237892 was reduced by 90% in relation to individuals carrying the TT genotype (OR = 0.100, 95% CI: 0.018–0.564, P = 0.009). The association of other 3 SNPs with premature CAD could not be detected, nor did there exist any association of these 4 SNPs among groups of patients with 0, 1, 2, and 3-vessel disease (all P > 0.05). Our data implicate rs2237892 in KCNQ1 as a protective gene variant against premature CAD and we couldn’t replicate any association of these 4 SNPs with T2DM or extent of coronary lesions in a Chinese population.     

The Type 2 Diabetes Associated Minor Allele of rs2237895 KCNQ1 Associates with Reduced Insulin Release Following an Oral Glucose Load

Background

Polymorphisms in the potassium channel, voltage-gated, KQT-like subfamily, member 1 (KCNQ1) have recently been reported to associate with type 2 diabetes. The primary aim of the present study was to investigate the putative impact of these KCNQ1 polymorphisms (rs2283228, rs2237892, rs2237895, and rs2237897) on estimates of glucose stimulated insulin release.

Methodology/Principal Findings

Genotypes were examined for associations with serum insulin levels following an oral glucose tolerance test (OGTT) in a population-based sample of 6,039 middle-aged and treatment-naïve individuals. Insulin release indices estimated from the OGTT and the interplay between insulin sensitivity and insulin release were investigated using linear regression and Hotelling T2 analyses.Applying an additive genetic model the minor C-allele of rs2237895 was associated with reduced serum insulin levels 30 min (mean±SD: (CC) 277±160 vs. (AC) 280±164 vs. (AA) 299±200 pmol/l, p = 0.008) after an oral glucose load, insulinogenic index (29.6±17.4 vs. 30.2±18.7vs. 32.2±22.1, p = 0.007), incremental area under the insulin curve (20,477±12,491 vs. 20,503±12,386 vs. 21,810±14,685, p = 0.02) among the 4,568 individuals who were glucose tolerant. Adjustment for the degree of insulin sensitivity had no effect on the measures of reduced insulin release. The rs2237895 genotype had a similar impact in the total sample of treatment-naïve individuals. No association with measures of insulin release were identified for the less common diabetes risk alleles of rs2237892, rs2237897, or rs2283228.

Conclusion

The minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk of type 2 diabetes, previously reported for this variant, likely is mediated through an impaired beta cell function.     

The rs2237892 Polymorphism in KCNQ1 Influences Gestational Diabetes Mellitus and Glucose Levels: A Case-Control Study and Meta-Analysis

Objective

Recent genetic studies have shown that potassium voltage-gated channel, KQT-like subfamily, member1 (KCNQ1) gene is related to gestational diabetes mellitus (GDM). However, studies for the rs2237892 polymorphism in KCNQ1 and GDM remain conflicting in Asians. Furthermore, associations of this polymorphism with glucose levels during oral glucose tolerance test (OGTT) have not been described in Chinese pregnant women. The present study aimed to provide evidence for the associations of rs2237892 in KCNQ1 with GDM and glucose levels, and to systematically evaluate the effect of rs2237892 on GDM in Asians.

Methods

A case-control study on 562 women with GDM and 453 controls was conducted in Beijing, China. The association of rs2237892 with risk of GDM was analyzed using logistic regression. The associations with quantitative glucose levels were assessed using linear regression models. A meta-analysis including the present case-control study and four previously published reports in Asians was conducted.

Results

The rs2237892 polymorphism in KCNQ1 was associated with GDM (OR (95%CI) =1.99(1.26-3.15)). Additionally, the polymorphism was associated with levels of 1h and 2h glucose during OGTT. The pre-pregnancy BMI, age and genotypes of KCNQ1 polymorphism were independent risk factors of GDM. Subsequently, we performed a meta-analysis in Asians. In total, C-allele carriers of rs2237892 polymorphism had a 50% higher risk for GDM (OR (95%CI) =1.50(1.15-1.78)).

Conclusion

The study demonstrated for the first time that the KCNQ1 rs2237892 polymorphism was associated with GDM and glucose levels in Chinese women. The study provides systematic evidence for the association between this polymorphism and GDM in Asians.     

Meta-Analysis of the Relationship between Common Type 2 Diabetes Risk Gene Variants with Gestational Diabetes Mellitus

Background

A number of case-control studies were conducted to investigate the association of common type 2 diabetes (T2D) risk gene polymorphisms with gestational diabetes mellitus (GDM). However, these studies have yielded contradictory results. We therefore performed a meta-analysis to derive a more precise estimation of the association between these polymorphisms and GDM, hence achieve a better understanding to the relationship between T2D and GDM.

Methods

PubMed, EMBASE, ISI web of science and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between 9 polymorphisms from 8 genes and susceptibility to GDM. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Heterogeneity among articles and their publication bias were also tested.

Results

We identified 22 eligible studies including a total of 10,336 GDM cases and 17,445 controls. We found 8 genetic polymorphisms were significantly associated with GDM in a random-effects meta-analysis. These polymorphisms were in or near the following genes: TCF7L2 (rs7903146), MTNR1B (rs10830963), IGF2BP2 (rs4402960), KCNJ11 (rs5219), CDKAL1 (rs7754840), KCNQ1 (rs2237892 and rs2237895) and GCK (rs4607517); while no association was found for PPARG with GDM risk. Similar results were also observed under dominant genetic model for these polymorphisms.

Conclusions

This meta-analysis found 8 genetic variants associated with GDM. The relative contribution and relevance of the identified genes in the pathogenesis of GDM should be the focus of future studies.     

Several polymorphisms of KCNQ1 gene are associated with plasma lipid levels in general Chinese populations

Background

Potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) is thought to be an important candidate gene of diabetes. Several single nucleotide polymorphisms (SNPs) in a 40-kb linkage disequilibrium (LD) block in its intron 15 have been identified to be associated with diabetes in East Asian populations in recent genome-wide association studies. The aim of this study was to investigate whether KCNQ1 polymorphisms influence the levels of the metabolic phenotypes in general Chinese populations.

Methodology/Principal Findings

We investigated the associations of two SNPs (rs2237892 and rs2237895) in the aforementioned 40-kb LD block, a missense variant rs12720449 (P448R) in exon 10, and a synonymous variant rs1057128 (S546S) in exon 13 with metabolic phenotypes in a Uyghur population (n = 478) and replicated these associations in a Han population (n = 2,485). We found that rs2237892-T allele was significantly associated with decreased triglyceride levels (p_combined = 0.001). The minor G allele of the rs12720449, with sharp difference of the allelic frequency between European and East Asian populations (0.2% versus 14%, respectively), was associated with a lower triglyceride levels than G allele in Uyghur subjects (p = 0.004), in Han subjects (p = 0.052), and in subjects of meta-analysis (p_combined = 0.001). Moreover, the minor A allele of the rs1057128 was also associated with decreased triglyceride levels in meta-analysis (p_combined = 0.010).

Conclusions

To the best of our knowledge, this is the first report associating a missense mutation of KCNQ1, rs12720449, with triglyceride levels. Rs2237892, representing the 40-kb LD block, is also associated with triglyceride levels in Han population. Further studies are required to replicate these findings in other East Asian populations.     

KCNQ1 rs2237892 C→T gene polymorphism and type 2 diabetes mellitus in the Asian population: a meta‐analysis of 15,736 patients

The KCNQ1 rs2237892 C→T gene polymorphism is reportedly associated with T2DM susceptibility, but various studies show conflicting results. To explore this association in the Asian population, a meta‐analysis of 15,736 patients from 10 individual studies was performed. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were evaluated using random‐effect or fixed‐effect models. A significant relationship between the KCNQ1 rs2237892 C→T gene polymorphism and T2DM was observed in the Asian population under the allelic (OR, 1.350; 95% CI, 1.240–1.480; P < 0.00001), recessive (OR: 0.650; 95% CI: 0.570–0.730; P < 0.00001), dominant (OR: 1.450; 95% CI: 1.286–1.634; P < 0.00001), and additive (OR: 1.346; 95% CI: 1.275–1.422; P < 0.00001) genetic models. In the subgroup analysis by race, a significant association was found in Chinese, Korean and Malaysia population, but not in Indian population. KCNQ1 rs2237892 C→T gene polymorphism was found to be significantly associated with increased T2DM risk in the Asian population, except Indian population. The C allele of the KCNQ1 rs2237892 C→T gene polymorphism may confer susceptibility to T2DM.     

The effect of KCNJ11 polymorphism on the risk of type 2 diabetes: a global meta-analysis based on 49 case-control studies

Potassium inwardly rectifying channel, subfamily-J, member 11 (KCNJ11) gene encodes Kir6.2 subunits of the adenosine triphosphate (ATP)-sensitive potassium channel involved in glucose-mediated metabolic signaling pathway and has attracted considerable attention as a candidate gene for type 2 diabetes (T2D) based on its function in glucose-stimulated insulin secretion. In the past decade, a number of case-control studies have been conducted to investigate the relationship between the KCNJ11 polymorphisms and T2D. However, these studies have yielded contradictory results. To investigate this inconsistency and derive a more precise estimation of the relationship, we conducted a comprehensive meta-analysis of 64,403 cases and 122,945 controls from 49 published studies. Using the random-effects model, we found a significant association between E23K (rs5219) polymorphism and T2D risk with per-allele odds ratio of 1.13 (95% confidence interval: 1.10-1.15; p<10(-5)). Significant results were found in East Asians and Caucasians when stratified by ethnicity; whereas no significant associations were found among South Asians and other ethnic populations. In subgroup analysis by sample size, mean age and body mass index (BMI) of cases, mean BMI of controls and diagnostic criterion, significantly increased risks were found in all genetic models. This meta-analysis suggests that the E23K polymorphism in KCNJ11 is associated with elevated T2D risk, but these associations vary in different ethnic populations.     

Common variants in the type 2 diabetes KCNQ1 gene are associated with impairments in insulin secretion during hyperglycaemic glucose clamp

Background

Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients.

Methodology

The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp.

Principal Findings

We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07–1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications.

Conclusions

Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism.     

Variant rs2237892 of KCNQ1 Is Potentially Associated with Hypertension and Macrovascular Complications in Type 2 Diabetes Mellitus in A Chinese Han Population

KCNQ1 has been identified as a susceptibility gene of type 2 diabetes mellitus(T2DM) in Asian populations through genome-wide association studies. However, studies on the association between gene polymorphism of KCNQ1 and T2 DM complications remain unclear. To further analyze the association between different alleles at the single nucleotide polymorphism(SNP) rs2237892 within KCNQ1 and TD2 M and its complications, we conducted a case-control study in a Chinese Han population. The C allele of rs2237892 variant contributed to susceptibility to T2DM(odds ratio [OR], 1.45; 95% confidence interval [CI], 1.20–1.75). Genotypes CT(OR, 1.97; 95% CI,1.24–3.15) and CC(OR, 2.49; 95% CI, 1.57–3.95) were associated with an increased risk of T2 DM. Multivariate regression analysis was performed with adjustment of age, gender, and body mass index. We found that systolic blood pressure(P = 0.015), prevalence of hypertension(P = 0.037), and risk of macrovascular disease(OR, 2.10; CI, 1.00–4.45) were significantly higher in subjects with the CC genotype than in the combined population with genotype either CT or     

Genetic Determinants for Gestational Diabetes Mellitus and Related Metabolic Traits in Mexican Women

Epidemiological and physiological similarities among Gestational Diabetes Mellitus (GDM) and Type 2 Diabetes (T2D) suggest that both diseases, share a common genetic background. T2D risk variants have been associated to GDM susceptibility. However, the genetic architecture of GDM is not yet completely understood. We analyzed 176 SNPs for 115 loci previously associated to T2D, GDM and body mass index (BMI), as well as a set of 118 Ancestry Informative Markers (AIMs), in 750 pregnant Mexican women. Association with GDM was found for two of the most frequently replicated T2D loci: a TCF7L2 haplotype (CTTC: rs7901695, rs4506565, rs7903146, rs12243326; P=2.16x10^-06; OR=2.95) and a KCNQ1 haplotype (TTT: rs2237892, rs163184, rs2237897; P=1.98x10^-05; OR=0.55). In addition, we found two loci associated to glycemic traits: CENTD2 (60’ OGTT glycemia: rs1552224, P=0.03727) and MTNR1B (HOMA B: rs1387153, P=0.05358). Remarkably, a major susceptibility SLC16A11 locus for T2D in Mexicans was not shown to play a role in GDM risk. The fact that two of the main T2D associated loci also contribute to the risk of developing GDM in Mexicans, confirm that both diseases share a common genetic background. However, lack of association with a Native American contribution T2D risk haplotype, SLC16A11, suggests that other genetic mechanisms may be in play for GDM.     

Population Specific Impact of Genetic Variants in KCNJ11 Gene to Type 2 Diabetes: A Case-Control and Meta-Analysis Study

Background and Objectives

Potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene have a key role in insulin secretion and is of substantial interest as a candidate gene for type 2 diabetes (T2D). The current work was performed to delineate the genetic influence of KCNJ11 polymorphisms on risk of T2D in South Indian population through case-control association study along with systematic review and meta-analysis.

Methods

A case-control study of 400 T2D cases and controls of South Indian origin were performed to analyze the association of KCNJ11 polymorphisms (rs5219, rs5215, rs41282930, rs1800467) and copy number variations (CNV) on the risk of T2D. In addition a systematic review and meta-analysis for KCNJ11 rs5219 was conducted in 3,831 cases and 3,543 controls from 5 published reports from South-Asian population by searching various databases. Odds ratio with 95% confidence interval (CI) was used to assess the association strength. Cochran''s Q, I² statistics were used to study heterogeneity between the eligible studies.

Results

KCNJ11 rs5215, C-G-C-C haplotype and two loci analysis (rs5219 vs rs1800467) showed a significant association with T2D but CNV analysis did not show significant variation between T2D cases and control subjects. Lower age of disease onset (P = 0.04) and higher body mass index (BMI) (P = 0.04) were associated with rs5219 TT genotype in T2D patients. The meta-analysis of KCNJ11 rs5219 on South Asian population showed no association on susceptibility to T2D with an overall pooled OR = 0.98, 95% CI = 0.83–1.16. Stratification analysis showed East Asian population and global population were associated with T2D when compared to South Asians.

Conclusion

KCNJ11 rs5219 is not independently associated with T2D in South-Indian population and our meta-analysis suggests that KCNJ11 polymorphism (rs5219) is associated with risk of T2D in East Asian population and global population but this outcome could not be replicated in South Asian sub groups.     

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.     

Presenilin-2 polymorphisms and risk of sporadic AD: Evidence from a meta-analysis

Association studies of presenilin-2 (PSEN2) polymorphisms and sporadic Alzheimer's disease (AD) have yielded inconsistent results, possibly because single studies often lack sufficient statistical power. In this study, we performed a meta-analysis to evaluate the association of the two most extensively studied PSEN2 polymorphisms, rs8383 and 5′indel, with the risk of sporadic AD. We systematically reviewed relevant studies retrieved by Medline, Pubmed, Embase, AlzGene, and CNKI. Data were analyzed using the Stata (v11.0) software package. The fixed effects model or random-effects model were applied depending on between-study heterogeneity. Publication bias was evaluated using Egger's test and Begg's funnel plots. Overall, the meta-analysis included 6 case–control studies for each polymorphism with 2186 confirmed AD cases and 2507 healthy controls in total. Analysis suggested a significant association between SNP rs8383 polymorphism and AD risk with no evidence of between-study heterogeneity or publication bias. In contrast, we found no evidence for an association between the 5′indel polymorphism and AD risk. Further stratified analyses by apolipoprotein ε4 status or ethnicity also failed to reveal a statistically significant association between the 5′indel polymorphism of PSEN2 and AD risk. Our analysis supports the hypothesis that the PSEN2 rs8383 polymorphism is associated with an enlarged risk of sporadic AD. However, larger scale association studies are necessary to further validate the association of PSEN2 polymorphisms with sporadic AD risk and to define potential gene–gene interactions.     

Combined effects of 19 common variations on type 2 diabetes in Chinese: results from two community-based studies

Background

Many susceptible loci for type 2 diabetes mellitus (T2DM) have recently been identified from Caucasians through genome wide association studies (GWAS). We aimed to determine the association of 11 known loci with T2DM and impaired glucose regulation (IGR), individually and in combination, in Chinese.

Methods/Principal Findings

Subjects were enrolled in: (1) a case-control study including 1825 subjects with T2DM, 1487 with IGR and 2200 with normal glucose regulation; and (2) a prospective cohort with 734 non-diabetic subjects at baseline. The latter was followed up for 3.5 years, in which 67 subjects developed T2DM. Nineteen single nucleotide polymorphisms (SNPs) were selected to replicate in both studies. We found that CDKAL1 (rs7756992), SLC30A8 (rs13266634, rs2466293), CDKN2A/2B (rs10811661) and KCNQ1 (rs2237892) were associated with T2DM with odds ratio from 1.21 to 1.35. In the prospective study, the fourth quartile of risk scores based on the combined effects of the risk alleles had 3.05 folds (95% CI, 1.31–7.12) higher risk for incident T2DM as compared with the first quartile, after adjustment for age, gender, body mass index and diabetes family history. This combined effect was confirmed in the case-control study after the same adjustments. The addition of the risk scores to the model of clinical risk factors modestly improved discrimination for T2DM by 1.6% in the case-control study and 2.9% in the prospective study.

Conclusions/Significance

Our study provided further evidence for these GWAS derived SNPs as the genetic susceptible loci for T2DM in Chinese and extended this association to IGR.     

HHEX gene polymorphisms and type 2 diabetes mellitus: A case-control report from Iran

Genome-wide association studies indicated that hematopoietically-expressed homeobox (HHEX) gene is a remarkable candidate for type 2 diabetes (T2D) mellitus susceptibility in spite of the fact that the results are ambiguous in some cases. So, this study aimed to evaluate the possible correlation between HHEX gene polymorphisms and T2D development in a sample of the Iranian population. The rs1111875G/A, rs7923837A/G, and rs5015480C/T HHEX gene polymorphisms were genotyped in 250 cases and 250 matched (age and sex) healthy controls using tetra-amplification-refractory mutation system-polymerase chain reaction method. The finding revealed the all measured inheritance models of rs1111875G/A and of rs5015480C/T variants dramatically increase the risk of T2D while another polymorphism (rs7923837A/G) was not associated with risk/protective role in T2D. The results indicated that rs1111875G/A and rs5015480C/T may contribute to the enhancement of T2D risk in a sample of the southeast Iranian population.     

Lack of association of IGFBP-3 gene polymorphisms with colorectal cancer: evidence from 17,380 subjects

Published data on the association of IGFBP-3 gene polymorphisms with colorectal cancer (CRC) are inconclusive. We conducted a meta-analysis to derive a precise estimation of the association. A literature search that included PubMed, EMBASE, Elsevier Science Direct and China National Knowledge Infrastructure was conducted to identify studies up to October 15, 2013. Summary odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for IGFBP-3 gene polymorphisms and CRC were calculated in a fixed effect model or a random effect model. We identified 10 separate studies including 7,000 cases and 10,380 controls using search. Meta-analysis was performed for two IGFBP-3 gene polymorphisms (rs2854744 and rs2854746). We found no association between IGFBP-3 gene rs2854744 polymorphism and CRC (P > 0.05). Similar result was observed between rs2854746 polymorphism and CRC (P > 0.05). This meta-analysis demonstrates that there is no association of IGFBP-3 gene rs2854744 and rs2854746 polymorphisms with CRC risk.     

Association between Common Polymorphism near the MC4R Gene and Obesity Risk: A Systematic Review and Meta-Analysis

Background

Genome-wide association studies on Europeans have shown that two polymorphisms (rs17782313, rs12970134) near the melanocortin 4 receptor (MC4R) gene were associated with increased risk of obesity. Subsequently studies among different ethnic populations have shown mixed results with some confirming and others showing inconsistent results, especially among East Asians and Africans. We performed a comprehensive meta-analysis of various studies from different ethnic populations to assess the association of the MC4R polymorphism with obesity risk.

Methods

We retrieved all published literature that investigated association of MC4R variants with obesity from PubMed and Embase. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model.

Results

A total of 61 studies (80,957 cases/220,223 controls) for rs17782313 polymorphism (or proxy) were included in the meta-analysis. The results suggested that rs17782313 polymorphism was significantly associated with obesity risk (OR = 1.18, 95%CI = 1.15–1.21, p<0.001). Similar trends were observed among subgroups of Europeans and East Asians, adults and children, studies with high quality score, and for each five MC4R polymorphisms independently.

Conclusions

The present meta-analysis confirms the significant association of MC4R polymorphism with risk of obesity. Further studies should be conducted to identify the causal variant and the underlying mechanisms of the identified association.     

Association between TL1A gene polymorphisms and systemic lupus erythematosus in a Chinese Han population

Our previous studies showed elevated tumor necrosis factor-like ligand 1 aberrance (TL1A) expression in systemic lupus erythematosus (SLE). However, TL1A polymorphisms with SLE susceptibility remain to be elucidated. In addition, we made meta-analysis to evaluate the relationship of TL1A polymorphisms and autoimmune diseases owing to inconsistent results. The present research was carried out by 404 SLE, 150 primary Sjogren's syndrome (pSS) patients, and 574 healthy individuals. Three TL1A polymorphisms (rs3810936, rs6478109, rs7848647) were genotyped using TaqMan genotyping assay. Then, the meta-analysis was performed by collecting the present case-control study and previously published research. Results showed that genotypes of rs3810936, rs7848647 were different between SLE patients and healthy controls, whereas no significant association was observed in the three polymorphisms and pSS patients. Genotypes distribution of rs6478109, rs7848647 were strongly related to lupus nephritis within SLE (p = 0.004, p = 0.011), respectively. Moreover, combined meta-analysis consisted of ten comparative research involving 4,305 patients and 5,600 controls. An association between autoimmune diseases and rs6478109 polymorphism was found. Our findings indicate that gene polymorphisms (rs3810936, rs7848647) of TL1A might correlate with lupus.