Gene-Gene Interactions Lead to Higher Risk for Development of Type 2 Diabetes in an Ashkenazi Jewish Population

Background

Evidence has accumulated that multiple genetic and environmental factors play important roles in determining susceptibility to type 2 diabetes (T2D). Although variants from candidate genes have become prime targets for genetic analysis, few studies have considered their interplay. Our goal was to evaluate interactions among SNPs within genes frequently identified as associated with T2D.

Methods/Principal Findings

Logistic regression was used to study interactions among 4 SNPs, one each from HNF4A[rs1884613], TCF7L2[rs12255372], WFS1[rs10010131], and KCNJ11[rs5219] in a case-control Ashkenazi sample of 974 diabetic subjects and 896 controls. Nonparametric multifactor dimensionality reduction (MDR) and generalized MDR (GMDR) were used to confirm findings from the logistic regression analysis. HNF4A and WFS1 SNPs were associated with T2D in logistic regression analyses [P<0.0001, P<0.0002, respectively]. Interaction between these SNPs were also strong using parametric or nonparametric methods: the unadjusted odds of being affected with T2D was 3 times greater in subjects with the HNF4A and WFS1 risk alleles than those without either (95% CI = [1.7–5.3]; P≤0.0001). Although the univariate association between the TCF7L2 SNP and T2D was relatively modest [P = 0.02], when paired with the HNF4A SNP, the OR for subjects with risk alleles in both SNPs was 2.4 [95% CI = 1.7–3.4; P≤0.0001]. The KCNJ11 variant reached significance only when paired with either the HNF4A or WFSI SNPs: unadjusted ORs were 2.0 [95% CI = 1.4–2.8; P≤0.0001] and 2.3 [95% CI = 1.2-4.4; P≤0.0001], respectively. MDR and GMDR results were consistent with the parametric findings.

Conclusions

These results provide evidence of strong independent associations between T2D and SNPs in HNF4A and WFS1 and their interaction in our Ashkenazi sample. We also observed an interaction in the nonparametric analysis between the HNF4A and KCNJ11 SNPs (P≤0.001), demonstrating that an independently non-significant variant may interact with another variant resulting in an increased disease risk.     

A Single Nucleotide Polymorphism within DUSP9 Is Associated with Susceptibility to Type 2 Diabetes in a Japanese Population

Aims

The DUSP9 locus on chromosome X was identified as a susceptibility locus for type 2 diabetes in a meta-analysis of European genome-wide association studies (GWAS), and GWAS in South Asian populations identified 6 additional single nucleotide polymorphism (SNP) loci for type 2 diabetes. However, the association of these loci with type 2 diabetes have not been examined in the Japanese. We performed a replication study to investigate the association of these 7 susceptibility loci with type 2 diabetes in the Japanese population.

Methods

We genotyped 11,319 Japanese participants (8,318 with type 2 diabetes and 3,001 controls) for each of the 7 SNPs–rs5945326 near DUSP9, rs3923113 near GRB14, rs16861329 in ST6GAL1, rs1802295 in VPS26A, rs7178572 in HMG20A, rs2028299 near AP3S2, and rs4812829 in HNF4A–and examined the association of each of these 7 SNPs with type 2 diabetes by using logistic regression analysis.

Results

All SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. One SNP, rs5945326 near DUSP9, was significantly associated with type 2 diabetes at a genome-wide significance level (p = 2.21×10⁻⁸; OR 1.39, 95% confidence interval [CI]: 1.24−1.56). The 6 SNPs derived from South Asian GWAS were not significantly associated with type 2 diabetes in the Japanese population by themselves (p≥0.007). However, a genetic risk score constructed from 6 South Asian GWAS derived SNPs was significantly associated with Japanese type 2 diabetes (p = 8.69×10⁻⁴, OR  = 1.06. 95% CI; 1.03−1.10).

Conclusions/interpretation

These results indicate that the DUSP9 locus is a common susceptibility locus for type 2 diabetes across different ethnicities, and 6 loci identified in South Asian GWAS also have significant effect on susceptibility to Japanese type 2 diabetes.     

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.     

Genetic Variations in the KCNJ5 Gene in Primary Aldosteronism Patients from Xinjiang,China

Background

Primary aldosteronism (PA) is the most common endocrine form of secondary hypertension, and one of the most common subtypes of sporadic PA is aldosterone-producing adenoma (APA). Recently, two somatic mutations of the KCNJ5 gene were implicated in APA, and two germline mutations were associated with familial hyperaldosteronism III.

Objectives

This case-control study was designed to investigate the relationship between genetic variations in the KCNJ5 gene and sporadic PA patients in Xinjiang, China.

Methods

Five common single nucleotide polymorphisms (SNPs) of the KCNJ5 gene (rs6590357, rs4937391, rs3740835, rs2604204, and rs11221497) were detected in patients with sporadic PA (n = 235) and essential hypertension (EH; n = 913) by the TaqMan polymerase chain reaction method.

Results

The EH group and the PA group showed significant differences in the distributions of genotypes and alleles of rs4937391 and rs2604204 in total and male subjects (P<0.05), as well as rs3740835 in male subjects (P<0.05). However, only the association between the rs2604204 genotype and male sporadic PA remained significant after Bonferroni’s correction (P<0.01). Furthermore, logistic regression analysis demonstrated that the CC genotype of rs2604204 was a risk factor for male patients with sporadic PA, after adjusting for age and body mass index (odds ratio = 2.228, 95% CI: 1.300–3.819, P = 0.004).

Conclusion

The genetic variant rs2604204 of KCNJ5 is associated with sporadic PA in Chinese males, suggesting that KCNJ5 may be involved in the pathogenesis of sporadic PA in these particular patients.     

A Genetic Variant rs1801274 in FCGR2A as a Potential Risk Marker for Kawasaki Disease: A Case-Control Study and Meta-Analysis

Objectives

Recent genome-wide association study found rs1801274, a functional single nucleotide polymorphism (SNP) in IgG receptor gene FCGR2A, was associated with increased risk of Kawasaki disease (KD). However, subsequent studies on the role of this SNP were limited and controversial.

Methods

A case-control study was conducted in a Chinese Han population including 428 KD patients and 493 controls to examine the association between rs1801274 and KD susceptibility. A meta-analysis was performed in combination with the relevant published studies to further clarify such an association.

Results

Our case-control study found that rs1801274 was significantly associated with increased risk of KD in the Chinese Han population, with an odds ratio (OR) of 1.58 (95% CI = 0.96–2.62) for the GA genotype and 1.93 (95% CI = 1.16–3.19) for the AA genotype compared with the GG genotype. The result of meta-analysis further demonstrated that the A allele of rs1801274 was significantly correlated with KD risk under the allelic model (OR = 1.35, 95% CI = 1.27–1.44) without heterogeneity by fixed-effects model analysis (Q = 17.30, p = 0.139). Moreover, sensitivity analysis supported the robustness of this meta-analysis.

Conclusion

These results further confirm that rs1801274 in the FCGR2A gene is significantly associated with increased risk of KD.     

Association between KCNJ11 gene polymorphisms and risk of type 2 diabetes mellitus in East Asian populations: a meta-analysis in 42,573 individuals

A number of studies have been performed to identify the association between potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) gene and type 2 diabetes mellitus (T2DM) in East Asian populations, with inconsistent results. The main aim of this work was to evaluate more precisely the genetic influence of KCNJ11 on T2DM in East Asian populations by means of a meta-analysis. We identified 20 articles for qualitative analysis and 16 were eligible for quantitative analysis (meta-analysis) by database searching up to May 2010. The association was assessed under different genetic models, and the pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. The allelic and genotypic contrast demonstrated that the association between KCNJ11 and T2DM was significant for rs5210. However, not all results for rs5215 and rs5218 showed significant associations. For rs5219, the combined ORs (95% CIs) for allelic contrast, dominant and recessive models contrast (with allelic frequency and genotypic distribution data) were 1.139 (1.093–1.188), 1.177 (1.099–1.259) and 1.207 (1.094–1.332), respectively (random effect model). The analysis on the most completely adjusted ORs (95% CIs) by the covariates of rs5219 all presented significant associations under different genetic models. Population-stratified analysis (Korean, Japanese and Chinese) and sensitivity analysis verified the significant results. Cumulative meta-analysis including publication time and sample size illustrated the exaggerated genetic effect in the earliest studies. Heterogeneity and publication bias were assessed. Our study verified that single nucleotide polymorphisms (SNPs) of KCNJ11 gene were significantly associated with the risk of T2DM in East Asian populations.     

The A Allele of the rs1990760 Polymorphism in the IFIH1 Gene Is Associated with Protection for Arterial Hypertension in Type 1 Diabetic Patients and with Expression of This Gene in Human Mononuclear Cells

Background

The rs1990760 polymorphism of interferon induced with helicase C domain 1 (IFIH1) has been associated with type 1 diabetes mellitus (T1DM). Here, we investigated whether this polymorphism is associated with T1DM or its clinical characteristics in a Brazilian population, and if IFIH1 gene expression in mononuclear cells from T1DM patients differs according to the genotypes of this polymorphism. A meta-analysis was also conducted to evaluate if the rs1990760 polymorphism is associated with T1DM.

Methods

Frequencies of the rs1990760 polymorphism were analyzed in 527 T1DM patients and in 517 healthy subjects. IFIH1 gene expressions according to genotypes were measured in a sub-sample of 26 T1DM patients by quantitative real-time PCR.

Results

Our data show the association of the A allele with risk to T1DM under a dominant model of inheritance [odds ratio (OR) = 1.421, P = 0.037], adjusting for ethnicity. The meta-analysis revealed significant association between the rs199760A allele and risk for T1DM for all analyzed inheritance models. Surprisingly, T1DM patients carrying the A allele showed lower levels of systolic (P = 0.001) and diastolic (P = 1×10⁻¹⁰) blood pressures as compared to G/G carriers. Furthermore, the A/A genotype seems to be associated with protection to arterial hypertension (AH) after adjustment for covariates (OR = 0.339, P = 0.019). IFIH1 gene expression in mononuclear cells from 26 T1DM patients did not differ among genotypes (P = 0.274). Nevertheless, IFIH1 gene expression was increased in mononuclear cells from T1DM patients with AH as compared with T1DM patients without AH [6.7 (1.7–2.0) vs. 1.8 (1.3–7.1) arbitrary units; P = 0.036]. The association with blood pressures and AH was not observed in patients with type 2 diabetes mellitus.

Conclusions

Our results indicate that the rs1990760 polymorphism is associated with T1DM. Interestingly, the rs1990760 A allele seems to be associated with protection for AH in T1DM patients. Further studies are needed to confirm the association with AH.     

Common Genetic Variants of Surfactant Protein-D (SP-D) Are Associated with Type 2 Diabetes

Context

Surfactant protein-D (SP-D) is a primordial component of the innate immune system intrinsically linked to metabolic pathways. We aimed to study the association of single nucleotide polymorphisms (SNPs) affecting SP-D with insulin resistance and type 2 diabetes (T2D).

Research Design and Methods

We evaluated a common genetic variant located in the SP-D coding region (rs721917, Met³¹Thr) in a sample of T2D patients and non-diabetic controls (n = 2,711). In a subset of subjects (n = 1,062), this SNP was analyzed in association with circulating SP-D concentrations, insulin resistance, and T2D. This SNP and others were also screened in the publicly available Genome Wide Association (GWA) database of the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC).

Results

We found the significant association of rs721917 with circulating SP-D, parameters of insulin resistance and T2D. Indeed, G carriers showed decreased circulating SP-D (p = 0.004), decreased fasting glucose (p = 0.0002), glycated hemoglobin (p = 0.0005), and 33% (p = 0.002) lower prevalence of T2D, estimated under a dominant model, especially among women. Interestingly, these differences remained significant after controlling for origin, age, gender, and circulating SP-D. Moreover, this SNP and others within the SP-D genomic region (i.e. rs10887344) were significantly associated with quantitative measures of glucose homeostasis, insulin sensitivity, and T2D, according to GWAS datasets from MAGIC.

Conclusions

SP-D gene polymorphisms are associated with insulin resistance and T2D. These associations are independent of circulating SP-D concentrations.     

A Common Polymorphism near the ESR1 Gene Is Associated with Risk of Breast Cancer: Evidence from a Case-Control Study and a Meta-Analysis

Background

Genome-wide association studies have reported that a polymorphism near the estrogen receptor gene (ESR1) (rs2046210) is associated with a risk of breast cancer, with the A allele conferring an increased risk. However, considering the controversial results from more recent replicated studies, we conducted a case-control study in an independent Chinese Han population and a meta-analysis to clarify the association of this polymorphism with breast cancer risk.

Method and Findings

A hospital-based case-control study including 461 cases and 537 controls from a Chinese Han population was conducted initially, and this study showed that the rs2046210 A allele was significantly associated with breast cancer risk, with an OR of 1.32 (95% CI  = 1.10–1.59). Subsequently, a meta-analysis integrating the current study and previous publications with a total of 53,379 cases and 55,493 controls was performed to further confirm our findings. Similarly, a significant association between this polymorphism and breast cancer risk was also observed in the overall population especially among Asians, with ORs for per A allele of 1.14 (95% CI  = 1.10–1.18) in the overall population and 1.27 (95% CI  = 1.23–1.31) in the Asian population.

Conclusion

Our results provide strong evidence to support that the common polymorphism near the ESR1 gene, rs2046210, is associated with an increased risk of breast cancer in Asian and European populations but not in Africans, although the biological mechanisms need to be further investigated.     

Association between Fat Mass- and Obesity- Associated (FTO) Gene Polymorphism and Polycystic Ovary Syndrome: A Meta-Analysis

Aims

Many studies have investigated the relationship between FTO gene polymorphism and polycystic ovary syndrome (PCOS) susceptibility but revealed mixed results. In this study, we aimed to perform a meta-analysis to clarify this association.

Methods

Published literature from PubMed, Embase and CNKI was retrieved. Meta-analysis was performed to calculate pooled odds ratio (OR) with 95% confidence interval (CI) using the random- or fix- effects model.

Results

A total of 5 studies (4778 cases and 4272 controls) were included in our meta-analysis. The results suggested that FTO rs9939609 polymorphism (or its proxy) was marginally associated with PCOS risk after adjustment for body mass index (BMI) (OR = 1.26; 95%CI: 1.02–1.55). However, the marginal association was not stable after sensitivity analysis. In the subgroup analysis by ethnicity, the association was significant in East Asians (OR = 1.43, 95%CI = 1.30–1.59) but not in Caucasians (OR = 1.04, 95%CI = 0.85–1.29).

Conclusions

Our present meta-analysis indicated that FTO rs9939609 polymorphism (or its proxy) might not be associated with risk of PCOS in overall population. However, in East Asians, there might be a direct association between FTO variant and PCOS risk, which is independent of BMI (adiposity).     

Genetic Association Study betweenSTK39 and CCDC62/HIP1R and Parkinson’s Disease

Background

The first large-scale meta-analysis of published genome-wide association studies (GWAS) in Parkinson’s disease (PD) identified 5 new genetic loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). Very recently, a large-scale replication and heterogeneity study also reported that STK39 and CCDC62/HIP1R increased risk of PD in Asian and Caucasian populations. However, their roles still remain unclear in a Han Chinese population from mainland China.

Methods

We examined genetic associations of STK39 rs2102808 and CCDC62/HIP1R rs12817488 with PD susceptibility in a Han Chinese population of 783 PD patients and 725 controls. We also performed further stratified analyses by the age of onset and accomplished in-depth clinical characteristics analyses between the different genotypes for each locus.

Results

No significant differences were observed in the minor allele frequency (MAF) among cases and controls at the two loci (STK39 rs2102808: OR = 1.06, 95% CI = 0.91, 1.23, P = 0.467; CCDC62/HIP1R rs12817488: OR = 0.88, 95% CI = 0.76, 1.01, P = 0.072). Subgroup analyses by the age of onset also showed no significant differences among different subgroups of the two loci. In addition, minor allele carriers cannot be distinguished from non-carriers based on their clinical features at the two loci.

Conclusions

We are unable to demonstrate the association between STK39 and CCDC62/HIP1R and PD susceptibility in a Han Chinese population from mainland China. Additional replication studies in other populations and functional studies are warranted to better validate the role of the two new loci in PD risk.     

Variation in CHI3LI in Relation to Type 2 Diabetes and Related Quantitative Traits

Background

CHI3LI encoding the inflammatory glycoprotein YKL-40 is located on chromosome 1q32.1. YKL-40 is involved in inflammatory processes and patients with Type 2 Diabetes (T2D) have elevated circulating YKL-40 levels which correlate with their level of insulin resistance. Interestingly, it has been reported that rs10399931 (−329 G/A) of CHI3LI contributes to the inter-individual plasma YKL-40 levels in patients with sarcoidosis, and that rs4950928 (−131 C/G) is a susceptibility polymorphism for asthma and a decline in lung function. We hypothesized that single nucleotide polymorphisms (SNPs) or haplotypes thereof the CHI3LI locus might influence risk of T2D. The aim of the present study was to investigate the putative association between SNPs and haplotype blocks of CHI3LI and T2D and T2D related quantitative traits.

Methods/Principal Findings

Eleven SNPs of CHI3LI were genotyped in 6514 individuals from the Inter99 cohort and 2924 individuals from the outpatient clinic at Steno Diabetes Center. In cas-control studies a total of 2345 T2D patients and 5302 individuals with a normal glucose tolerance test were examined.We found no association between rs10399931 (OR, 0.98 (CI, 0.88–1.10), p = 0.76), rs4950928 (0.98 (0.87–1.10), p = 0.68) or any of the other SNPs with T2D. Similarly, we found no significant association between any of the 11 tgSNPs and T2D related quantitative traits, all p>0.14. None of the identified haplotype blocks of CHI3LI showed any association with T2D, all p>0.16.

Conclusions/Significance

None of the examined SNPs or haplotype blocks of CHI3LI showed any association with T2D or T2D related quantitative traits. Estimates of insulin resistance and dysregulated glucose homeostasis in T2D do not seem to be accounted for by the examined variations of CHI3LI.     

Association between the Melatonin Receptor 1B Gene Polymorphism on the Risk of Type 2 Diabetes,Impaired Glucose Regulation: A Meta-Analysis

Background

Melatonin receptor 1B (MTNR1B) belongs to the seven-transmembrane G protein-coupled receptor superfamily involved in insulin secretion, which has attracted considerable attention as a candidate gene for type 2 diabetes (T2D) since it was first identified as a loci associated with fasting plasma glucose level through genome wide association approach. The relationship between MTNR1B and T2D has been reported in various ethnic groups. The aim of this study was to consolidate and summarize published data on the potential of MTNR1B polymorphisms in T2D risk prediction.

Methods

PubMed, EMBASE, ISI web of science and the CNKI databases were systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Heterogeneity and publication bias were also tested.

Results

A total of 23 studies involving 172,963 subjects for two common polymorphisms (rs10830963, rs1387153) on MTNR1B were included. An overall random effects per-allele OR of 1.05 (95% CI: 1.02–1.08; P<10⁻⁴) and 1.04 (95% CI: 0.98–1.10; P = 0.20) were found for the two variants respectively. Similar results were also observed using dominant or recessive genetic model. There was strong evidence of heterogeneity, which largely disappeared after stratification by ethnicity. Significant results were found in Caucasians when stratified by ethnicity; while no significant associations were observed in East Asians and South Asians. Besides, we found that the rs10830963 polymorphism is a risk factor associated with increased impaired glucose regulation susceptibility.

Conclusions

This meta-analysis demonstrated that the rs10830963 polymorphism is a risk factor for developing impaired glucose regulation and T2D.     

Comprehensive Review of Genetic Association Studies and Meta-Analyses on miRNA Polymorphisms and Cancer Risk

Background

MicroRNAs (miRNAs) are small RNA molecules that regulate the expression of corresponding messenger RNAs (mRNAs). Variations in the level of expression of distinct miRNAs have been observed in the genesis, progression and prognosis of multiple human malignancies. The present study was aimed to investigate the association between four highly studied miRNA polymorphisms (mir-146a rs2910164, mir-196a2 rs11614913, mir-149 rs2292832 and mir-499 rs3746444) and cancer risk by using a two-sided meta-analytic approach.

Methods

An updated meta-analysis based on 53 independent case-control studies consisting of 27573 cancer cases and 34791 controls was performed. Odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association.

Results

Overall, the pooled analysis showed that mir-196a2 rs11614913 was associated with a decreased cancer risk (OR = 0.846, P = 0.004, TT vs. CC) while other miRNA SNPs showed no association with overall cancer risk. Subgroup analyses based on type of cancer and ethnicity were also performed, and results indicated that there was a strong association between miR-146a rs2910164 and overall cancer risk in Caucasian population under recessive model (OR = 1.274, 95%CI = 1.096–1.481, P = 0.002). Stratified analysis by cancer type also associated mir-196a2 rs11614913 with lung and colorectal cancer at allelic and genotypic level.

Conclusions

The present meta-analysis suggests an important role of mir-196a2 rs11614913 polymorphism with overall cancer risk especially in Asian population. Further studies with large sample size are needed to evaluate and confirm this association.     

A Meta-Analysis of PTGS1 and PTGS2 Polymorphisms and NSAID Intake on the Risk of Developing Cancer

Background

Several studies have investigated whether the polymorphisms in the prostaglandin endoperoxide synthase 1 (PTGS1) and PTGS2 genes and nonsteroidal anti-inflammatory drug (NSAID) use are associated with cancer risk; however, those studies have produced mixed results. Therefore, we performed a meta-analysis to evaluate the association between the PTGS1 and PTGS2 polymorphisms and the effect of NSAID use on the risk of developing cancer.

Methods

We conducted a comprehensive search in PubMed through March 2012. The odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were calculated using the fixed-effect model or the random-effect model.

Results

The database search generated 13 studies that met the inclusion criteria. For PTGS1 rs3842787, NSAID users homozygous for the major allele (CC) had a significantly decreased cancer risk compared with non-NSAID users (OR = 0.73, 95% CI = 0.59–0.89). For PTGS2 rs5275 and rs20417, there were no significant differences between the gene polymorphism and NSAID use on cancer risk among the 8 and 7 studies, respectively. However, in the stratified analysis by the type of cancer or ethnicity population, NSAID users homozygous for the major allele (TT) in rs5275 demonstrated significantly decreased cancer risk compared with non-NSAID users in cancer type not involving colorectal adenoma (OR = 0.70, 95% CI = 0.59–0.83) and among the USA population (OR = 0.67, 95% CI = 0.56–0.82). NSAID users homozygous for the major allele (GG) in rs20417 displayed a significantly decreased cancer risk than non-NSAID users among the US population (OR = 0.72, 95% CI = 0.58–0.88). For the PTGS2 rs689466 and rs2745557 SNPs, there were no significant differences.

Conclusion

This meta-analysis suggests that the associations between PTGS polymorphisms and NSAID use on cancer risk may differ with regard to the type of cancer and nationality.     

Association between Type 2 Diabetes Loci and Measures of Fatness

Background

Type 2 diabetes (T2D) is a metabolic disorder characterized by disturbances of carbohydrate, fat and protein metabolism and insulin resistance. The majority of T2D patients are obese and obesity by itself may be a cause of insulin resistance. Our aim was to evaluate whether the recently identified T2D risk alleles are associated with human measures of fatness as characterized with Dual Energy X-ray Absorptiometry (DEXA).

Methodology/Principal Findings

Genotypes and phenotypes of approximately 3,000 participants from cross-sectional ERF study were analyzed. Nine single nucleotide polymorphisms (SNPs) in CDKN2AB, CDKAL1, FTO, HHEX, IGF2BP2, KCNJ11, PPARG, SLC30A8 and TCF7L2 were genotyped. We used linear regression to study association between individual SNPs and the combined allelic risk score with body mass index (BMI), fat mass index (FMI), fat percentage (FAT), waist circumference (WC) and waist to hip ratio (WHR). Significant association was observed between rs8050136 (FTO) and BMI (p = 0.003), FMI (p = 0.007) and WC (p = 0.03); fat percentage was borderline significant (p = 0.053). No other SNPs alone or combined in a risk score demonstrated significant association to the measures of fatness.

Conclusions/Significance

From the recently identified T2D risk variants only the risk variant of the FTO gene (rs8050136) showed statistically significant association with BMI, FMI, and WC.     

Association of TLR2 and TLR4 Polymorphisms with Risk of Cancer: A Meta-Analysis

Backgrounds

The activation of Toll-like receptors (TLRs) may be an important event in the immune evasion of tumor cell. Recently, numerous studies have investigated the associations between TLR2 −196 to −174 del and two SNPs of TLR4 (rs4986790 and rs4986791) and the susceptibility to different types of cancer; however, the results remain conflicting. The aim of this study was to assess the association between TLR2 and TLR4 polymorphisms and cancer risk in a meta-analysis with eligible published studies.

Methodology/Principle Findings

A dataset composed of 14627 cases and 17438 controls from 34 publications were included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and three SNPs of TLRs (TLR2 −196 to −174 del, TLR4 rs4986790 and rs4986791). The results showed that all of these three polymorphisms were significantly associated with the increased cancer risk (dominant model: OR = 1.64, 95% CI: 1.04–2.60 for TLR2 −196 to −174 del; OR = 1.19, 95% CI: 1.01–1.41 for TLR4 rs4986790; and OR = 1.47, 95% CI: 1.120–1.80 for TLR4 rs4986791; respectively). In stratified analysis, we found the effect of TLR2 −196 to −174 del on cancer risk remained significant in the subgroup of Caucasians and South Asians, but not in East Asians. However, the association between rs4986791 and cancer risk was significant in both South Asians and East Asians, but not in Caucasians. Furthermore, the association between rs4986790 and cancer risk was statistically significant in digestive cancers (dominant model: OR = 1.76, 95% CI: 1.13–2.73) and female-specific cancers (dominant model: OR = 1.50, 95% CI: 1.16–1.94). However, no significant association with risk of digestive system cancers was observed for TLR2 −196 to −174 del and TLR4 rs4986791.

Conclusions/Significance

This meta-analysis presented additional evidence for the association between TLR2 and TLR4 polymorphisms and cancer risk. Further well-designed investigations with large sample sizes are required to confirm this conclusion.     

Circadian gene variants and susceptibility to type 2 diabetes: a pilot study

Background

Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs) in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants.

Methodology/Principal Findings

The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732) and without (N = 1780) type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium) and white European cohorts (DIAGRAM+) using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66–0.86], p = 3.18×10⁻⁵), while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07–1.39], p = 0.003). Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01–1.08], p = 0.008 and OR = 0.95 [0.91–0.99], p = 0.015 respectively).

Conclusions/significance

None of the selected circadian gene variants was associated with type 2 diabetes with study-wide significance after meta-analysis. The nominal association observed with the CRY2 SNP, however, complements previous findings and confirms a role for this locus in disease susceptibility.     

The KCNJ11 E23K polymorphism and progression of glycaemia in Southern Chinese: a long-term prospective study

Context

The KCNJ11 E23K variant is associated with type 2 diabetes mellitus (T2DM) in cross-sectional studies, but conflicting findings have been reported from prospective studies.

Objective

This study aimed to evaluate whether the E23K variant could predict glycaemic progression in a Southern Chinese population.

Methods/Principal Findings

We performed a long-term prospective study on 1912 subjects from the Hong Kong Cardiovascular Risk Factors Prevalence Study (CRISPS). The KCNJ11 E23K variant was associated with the progression to prediabetes after a median interval of 12 years on multinomial logistic regression analysis, even after adjustment for traditional risk factors (OR 1.29, P_{age, sex, BMI and fasting plasma glucose [FPG] adjusted}  = 0.02). Based on Cox proportional hazard regression analysis, the E23K variant also predicted incident prediabetes (HR 1.18, P_{age, sex, BMI and FPG adjusted}  = 0.021). However, E23K was not associated with the progression to T2DM in either multinomial or Cox regression analysis, and the association of E23K with glycaemic progression to either prediabetes or T2DM was significant only in unadjusted Cox regression analysis (P = 0.039). In a meta-analysis of eight prospective studies including our own, involving 15680 subjects, the E23K variant was associated with incident T2DM (fixed effect: OR 1.10, P = 4×10⁻³; random effect: OR 1.11, P = 0.035).

Conclusions

Our study has provided supporting evidence for the role of the E23K variant in glycaemic progression in Chinese, with its effect being more evident in the early stage of T2DM, as the subjects progressed from normal glucose tolerance to prediabetes.