Hematopoietically-Expressed Homeobox Gene Three Widely-Evaluated Polymorphisms and Risk for Diabetes: A Meta-Analysis

Background

The hematopoietically-expressed homeobox (HHEX) gene is identified as a promising candidate for type 2 diabetes by genome-wide association studies, triggering plenty of subsequent replications; however, the results are conflicting. We therefore conducted a meta-analysis of three widely-evaluated polymorphisms in HHEX gene and diabetes risk.

Methodology/Principal Findings

A random-effects model was adopted irrespective of heterogeneity. Data and study quality were assessed in duplicate. There were 49 studies (cases/controls: 57931/74658) for rs1111875, 18 studies (18227/30366) for rs5015480 and 26 studies (25725/30579) for rs7923837, respectively. Overall analyses indicated that rs1111875-C allele (odds ratio [OR] = 1.16; 95% confidence interval [CI]: 1.13–1.2; P<0.0005), rs5015480-C allele (OR = 1.16; 95% CI: 1.06–1.26; P = 0.001) and rs7923837-G allele (OR = 1.18; 95% CI: 1.12–1.24; P<0.0005) conferred significantly increased risk for type 2 diabetes, yet accompanying moderate to strong evidence of heterogeneity. Despite vast divergence in allele distributions, subgroup analyses by ethnicity showed comparable risk estimates between Asians and Caucasians for three examined polymorphisms. Moreover, results of studies with hospital-based controls deviated greatly from that of all qualified studies, especially for rs7923837-G allele carrying a doubled risk (OR = 1.37 versus 1.18). Furthermore, when only large studies (≥500 case-patients) were considered, risk effects were identical to the overall estimates for three examined polymorphisms. The Begg''s funnel plot and Egger''s test indicated low probability of publication bias.

Conclusions

Our results provide clarification to the significant association of rs1111875, rs5015480 and rs7923837 in HHEX gene with type 2 diabetes.     

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.     

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.     

The PTPN22 locus and rheumatoid arthritis: no evidence for an effect on risk independent of Arg620Trp

Objectives

The Trp⁶²⁰ allotype of PTPN22 confers susceptibility to rheumatoid arthritis (RA) and certain other classical autoimmune diseases. There has been a report of other variants within the PTPN22 locus that alter risk of RA; protective haplotype ‘5’, haplotype group ‘6–10’ and susceptibility haplotype ‘4’, suggesting the possibility of other PTPN22 variants involved in the pathogenesis of RA independent of R620W (rs2476601). Our aim was to further investigate this possibility.

Methods

A total of 4,460 RA cases and 4,481 controls, all European, were analysed. Single nucleotide polymorphisms rs3789607, rs12144309, rs3811021 and rs12566340 were genotyped over New Zealand (NZ) and UK samples. Publically-available Wellcome Trust Case Control Consortium (WTCCC) genotype data were used.

Results

The protective effect of haplotype 5 was confirmed (rs3789607; (OR = 0.91, P = 0.016), and a second protective effect (possibly of haplotype 6) was observed (rs12144309; OR = 0.90, P = 0.021). The previously reported susceptibility effect of haplotype 4 was not replicated; instead a protective effect was observed (rs3811021; OR = 0.85, P = 1.4×10⁻⁵). Haplotypes defined by rs3789607, rs12144309 and rs3811021 coalesced with the major allele of rs12566340 within the adjacent BFK (B-cell lymphoma 2 (BCL2) family kin) gene. We, therefore, tested rs12566340 for association with RA conditional on rs2476601; there was no evidence for an independent effect at rs12566340 (P = 0.76). Similarly, there was no evidence for an independent effect at rs12566340 in type 1 diabetes (P = 0.85).

Conclusions

We have no evidence for a common variant additional to rs2476601 within the PTPN22 locus that influences the risk of RA. Arg620Trp is almost certainly the single common causal variant.     

Association of new loci identified in European genome-wide association studies with susceptibility to type 2 diabetes in the Japanese

Background

Several novel susceptibility loci for type 2 diabetes have been identified through genome-wide association studies (GWAS) for type 2 diabetes or quantitative traits related to glucose metabolism in European populations. To investigate the association of the 13 new European GWAS-derived susceptibility loci with type 2 diabetes in the Japanese population, we conducted a replication study using 3 independent Japanese case-control studies.

Methodology/Principal Findings

We examined the association of single nucleotide polymorphisms (SNPs) within 13 loci (MTNR1B, GCK, IRS1, PROX1, BCL11A, ZBED3, KLF14, TP53INP1, KCNQ1, CENTD2, HMGA2, ZFAND6 and PRC1) with type 2 diabetes using 4,964 participants (2,839 cases and 2,125 controls) from 3 independent Japanese samples. The association of each SNP with type 2 diabetes was analyzed by logistic regression analysis. Further, we performed combined meta-analyses for the 3 studies and previously performed Japanese GWAS data (4,470 cases vs. 3,071 controls). The meta-analysis revealed that rs2943641 in the IRS1 locus was significantly associated with type 2 diabetes, (P = 0.0034, OR = 1.15 95% confidence interval; 1.05–1.26) and 3 SNPs, rs10930963 in the MTNR1B locus, rs972283 in the KLF14 locus, and rs231362 in the KCNQ1 locus, had nominal association with type 2 diabetes in the present Japanese samples (P<0.05).

Conclusions

These results indicate that IRS1 locus may be common locus for type 2 diabetes across different ethnicities.     

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.     

An exploratory study on CLU, CR1 and PICALM and Parkinson disease

Background

Recent GWAS and subsequent confirmation studies reported several single-nucleotide polymorphisms (SNPs) at the CLU, CR1 and PICALM loci in association with late-onset Alzheimer''s disease (AD). Parkinson disease (PD) shares several clinical and pathologic characteristics with AD; we therefore explored whether these SNPs were also associated with PD risk.

Methodology/Principal Findings

791 non-Hispanic Whites cases and 1,580 matched controls were included in the study. Odds ratios (OR) and 95% confidence intervals (CI) were obtained from logistic regression models. rs11136000 at the CLU locus was associated with PD risk under the recessive model (comparing TT versus CC+CT: OR = 0.71, 95% CI: 0.55-0.92, p = 0.008) after adjusting for year of birth, gender, smoking, and caffeine intake. Further adjustment for family history of PD and ApoE ε4 status did not change the result. In addition, we did not find evidence for effect modification by ApoE or known PD risk factors. The association, however, appeared to be stronger for PD with dementia (OR = 0.49, 95% CI: 0.27-0.91) than for PD without dementia (OR = 0.81, 95% CI: 0.61-1.06). The two other SNPs, rs6656401 from CR1, and rs3851179 from PICALM region were not associated with PD (p>0.05).

Conclusion

Our exploratory analysis suggests an association of CLU with PD. This exploratory finding and the role of dementia in explaining this finding needs further investigation.     

Evaluation of genetic susceptibility loci for chronic hepatitis B in Chinese: two independent case-control studies

Background

A recent genome-wide scan has identified two genetic variants in the HLA-DP region strongly associated with hepatitis B infection in Japanese. This study evaluates the effects of these risk variants in Chinese, where the HBV infection is the most popular in the world.

Methods and Findings

We have assessed the relationship between these two single nucleotide polymorphisms (rs3077 and rs9277535) and chronic hepatitis B infection in two independent case-control studies. The first population in Chinese Han included 736 patients and 782 spontaneously recovered controls. The second set was established in Chinese Zhuang minority of 177 patients and 208 controls. Both A alleles of rs3077 and rs9277535 significantly deceased the risk to CHB in Chinese Han (OR = 0.540, 95%CI: 0.464–0.628, P = 4.068×10⁻¹⁶ and OR = 0.696, 95%CI: 0.601–0.806, P = 1.062×10⁻⁶, respectively). Conceivably, rs9277535 was found to be associated with decreased risk of the disease in Chinese Zhuang, with an OR of 0.606 (95%CI, 0.441–0.833, P = 0.002).

Conclusion

Chronic hepatitis B susceptibility loci in HLA-DP region (rs3077 and rs9277535) identified by genome-wide scan in Japanese population were validated in Chinese population. These findings might provide clues to develop screening and surveillance strategies.     

PPARG,KCNJ11, CDKAL1, CDKN2A-CDKN2B,IDE-KIF11-HHEX,IGF2BP2 and SLC30A8 Are Associated with Type 2 Diabetes in a Chinese Population

Background

Recent advance in genetic studies added the confirmed susceptible loci for type 2 diabetes to eighteen. In this study, we attempt to analyze the independent and joint effect of variants from these loci on type 2 diabetes and clinical phenotypes related to glucose metabolism.

Methods/Principal Findings

Twenty-one single nucleotide polymorphisms (SNPs) from fourteen loci were successfully genotyped in 1,849 subjects with type 2 diabetes and 1,785 subjects with normal glucose regulation. We analyzed the allele and genotype distribution between the cases and controls of these SNPs as well as the joint effects of the susceptible loci on type 2 diabetes risk. The associations between SNPs and type 2 diabetes were examined by logistic regression. The associations between SNPs and quantitative traits were examined by linear regression. The discriminative accuracy of the prediction models was assessed by area under the receiver operating characteristic curves. We confirmed the effects of SNPs from PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 on risk for type 2 diabetes, with odds ratios ranging from 1.114 to 1.406 (P value range from 0.0335 to 1.37E-12). But no significant association was detected between SNPs from WFS1, FTO, JAZF1, TSPAN8-LGR5, THADA, ADAMTS9, NOTCH2-ADAM30 and type 2 diabetes. Analyses on the quantitative traits in the control subjects showed that THADA SNP rs7578597 was association with 2-h insulin during oral glucose tolerance tests (P = 0.0005, empirical P = 0.0090). The joint effect analysis of SNPs from eleven loci showed the individual carrying more risk alleles had a significantly higher risk for type 2 diabetes. And the type 2 diabetes patients with more risk allele tended to have earlier diagnostic ages (P = 0.0006).

Conclusions/Significance

The current study confirmed the association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes. These type 2 diabetes risk loci contributed to the disease additively.     

Significant role of estrogen and progesterone receptor sequence variants in gallbladder cancer predisposition: a multi-analytical strategy

Background

Carcinoma of gallbladder (GBC) is an aggressive malignancy. The higher incidence of gallbladder cancer in women has been partly attributed to hormonal factors. Therefore the present study was designed to explore the role of genetic variants in estrogen (ESR1, ESR2) and progesterone (PGR) receptors in conferring risk of gallbladder cancer.

Materials and Methods

The present case-control study recruited total of 860 subjects, including 410 GBC patients, 230 gallstone patients and 220 controls. We examined the associations of 6 selected polymorphisms in three genes: ESR1 (rs2234693, rs9340799, rs1801132), ESR2 (rs1271572, rs1256049) and PGR (rs1042838) with GBC risk. Genotyping for all the polymorphisms was done using PCR-RFLP. Multifactor dimensionality reduction and classification and regression tree approaches were combined with logistic regression to discover high-order gene-gene interactions in hormonal pathway.

Results

On comparing the genotype frequency distribution in gallstone and GBC patients with that of healthy subjects, the homozygous variant genotypes of ESR1-397TT (rs2234693) polymorphism showed significant risk for developing gallstone [odds ratio: OR = 2.9] and GBC [OR = 1.8] respectively. Detailed haplotypes analysis suggested that ESR1 T _rs2234693G _rs9340799C _rs1801132 have significant association in conferring risk for both gallstones [OR = 2.2] and GBC [OR = 3.0]. However, the variant-containing genotypes (DI+II) of PGR (rs1042838) showed low risk in both GBC [OR = 0.4] and gallstone patients [OR = 0.4].On performing the MDR analysis, ESR1 IVS1-397C>T, ESR1 IVS1-351A>G, and ESR2-789 A>C yielded the highest testing accuracy of 0.634. These results were further supported by the CART analysis which revealed that individuals with the combined genotypes of ESR1-397 CT or TT, ESR1-351 AG or GG and ESR2 -789 AA had the highest risk for GBC [OR  = 3.9].

Conclusion

Using multi-analytical approaches, our study showed important role of ESR1 IVS1-397C>T, ESR1 IVS1-351A>G, and ESR2-789 A>C variants in GBC susceptibility and the risk appears to be mediated through gallstone dependent pathway.     

Comprehensive analysis of 5-aminolevulinic acid dehydrogenase (ALAD) variants and renal cell carcinoma risk among individuals exposed to lead

Background

Epidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead.

Methods

The objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression.

Results

The adjusted risk associated with the ALAD variant rs8177796^CT/TT was increased (OR = 1.35, 95%CI = 1.05–1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles (^GGOR = 2.68, 95%CI = 1.17–6.12, p = 0.01; ^GAOR = 1.79, 95%CI = 1.06–3.04 with an interaction approaching significance (p_int = 0.06).. No significant modification in RCC risk was observed for the functional variant rs1800435^(K68N). Haplotype analysis identified a region associated with risk supporting tagging SNP results.

Conclusion

A common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure.     

Hsa-miR-196a2 Rs11614913 polymorphism contributes to cancer susceptibility: evidence from 15 case-control studies

Background

MicroRNAs (miRNAs) are a family of endogenous, small and noncoding RNAs that negatively regulate gene expression by suppressing translation or degrading mRNAs. Recently, many studies investigated the association between hsa-miR-196a2 rs11614913 polymorphism and cancer risk, which showed inconclusive results.

Methodology/Principal Findings

We conducted a meta-analysis of 15 studies that included 9,341 cancer cases and 10,569 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, individuals with the TC/CC genotypes were associated with higher cancer risk than those with the TT genotype (OR = 1.18, 95% CI = 1.03–1.34, P<0.001 for heterogeneity test). In the stratified analyses, we observed that the CC genotype might modulate breast cancer risk (OR = 1.11, 95%CI = 1.01–1.23, P _{heterogeneity} = 0.210) and lung cancer risk (OR = 1.25, 95%CI = 1.06–1.46, P _{heterogeneity} = 0.958), comparing with the TC/TT genotype. Moreover, a significantly increased risk was found among Asian populations in a dominant model (TC/CC versus TT, OR = 1.24, 95% CI = 1.07–1.43, P _{heterogeneity} = 0.006).

Conclusions

These findings supported that hsa-miR-196a2 rs11614913 polymorphism may contribute to the susceptibility of cancers.     

A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers

Background and Aims

Chronic infection with the hepatitis B virus (HBV) is a major health issue worldwide. Recently, single nucleotide polymorphisms (SNPs) within the human leukocyte antigen (HLA)-DP locus were identified to be associated with HBV infection in Asian populations. Most significant associations were observed for the A alleles of HLA-DPA1 rs3077 and HLA-DPB1 rs9277535, which conferred a decreased risk for HBV infection. We assessed the implications of these variants for HBV infection in Caucasians.

Methods

Two HLA-DP gene variants (rs3077 and rs9277535) were analyzed for associations with persistent HBV infection and with different clinical outcomes, i.e., inactive HBsAg carrier status versus progressive chronic HBV (CHB) infection in Caucasian patients (n = 201) and HBsAg negative controls (n = 235).

Results

The HLA-DPA1 rs3077 C allele was significantly associated with HBV infection (odds ratio, OR = 5.1, 95% confidence interval, CI: 1.9–13.7; p = 0.00093). However, no significant association was seen for rs3077 with progressive CHB infection versus inactive HBsAg carrier status (OR = 2.7, 95% CI: 0.6–11.1; p = 0.31). In contrast, HLA-DPB1 rs9277535 was not associated with HBV infection in Caucasians (OR = 0.8, 95% CI: 0.4–1.9; p = 1).

Conclusions

A highly significant association of HLA-DPA1 rs3077 with HBV infection was observed in Caucasians. However, as a differentiation between different clinical courses of HBV infection was not possible, knowledge of the HLA-DPA1 genotype cannot be translated into personalized anti-HBV therapy approaches.     

Associations of type 2 diabetes with common variants in PPARD and the modifying effect of vitamin D among middle-aged and elderly Chinese

Background

Previous studies have identified that variants in peroxisome proliferator-activated receptor PPAR-δ (PPARD), a target gene of vitamin D, were significantly associated with fasting glucose and insulin sensitivity in European populations. This current study sought to determine (1) whether the genetic associations of PPARD variants with type 2 diabetes and its related traits could be replicated in Chinese Han population, and (2) whether the associations would be modified by the effect of vitamin D status.

Methods and Findings

We genotyped 9 tag single nucleotide polymorphisms (SNPs) that cover the gene of PPARD (rs2267664, rs6902123, rs3798343, rs2267665, rs2267668, rs2016520, rs2299869, rs1053049, and rs9658056) and tested their associations with type 2 diabetes risk and its related traits, including fasting glucose, insulin and HbA1c in 3,210 Chinese Hans. Among the 9 PPARD tag SNPs, rs6902123 was significantly associated with risk of type 2 diabetes (odds ratio 1.75 [95%CI 1.22–2.53]; P = 0.0025) and combined type 2 diabetes and impaired fasting glucose (IFG) (odds ratio 1.47 [95%CI 1.12–1.92]; P = 0.0054). The minor C allele of rs6902123 was associated with increased levels of fasting glucose (P = 0.0316) and HbA1c (P = 0.0180). In addition, we observed that vitamin D modified the effect of rs6902123 on HbA1c (P for interaction = 0.0347).

Conclusions/Significance

Our findings demonstrate that common variants in PPARD contribute to the risk of type 2 diabetes in Chinese Hans, and provided suggestive evidence of interaction between 25(OH)D levels and PPARD-rs6902123 on HbA1c.     

Oncogenic CagA promotes gastric cancer risk via activating ERK signaling pathways: a nested case-control study

Background

CagA cellular interaction via activation of the ERK signaling pathway may be a starting point in the development of gastric cancer. This study aimed to evaluate whether genes involved in ERK downstream signaling pathways activated by CagA are susceptible genetic markers for gastric cancer.

Methods

In the discovery phase, a total of 580 SNPs within +/−5 kbp of 30 candidate genes were genotyped to examine an association with gastric cancer risk in the Korean Multi-center Cancer Cohort (100 incident gastric cancer case-control sets). The most significant SNPs (raw or permutated p value<0.02) identified in the discovery analysis were re-evaluated in the extension phase using unconditional logistic regression model (400 gastric cancer case-control sets). Combined analyses including pooled- and meta-analysis were conducted to summarize all the results.

Results

24 SNPs in eight genes (ERK, Dock180, C3G, Rap1, Src, CrkL, Mek and Crk) were significantly associated with gastric cancer risk in the individual SNP analyses in the discovery phase (p<0.05). In the extension analyses, ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 showed marginally significant gene-dose effects for gastric cancer. Consistently, final combined analysis presented the SNPs as significantly associated with gastric cancer risk (OR = 1.56, [95% CI: 1.19–2.06], OR = 0.61, [95% CI: 0.43–0.87], OR = 0.59, [95% CI: 0.54–0.76], respectively).

Conclusions

Our findings suggest that ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 are genetic determinants in gastric carcinogenesis.     

Polymorphisms in the ERCC5 Gene and Risk of Esophageal Squamous Cell Carcinoma (ESCC) in Eastern Chinese Populations

Background

Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair; its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity and thus contribute to cancer risk.

Methodology/Principal Findings

In a hospital-based case-control study of 1115 esophageal squamous cell carcinoma (ESCC) cases and 1117 cancer-free controls, we genotyped three potentially functional SNPs of ERCC5 (SNPs, rs2296147T>C, rs2094258C>T and rs873601G>A) and estimated crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for their associations with risk of ESCC using unconditional logistic regression models. We also calculated false-positive report probabilities (FPRPs) for significant findings. We found that compared with the TT genotype, ERCC5 rs2296147 C variant genotypes were associated with a significantly lower ESCC risk (CT: adjusted OR = 0.76, 95% CI = 0.63–0.93, CT/CC: adjusted OR = 0.80, 95% CI = 0.67–0.96); however, this risk was not observed for the other two SNPs (rs2094258C>T and rs873601 G>A), nor in further stratification and haplotype analysis.

Conclusions/Significances

These findings suggested that ERCC5 polymorphisms may contribute to risk of ESCC in Eastern Chinese populations, but the effect was weak and needs further validation by larger population-based case-control studies.     

Variants in GLIS3 and CRY2 are associated with type 2 diabetes and impaired fasting glucose in Chinese Hans

Background

Recent genome-wide association studies have identified a number of common variants associated with fasting glucose homeostasis and type 2 diabetes in populations of European origin. This is a replication study to examine whether such associations are also observed in Chinese Hans.

Methods

We genotyped nine variants in or near MADD, ADRA2A, CRY2, GLIS3, PROX1, FADS1, C2CD4B, IGF1 and IRS1 in a population-based cohort including 3,210 unrelated Chinese Hans from Beijing and Shanghai.

Results

We confirmed the associations of GLIS3-rs7034200 with fasting glucose (beta = 0.07 mmol/l, P = 0.03), beta cell function (HOMA-B) (beta = −3.03%, P = 0.009), and type 2 diabetes (OR [95%CI]  = 1.27 [1.09–1.49], P = 0.003) after adjustment for age, sex, region and BMI. The association for type 2 diabetes remained significant after adjusting for other diabetes related risk factors including family history of diabetes, lipid profile, medication information, hypertension and life style factors, while further adjustment for HOMA-B abolished the association. The A-allele of CRY2-rs11605924 was moderately associated with increased risk of combined IFG/type 2 diabetes (OR [95%CI]  = 1.15[1.01–1.30], P = 0.04). SNPs in or near MADD, ADRA2A, PROX1, FADS1, C2CD4B, IGF1, and IRS1 did not exhibit significant associations with type 2 diabetes or related glycemic traits (P≥0.10).

Conclusions

In conclusion, our results indicate the associations of GLIS3 locus with type 2 diabetes and impaired fasting glucose in Chinese Hans, partially mediated through impaired beta-cell function. In addition, we also found modest evidence for the association of CRY2-rs11605924 with combined IFG/type 2 diabetes.     

Genetic variant of AMD1 is associated with obesity in urban Indian children

Background

Hyperhomocysteinemia is regarded as a risk factor for cardiovascular diseases, diabetes and obesity. Manifestation of these chronic metabolic disorders starts in early life marked by increase in body mass index (BMI). We hypothesized that perturbations in homocysteine metabolism in early life could be a link between childhood obesity and adult metabolic disorders. Thus here we investigated association of common variants from homocysteine metabolism pathway genes with obesity in 3,168 urban Indian children.

Methodology/Principal Findings

We genotyped 90 common variants from 18 genes in 1,325 children comprising of 862 normal-weight (NW) and 463 over-weight/obese (OW/OB) children in stage 1. The top signal obtained was replicated in an independent sample set of 1843 children (1,399 NW and 444 OW/OB) in stage 2. Stage 1 association analysis revealed association between seven variants and childhood obesity at P<0.05, but association of only rs2796749 in AMD1 [OR = 1.41, P = 1.5×10^-4] remained significant after multiple testing correction. Association of rs2796749 with childhood obesity was validated in stage 2 [OR = 1.28, P = 4.2×10^-3] and meta-analysis [OR = 1.35, P = 1.9×10^-6]. AMD1 variant rs2796749 was also associated with quantitative measures of adiposity and plasma leptin levels that was also replicated and corroborated in combined analysis.

Conclusions/Significance

Our study provides first evidence for the association of AMD1 variant with obesity and plasma leptin levels in children. Further studies to confirm this association, its functional significance and mechanism of action need to be undertaken.     

Genetic variations in a PTEN/AKT/mTOR axis and prostate cancer risk in a Chinese population

Backgroud

Genetic variations in a PTEN/AKT/mTOR signaling axis may influence cellular functions including cell growth, proliferation and apoptosis, and then increase the individual’s risk of cancer. Accordingly, we explore the association between single nucleotide polymorphisms (SNPs) of these genes and prostate cancer (PCa) in our Chinese population.

Methods

Subjects were recruited from 666 PCa patients and 708 cancer-free controls, and eight SNPs in the PTEN/AKT/mTOR axis were determined by the TaqMan assay. Odds ratios (OR) and 95% confidence intervals (95% CI) were evaluated by logistic regression.

Results

We observed significant associations between PCa risk and mTOR rs2295080 [P = 0.027, OR = 0.85, 95%CI = 0.74–0.98], and AKT2 rs7254617 (P = 0.003, OR = 1.35, 95%CI = 1.11–1.64). When estimated these two SNPs together, the combined genotypes with 2–4 risk alleles (rs2295080 T and rs7254617 A alleles) were associated with an increased risk of PCa compared with 0–1 risk alleles, which was more pronounced among subgroups of age >71 years, smokers, drinkers and no family history of cancer. Results of stratified analyses by cliniopathological parameters revealed that the frequencies of the combined genotypes with 2–4 risk alleles in advanced stage were significantly higher than in localized stage(P = 0.022), but there was no significant association in Gleason score and PSA level.

Conclusion

Our results indicate, for the first time that the two variants in AKT2 and mTOR, particularly the joint genotypes with 2–4 risk alleles may influence PCa susceptibility and progression in Chinese, and the association appeared to be more strong in the subgroup of smokers and drinkers.