E-cadherin gene promoter hypermethylation may contribute to the risk of bladder cancer among Asian populations

There are increasing scientific evidences suggesting that E-cadherin gene promoter hypermethylation may contribute to the development and progression of bladder cancer, but existing studies have yielded inconclusive results. This meta-analysis aims to assess the role of E-cadherin promoter hypermethylation in bladder carcinogenesis. We conducted an extensive literature search for relevant studies on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through May 1st, 2013. This meta-analysis was performed using the STATA 12.0 software. Crude risk ratio (RR) with 95% confidence interval (CI) was calculated. Ten clinical studies were included in this meta-analysis with a total of 620 bladder cancer samples, 199 normal adjacent samples and 131 normal urothelium tissue. Our meta-analysis revealed that the methylation frequencies in bladder cancer tissues were obviously higher than those in normal control tissues (RR = 2.02, 95%CI: 1.00–4.12, P = 0.050). Subgroup analysis by ethnicity indicated that higher methylation frequencies were observed in bladder cancer tissues among Asian populations (RR = 2.35, 95%CI: 1.11–4.95, P = 0.025), but not among Caucasian populations (RR = 1.62, 95%CI: 0.48–5.53, P = 0.439). Univariate and multivariate meta-regression analyses showed that ethnicity may be the major source of heterogeneity (P < 0.05). No publication bias was detected in this meta-analysis (P = 0.358). The present meta-analysis indicates that E-cadherin gene promoter hypermethylation may contribute to increased risk of bladder cancer among Asian populations.     

Further evidence for the contribution of the vascular endothelial growth factor gene in coronary artery disease susceptibility

Coronary artery disease (CAD) receives intensive attentions in the research of cardiovascular diseases, due to its high incidence and severe impact on the quality of life vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, has been strongly implicated in the pathogenesis of CAD. Genetic markers in different regions of the VEGF gene have a plausible role in modulating the risk of CAD. To identify the markers contributing to the genetic susceptibility to CAD, we examined the potential association between CAD and 10 single nucleotide polymorphisms (SNPs, rs699947, rs1570360, rs2010963, rs833068, rs3024997, rs3025000, rs3025010, rs3025020, rs3025030, rs3025039) of the VEGF gene using the MassARRAY system. Participants included 242 CAD patients and 253 healthy controls from a Chinese Han Population (He'nan Province, China). The allelic or genotypic frequencies of the rs699947 (5′ untranslated regions, 5′UTR) and rs2010963 (5′UTR) polymorphisms in the CAD patients were significantly different from those in the healthy controls. The CAD patients had significantly higher frequency of the rs699947 A allele (χ² = 11.141, P = 0.001, OR = 1.665, 95% CI = 1.232–2.250) and rs2010963 C allele (χ² = 13.593, P = 0.0002, OR = 1.611, 95% CI = 1.249–2.077). Strong linkage disequilibrium was observed in the rs699947–rs1570360–rs2010963 haplotype block (D’ > 0.9). Significantly more C–G–C haplotypes (P = 0.040) and significantly fewer C–G–G haplotypes (P = 0.0004) were found in the CAD patients. The possible association of rs699947 and rs2010963 with CAD risks warrant confirmation in independent case–control studies and may be informative for future investigations on the pathogenesis of CAD.     

Null genotypes of GSTM1 and GSTT1 contribute to increased risk of diabetes mellitus: A meta-analysis

Diabetes mellitus (DM) is a common disease which results from various causes including genetic and environmental factors. Glutathione S-Transferase M1 (GSTM1) and Glutathione S-Transferase T1 (GSTT1) genes are polymorphic in human and the null genotypes lead to the absence of enzyme function. Many studies assessed the associations between GSTM1/GSTT1 null genotypes and DM risk but reported conflicting results. In order to get a more precise estimate of the associations of GSTM1/GSTT1 null genotypes with DM risk, we performed this meta-analysis. Published literature from PubMed, Embase and China Biology Medicine (CBM) databases was searched for eligible studies. Pooled odds ratios (OR) and corresponding 95% confidence intervals (95%CI) were calculated using a fixed- or random-effects model. 11 publications (a total of 2577 cases and 4572 controls) were finally included into this meta-analysis. Meta-analyses indicated that null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1–GSTT1 were all associated with increased risk of DM (GSTM1: OR _{random-effects} = 1.60, 95%CI 1.10–2.34, P_OR = 0.014; GSTT1: OR _{random-effects} = 1.47, 95%CI 1.12–1.92, P_OR = 0.005; GSTM1–GSTT1: OR _{fixed-effects} = 1.83, 95%CI 1.30–2.59, P_OR = 0.001). Subgroup by ethnicity suggested significant associations between null genotypes of GSTM1 and GSTT1 and DM risk among Asians (GSTM1: OR _{random-effects} = 1.77, 95%CI 1.24–2.53, P_OR = 0.002; GSTT1: OR _{random-effects} = 1.58, 95%CI 1.09–2.27, P_OR = 0.015). This meta-analysis suggests null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1–GSTT1 are all associated with increased risk of DM, and null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1–GSTT1 are potential biomarkers of DM.     

The genetic polymorphisms of cathepsin S were associated with metabolic disorders in a Chinese Han population

Cathepsin S (CTSS) played an important role in the etiology of cardiovascular disease and metabolic syndrome. Few studies had been reported on the association between the polymorphisms of CTSS and metabolic disorders in Asian population. Therefore we explored the association between the polymorphisms of CTSS and metabolic disorders in a Chinese Han population. The subjects were a Chinese Han cohort with 1160 participants, and the genotyping was performed with PCR-RFLP. Polymorphism rs16827671 was associated with BMI and serum total cholesterol (P = 0.001; P = 0.02, respectively). Subjects with CT genotype of rs16827671 had a higher risk of hypercholesterolemia (OR = 1.64, 95% CI: 1.15–2.33, P = 0.006) compared with TT genotype. Subjects with AG genotype of rs11576175 had lower risks of hypertriglyceridemia and borderline hypercholesterolemia (OR = 0.52, 95% CI: 0.36–0.73, P = 0.0001; OR = 0.52, 95% CI: 0.35–0.77, P = 0.001, respectively) compared with GG genotype. Compared with the haplotype TG, haplotype TA had a lower risk of hypertriglyceridemia and a higher risk of borderline hypercholesterolemia (OR = 0.62, 95% CI: 0.44–0.88, P = 0.002; OR = 1.59, 95% CI: 1.10–2.31, P = 0.008, respectively), and haplotype CA had a lower risk of hypercholesterolemia (OR = 0.35, 95% CI: 0.18–0.68, P = 0.002). In conclusion, we found that the genetic polymorphisms of CTSS were associated with metabolic disorders in a Chinese Han population, which would enrich the knowledge on genetic mechanisms of the pathogenesis of metabolic disorders.     

The effect of XPD/ERCC2 Lys751Gln polymorphism on acute leukemia risk: A systematic review and meta-analysis

Aims

Epidemiological studies have assessed the association between xeroderma pigmentosum group D (XPD) Lys751Gln and acute leukemia risk with conflicting results. We performed this meta-analysis to derive a more precise estimation of the relationship. Pooled odds ratio (OR) with 95% confidence interval (95% CI) was used to assess the strength of the association.

Results

Ten published case–control studies including a total of 1494 cases and 2259 controls were identified. Overall, significant risk effects of Lys751Gln genotype was found under the dominant model (OR = 1.16; 95% CI = 1.01–1.34; P = 0.032). When stratified by clinical types, the variant genotype was associated with the acute myeloid leukemia (AML) risk under the heterozygote comparison (OR = 1.20; 95% CI = 1.00–1.43; P = 0.048), the homozygote comparison (OR = 1.35; 95% CI = 1.05–1.74; P = 0.019) and the dominant model (OR = 1.23; 95% CI = 1.04–1.45; P = 0.015), respectively. Furthermore, significantly increased risks were also pronounced in Caucasian AML patients (the homozygote comparison: OR = 1.38; 95% CI = 1.07–1.78; P = 0.013; the dominant model: OR = 1.23; 95% CI = 1.03–1.46; P = 0.020; and the recessive model: OR = 1.26; 95% CI = 1.00–1.60; P = 0.050). No evident heterogeneities were observed for the overall data under all genetic models. In addition, no statistical evidence for publication bias was found using the method of Begg's and Egger's tests.

Conclusion

This meta-analysis suggested that XPD Lys751Gln polymorphism might be a risk factor for AML and Caucasian acute leukemia patients.     

Association of TLR and TREM-1 gene polymorphisms with risk of coronary artery disease in a Russian population

Atherosclerosis, manifesting itself as acute coronary syndrome, stroke, and peripheral arterial diseases, is a chronic progressive inflammatory disease which is driven by responses of both innate and adaptive immunity. Toll-like receptors (TLRs) and Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) are important effectors of the innate immune system, and polymorphisms within genes encoding them may increase risk of occurrence of various pathologies including cardiovascular disorders. Thus, we carried out a genetic association study on the sample of 702 consecutive Caucasian (Russian) patients with coronary artery disease (CAD) and 300 age-, sex-, and ethnicity-matched healthy controls. We revealed that the C/C genotype of the TLR1 rs5743551 polymorphism was significantly associated with a reduced risk of CAD according to the recessive model (OR = 0.41, 95% CI = 0.20–0.84, P = 0.017, adjusted by age and gender). Concerning TREM-1 gene polymorphisms, we found that A/A genotype of the rs2234237 polymorphism, the G/G genotype of the rs6910730 polymorphism, the C/C genotype of the rs9471535 polymorphism, and the T/T genotype of the rs4711668 polymorphism were significantly associated with elevated CAD risk according to the recessive model (OR = 5.52, 95% CI = 1.17–25.98, P = 0.011; OR = 4.28, 95% CI = 1.09–16.81, P = 0.021; OR = 5.55, 95% CI = 1.18–26.09, P = 0.011, and OR = 1.66, 95% CI = 1.10–2.52, P = 0.014, respectively, adjusted by age and gender). Conversely, the G allele of the rs1817537 polymorphism, the T allele of the rs2234246 polymorphism, and the T allele of the rs3804277 polymorphism significantly correlated with similarly decreased risk of CAD according to the dominant model (OR = 0.57, 95% CI = 0.40–0.81, P = 0.0013; OR = 0.59, 95% CI = 0.42–0.84, P = 0.003, and OR = 0.58, 95% CI = 0.41–0.81, P = 0.0014, respectively, adjusted by age and gender). We conclude that certain TLR and TREM-1 gene polymorphisms may be associated with CAD in Russian population; however, their significance as predictive and pathogenic markers of CAD should be interpreted with caution in other populations.     

Interleukin-23 receptor genetic variants contribute to susceptibility of multiple cancers

Aim

Interleukin-23 (IL-23) and IL-23 receptor (IL23R) play an important role during the T-helper 17 (Th17) cell-mediated inflammatory process as well as pathogenesis of multiple cancers. Several IL-23R single nucleotide polymorphisms (SNPs), especially rs6682925, rs10889677 and rs1884444 polymorphisms, are considered to have significant impacts on susceptibility of multiple cancers. A number of case-control studies have explored the role these genetic polymorphisms in development of carcinogenesis, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically investigate the associations between the three genetic variants and multiple cancer risk.

Methods

A total of ten studies are eligible (12,211 patients and 14,650 controls). Pooled odds ratios (ORs) and the 95% confidence interval (95% CI) were appropriately calculated using either fixed-effect model or random-effect model.

Results

Significant associations between rs6682925 or rs10889677 polymorphism and cancer risk were found (OR = 1.11, 95% CI = 1.03–1.21, P = 0.007; or OR = 0.85, 95% CI = 0.71–0.92, P = 0.001). However, there was no such association between rs1884444 genotypes and cancer susceptibility (P > 0.05).

Conclusion

These findings reveal that the IL-23R rs6682925 and rs10889677 genetic variants play a more important part in pathogenesis of multiple cancers.     

Tumor necrosis factor alpha − 308G>A, − 863C>A, − 857C>T gene polymorphisms and tuberculosis susceptibility: A meta-analysis

Background/aims

A large number of studies have shown that polymorphisms in the tumor necrosis factor-α (TNF-α, TNFA) gene are implicated in susceptibility to tuberculosis (TB). However, the results are inconsistent. We performed this meta-analysis to estimate the association between polymorphisms in the TNFA gene and TB susceptibility.

Methods

Relevant studies published before March 2012 were identified by searching PubMed, ISI web of knowledge, EBSCO and CNKI. The strength of relationship between the TNFA gene and TB susceptibility was assessed using odds ratios (ORs).

Results

A total number of twenty-three case–control studies including 3630 cases and 4055 controls were identified referring to three previously chosen single-nucleotide polymorphisms (SNPs): − 308G>A, − 863C>A and − 857C>T. No association was found between − 308G>A, − 863C>A and TB susceptibility: − 308G>A (GG + GA vs. AA): OR 0.85, 95%CI: 0.55–1.30, P = 0.44; − 863C>A (CC + CA vs. AA): OR 0.93, 95%CI: 0.84–1.81, P = 0.83. Increased risk of TB was associated with − 857C>T in the dominant genetic model (CC + CT vs. TT: OR 2.13, 95%CI: 1.25–3.63, P = 0.01), the heterozygote comparison (CT vs. TT: OR 2.69, 95%CI: 1.44–5.02, P = 0.00) and the homozygote comparison (CC vs. TT: OR 2.08, 95%CI: 1.22–3.53, P = 0.01) in Asian subjects.

Conclusion

There is an increased association between TNFA − 857C>T polymorphism and TB risk among Asian subjects. No association was found between − 308G>A and − 863C>A with TB risk. Due to several limitations in the present study, well-designed epidemiological studies with large sample size among different ethnicities should be performed in the future.     

Myeloperoxidase G-463A polymorphism and susceptibility to coronary artery disease: A meta-analysis

Published data on the association between the myeloperoxidase (MPO) G-463A polymorphism and coronary artery disease (CAD) are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis on this topic was performed. PubMed, EMBASE and Chinese national knowledge infrastructure were searched for studies regarding the association between the MPO G-463A polymorphism and CAD. A logistic regression analysis was used to estimate the genetic effect and the possible genetic model of action. Summary odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were calculated. There was strong evidence for an association between the MPO G-463A polymorphism and CAD. The genetic model of action was most likely to be co-dominant. Overall, the data showed that AA and GA genotypes were significantly associated with reduced risk of CAD (AA vs. GG: OR = 0.37, 95% CI = 0.17–0.78; GA vs. GG: OR = 0.73, 95% CI = 0.57–0.92). In subgroup analyses by study population and sources of controls, statistically significant results were observed in the Chinese population (AA vs. GG: OR = 0.21, 95% CI = 0.10–0.43; GA vs. GG: OR = 0.57, 95% CI =0.44–0.74) and in hospital-based control studies (AA vs. GG: OR = 0.20, 95% CI = 0.10–0.39; GA vs. GG: OR = 0.61, 95% CI = 0.48–0.77). This meta-analysis suggests that the MPO G-463A variant genotypes may be associated with decreased risk of CAD. However, given the limited number of studies and the potential biases, the influence of this polymorphism on CAD risk needs further investigation.     

Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: A meta-analysis

Background

Recurrent pregnancy loss is an important clinical problem. Recently, high-level homocysteine in blood has been considered as a possible cause. Genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) have been proved to be the common hereditary factors of high-level homocysteine. The association between MTHFR polymorphisms and unexplained recurrent pregnancy loss (URPL) has been reported but with controversial results. The purpose of present study is to collect and analyze published available data, and evaluate the association between MTHFR polymorphisms and URPL.

Methods

A meta-analysis was performed to examine the association between MTHFR polymorphisms (C677T and A1298C) and URPL. Odds ratio (OR) and its 95% confidence interval (CI) were used in each study of genotype and allele contrast.

Result(s)

MTHFR C677T: The analysis included 3559 URPL cases and 5097 healthy controls. Overall random-effects odds ratios (ORs) were 1.68 (95% CI, 1.32–2.13; P < 0.0001) for TT versus total genotypes, 1.35 (95% CI, 1.04–1.76; P = 0.0224) for TT and CT genotype combined versus total genotypes and 1.34 (95%CI, 1.13–1.58; P < 0.0001) for T versus total alleles. Although significant heterogeneity was found in C677T, it became weaker in the East Asian subgroup and the mixed subgroup when separated by ethnic subgroups. The results showed significant association between MTHFR C677T and URPL in the East Asian subgroup (ORs 2.11 for TT versus total genotype (P = 0.0004) and 1.53 for T versus total alleles (P < 0.0001)) and in the mixed subgroup (ORs 3.47 for TT versus total genotypes (P < 0.0001) and 1.80 for T versus total alleles (P < 0.027)), but not in Caucasian subgroup.

MTHFR A1298C

The study involved 1163 URPL cases and 1061 healthy controls. Overall random-effects odds ratios (ORs) were 1.37 (95% CI, 0.71–2.67; P = 0.3456) for CC versus total genotypes, 1.16 (95%CI, 0.98–1.38; P = 0.0833) for CC + AC versus total genotypes and 1.04 (95%CI, 0.84–1.29; P = 0.7112) for C versus total alleles. No significant association between MTHFR A1298C polymorphism and URPL was found.

Conclusions

These results indicate a significant association between MTHFR C677T mutation and URPL in the East Asian subgroup and mixed subgroup, but no significance in MTHFR A1298C mutation.     

Lack of association between EGF + 61A>G polymorphism and melanoma susceptibility in Caucasians: A HuGE review and meta-analysis

Emerging evidence showed that the common polymorphism (+ 61A>G, rs4444903) in the promoter region of epidermal growth factor (EGF) gene might be associated with melanoma susceptibility in humans. But individually published results are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis is to derive a more precise estimation of the association between EGF + 61A>G polymorphism and melanoma risk. The PubMed, Embase, Web of Science and CBM databases were searched for all articles published up to July 1st, 2012. Seven case–control studies were included with a total of 2367 melanoma cases and 4184 healthy controls. Meta-analysis results showed that there was no significant relationship between EGF + 61A>G polymorphism and the risk of melanoma (G vs A: odds ratio [OR] = 1.08, 95% confidence interval [CI]: 0.91–1.28, P = 0.386; GG + AG vs AA: OR = 1.05, 95%CI: 0.88–1.26, P = 0.580; GG vs AA + AG: OR = 1.10, 95%CI: 0.81–1.49, P = 0.552; GG vs AA: OR = 1.06, 95%CI: 0.80–1.41, P = 0.700; GG vs AG: OR = 1.12, 95%CI: 0.81–1.56, P = 0.494). Further subgroup analyses based on source of controls, country, detection samples, genotype methods, and Breslow thickness of tumor, we also found no significant association between EGF + 61A>G polymorphism and melanoma risk. In conclusion, this meta-analysis indicates that EGF + 61A>G polymorphism might not be a primary determinant in melanoma development and progression; EGF gene might be expected to interact with other genes in different signaling pathways to initiate and promote the carcinogenic process.     

Meta-analysis of genetic association of chromosome 9p21 with early-onset coronary artery disease

Purpose

A number of studies reported on associations of single nucleotide polymorphisms (SNPs) present in chromosome 9p21 with early-onset coronary artery disease (CAD). The present study was then undertaken to perform a meta-analysis of all the results published to date.

Methods

All studies of the 9p21 association with early-onset CAD that were published between 2007 and 2012 were retrieved from the PubMed database. RevMan 5.0 software was used to perform meta-analysis of the data that fulfilled the criteria for our meta-analysis. The effect size of four SNPs in the 9p21 region on early-onset CAD risk was assessed based on the odds ratios (ORs) with calculation of 95% confidence interval (CI).

Results

A total of 7123 subjects from 7 case–control studies were genotyped. Meta-analysis demonstrated disease association for rs2383207 (OR = 0.79, 95% CI 0.71–0.88, P < 0.0001), rs2383206 (OR = 1.17, 95% CI 1.10–1.25, P < 0.00001), rs10757278 (OR = 1.28, 95% CI 1.15–1.42, P < 0.00001), and rs10757274 (OR = 1.17, 95% CI 1.08–1.33, P = 0.02).

Conclusion

Genetic variation in the chromosome 9p21 region may contribute to the etiology of early-onset CAD although their effect size is rather small.     

Association of functional FEN1 genetic variants and haplotypes and breast cancer risk

Aim

As a tumor suppressor, FEN1 plays an essential role in preventing tumorigenesis. Two functional germline variants (-69G > A and 4150G > T) in the FEN1 gene have been associated with DNA damage levels in coke-oven workers and multiple cancer risk in general populations. However, it is still unknown how these genetic variants are involved in breast cancer susceptibility.

Methods

We investigated the association between these polymorphisms and breast cancer risk in two independent case–control sets consisted of a total of 1100 breast cancer cases and 1400 controls. The influence of these variations on FEN1 expression was also examined using breast normal tissues.

Results

It was found that the FEN1-69GG genotypes were significantly correlated to increased risk for developing breast cancer compared with the -69AA genotype in both sets [Jinan set: odds ratios (OR) = 1.41, 95% confidence interval (CI) = 1.20–1.65, P = 1.9×10^− 5; Huaian set: OR = 1.51, 95% CI = 1.22–1.86, P = 1.7×10^− 4]. Similar results were observed for 4150G > T polymorphism. The genotype–phenotype correlation analyses demonstrated that the -69G or 4150G allele carriers had more than 2-fold decreased FEN1 expression in breast tissues compared with -69A or 4150T carriers, suggesting that lower FEN1 expression may lead to higher risk for malignant transformation of breast cells.

Conclusion

Our findings highlight FEN1 as an important gene in human breast carcinogenesis and genetic variants in FEN1 confer susceptibility to breast cancer.     

Promoter polymorphisms in DNA repair gene ERCC5 and susceptibility to gastric cancer in Chinese

Genetic variations in excision repair cross-complementing group 5 (ERCC5) might influence individual vulnerability to gastric cancer (GC). We investigated effects of two putatively functional polymorphisms in ERCC5 promoter region, rs751402 (+ 25A > G) and rs2296147 (+ 202C > T), and their potential interaction with environment factors on the risk of developing GC. We performed a sex- and age-matched case–control design with 400 GC cases and 400 healthy controls for rs751402 and 403 GC cases and 403 healthy controls for rs2296147. Our results showed that rs751402 were associated with increased GC risk (AA vs. GG: OR = 1.99, 95%CI: 1.20–3.31, P = 0.008; AG + AA vs. GG: OR = 1.41, 95%CI: 1.07–1.86, P = 0.016), and rs2296147 was also associated with increased cancer risk (CC vs. TT: OR = 2.17, 95%CI: 1.04–4.54, P = 0.039; CC vs. CT + TT: OR = 2.26, 95%CI: 1.09–4.69, P = 0.028). In a stratified analysis, rs751402 (AG + AA vs. GG: OR = 1.44, 95%CI: 1.02–2.02, P = 0.037) and rs2296147 (CC vs. CT + TT: OR = 2.33, 95%CI: 1.00–5.44, P = 0.050) were also found to be associated with diffuse-type GC risk. The most common GT haplotype (rs751402–rs2296147) showed protective effect for GC development (OR = 0.73, 95%CI: 0.58–0.91, P = 0.005), and especially for diffuse-type GC (OR = 0.68, 95%CI: 0.52–0.90, P = 0.006). Genetic effects on increased GC risk seemed to be enhanced by Helicobacter pylori infection, smoking and alcohol drinking, with corresponding adjusted ORs of 4.57, 2.42 and 2.50 for the rs751402 AG/AA variants, and of 5.32, 3.20 and 6.87 for the rs2296147 CC variant, but their interaction effects on GC risk didn't reach statistically significance. ERCC5 rs751402 and rs2296147 polymorphisms might alter the risk of developing GC and especially the diffuse subtype. Further validation of our results in larger populations and additional studies evaluating their function impact are required.     

Vitamin D status and vitamin D receptor gene polymorphisms and susceptibility to type 1 diabetes in Egyptian children

Background

Type 1 diabetes mellitus (T1DM) is recognized as a T-cell-mediated autoimmune disease. Vitamin D compounds are known to suppress T-cell activation by binding to vitamin D receptor (VDR); and thus, VDR gene polymorphisms may be related to T-cell-mediated autoimmune diseases. The aim of this study was to investigate the association between vitamin D status and VDR gene polymorphisms and T1DM.

Materials and methods

One hundred and twenty patients with T1DM and one hundred and twenty controls were enrolled in the study. VDR gene BsmI, FokI, ApaI and TaqI polymorphisms were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum 25-hydroxyvitamin D (25(OH)D) was determined using ELISA.

Result

Serum 25(OH)D levels revealed a vitamin D deficiency or insufficiency in 75% of the patients. The mean levels of vitamin D were significantly lower in patients as compared to their controls (P = < 0.001). VDR BsmI Bb and bb genotypes and VDR FokI Ff and ff genotypes were associated with increased risk of T1DM (OR = 2.3, 95% CI = 1.3–4.2, P = 0.005; OR = 2.2, 95% CI = 1.1–4.7, P = 0.04; OR = 1.8, 95% CI = 1.03–3.04, P = 0.04; OR = 4.03, 95% CI = 1.2–13.1, P = 0.01 respectively), while the VDR ApaI and TaqI polymorphisms were not.

Conclusion

Our study indicated that vitamin D deficiency and VDR BsmI and FokI polymorphisms were associated with T1DM in Egyptian children.     

Multi-allelic haplotype association identifies novel information different from single-SNP analysis: A new protective haplotype in the LRP8 gene is against familial and early-onset CAD and MI

Our previous studies identified a functional SNP, R952Q in the LRP8 gene, that was associated with increased platelet activation and familial and early-onset coronary artery disease (CAD) and myocardial infarction (MI) in American and Italian Caucasian populations. In this study, we analyzed four additional SNPs near R952Q (rs7546246, rs2297660, rs3737983, rs5177) to identify a specific LRP8 SNP haplotype that is associated with familial and early-onset CAD and MI. We employed a case–control association design involving 381 premature CAD and MI probands and 560 controls in GeneQuest, 441 individuals from 22 large pedigrees in GeneQuest II, and 248 MI patients with family history and 308 controls in an Italian cohort. Like R952Q, LRP8 SNPs rs7546246, rs2297660, rs3737983, and rs5177 were significantly associated with early-onset CAD/MI in both population-based and family-based association studies in GeneQuest. The results were replicated in the GeneQuest II family-based population and the Italian population. We then carried out a haplotype analysis for all five SNPs including R952Q. One common haplotype (TCCGC) was significantly associated with CAD (P = 4.0 × 10^− 11) and MI (P = 6.5 × 10^− 12) in GeneQuest with odds ratios of 0.53 and 0.42, respectively. The results were replicated in the Italian cohort (P = 0.004, OR = 0.71). The sib-TDT analysis also showed significant association between the TCCGC haplotype and CAD in GeneQuest II (P = 0.001). These results suggest that a common LRP8 haplotype TCCGC confers a significant protective effect on the development of familial, early-onset CAD and/or MI.     

Synergistic Association between Two Alcohol Metabolism Relevant Genes and Coronary Artery Disease among Chinese Hypertensive Patients

Objective

Coronary artery disease (CAD) is a multifactorial and polygenic disease. The aim of this study was to examine the association between six polymorphisms of four alcohol metabolism relevant genes (ADH1B, ADH1C, ALDH1b1, ALDH2) and the risk of CAD in Han Chinese.

Methods and Results

This was a hospital-based case-control study involving 1365 hypertensive patients. All study subjects were angiographically confirmed. Genotypes were determined with ligase detection reaction method. There was no observable deviation from the Hardy-Weinberg equilibrium for six examined polymorphisms in controls. The genotype and allele distributions of ALDH1b1 rs2073478 and ALDH2 rs671 polymorphisms differed significantly between the two groups (P≤0.005), even after the Bonferroni correction. The most common allele combination was A-C-C-G-C-G (alleles in order of rs1229984, rs1693482, rs2228093, rs2073478, rs886205, rs671) and its frequency was slightly higher in controls than in CAD patients (P = 0.067). After assigning the most common allele combination as a reference, allele combination A-C-C-T-C-A, which simultaneously possessed the risk alleles of rs2073478 and rs671 polymorphisms, was associated with a 1.80-fold greater risk of CAD. Further, a two-locus model including rs2073478 and rs671 that had a maximal testing accuracy of 0.598 and a cross-validation consistency of 10 (P = 0.008) was deemed as the overall best MDR model, which was further validated by classical Logistic regression model.

Conclusion

Our findings provide clear evidence for both individual and interactive associations of ALDH1b1 and ALDH2 genes with the development of CAD in Han Chinese.     

Association of ERCC1-C118T and -C8092A polymorphisms with lung cancer risk and survival of advanced-stage non-small cell lung cancer patients receiving platinum-based chemotherapy: A pooled analysis based on 39 reports

The published data on the predictive role of ERCC1 polymorphisms in lung cancer risk and survival of patients with advanced non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy remains inconsistent. The aim of this meta-analysis was to determine the role of ERCC1 gene polymorphisms (C118T and C8092A) in this clinical situation. Eligible studies were included and assessed for quality using multiple search strategies. Thirty-nine published papers involving 9615 cases (4606 with Stage III/IV disease) and 5542 controls were included in the analysis. Pooled odds ratios (OR) or hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate risk. ERCC1-C118T was associated with lung cancer risk. The OR was 0.90 (95% CI: 0.81–0.99, p = 0.043) in an additive genetic model (C allele vs. T allele) and 0.77 (95% CI: 0.63–0.95, p = 0.013) in a recessive genetic model (CC/CT vs. TT). The corresponding risk was 0.74 (95% CI: 0.58–0.94, p = 0.013) based on a homozygous comparison (CC vs. TT). No significant correlation was found for ERCC1 C8092A and there was no obvious relationship between ERCC1 C118T/C8092A polymorphisms and objective response to platinum-based chemotherapy. Overall survival (OS) of patients with non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy was significantly related to ERCC1 C118T (HR: 1.29, 95% CI: 1.07–1.56, p = 0.007, CT/TT vs. CC). There was no relationship between ERCC1 C8092A and survival (HR: 1.32, 95% CI: 0.84–2.10, p = 0.23, CA/AA vs. CC). These findings suggest that ERCC1 C118T polymorphisms may serve as a biomarker for lung cancer risk and have prognostic value in patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based treatment. Further studies with larger numbers of subjects from a worldwide arena are needed to validate the associations.     

XRCC1 polymorphisms and differentiated thyroid carcinoma risk: A meta-analysis

The objective of this study is to quantitatively derive a more precise estimation of the association between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms and differentiated thyroid carcinoma risk. A comprehensive literature search of three databases was conducted. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with fixed-effect models and random-effect models when appropriate. Overall, no association of the XRCC1 Arg399Gln, Arg280His, and Arg194Trp polymorphisms with differentiated thyroid carcinoma risk was found. In subgroup analyses, a decreased differentiated thyroid carcinoma risk was observed among Caucasians (Gln vs. Arg, OR = 0.86, 95% CI = 0.77–0.96, P = 0.343 for heterogeneity; Gln/Arg vs. Arg/Arg, OR = 0.84, 95% CI = 0.71–0.98, P = 0.229 for heterogeneity; Gln/Gln vs. Arg/Arg, OR = 0.77, 95% CI = 0.60–0.99, P = 0.477 for heterogeneity; dominant genetic model, OR = 0.82, 95% CI = 0.71–0.95, P = 0.272 for heterogeneity), not among Asians. No publication bias was observed. Our results suggest that XRCC1 Arg399Gln polymorphism is not associated with differentiated thyroid carcinoma risk, while a decreased risk is observed among Caucasian population.     

Genetic association of interleukin-10 promoter polymorphisms and susceptibility to diffuse large B-cell lymphoma: A meta-analysis

Published data on the association between interleukin-10 (IL-10) gene polymorphisms and diffuse large B-cell lymphoma (DLBCL) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed, focusing on four major IL-10 gene variants in the promoter region: –3575T/A, –1082A/G, –819C/T and –592C/A. We applied the false discovery rate (FDR) method to adjust for multiple testing. A significant association between IL-10 –3575T/A polymorphism and the risk of DLBCL was observed in the pooled 10 case–control studies (A vs. T: OR = 1.16, 95% CI = 1.08–1.25, P < 0.0001; AA + TA vs. TT: OR = 1.20, 95% CI = 1.08–1.33, P = 0.0009; AA vs. TA + TT: OR = 1.25, 95% CI = 1.09–1.44, P = 0.001). The results indicated that carriers of –1082G allele (–1082GG/GA genotypes) had a nearly 30% increased risk of DLBCL, as compared with carriers of –1082AA genotype (GG + GA vs. AA: OR = 1.30, 95% CI = 1.08–1.57, P = 0.005). When P-values were not adjusted for multiple testing, the risk was significantly decreased among people with –592AA genotype (AA vs. AC + CC: OR = 0.63, 95% CI = 0.43–0.94, P = 0.02), while carriers with –819TT genotype also modestly weakened the DLBCL susceptibility at a marginal level of significance (TT vs. CT + CC: OR = 0.59, 95% CI = 0.35–0.99, P = 0.05). However, these associations were not significant after correction for multiple testing. This meta-analysis suggests that IL-10 –3575A allele confers a greater risk to DLBCL susceptibility, while –1082A/G polymorphism also has significant association with DLBCL risk. These results may help to further clarify the malignancy-risk gene signature of DLBCL, and thus have prognostic and predictive value especially for early-stage DLBCL.