TNF-Alpha rs1800629 Polymorphism Is Not Associated with HPV Infection or Cervical Cancer in the Chinese Population

Background

While HPV infection is the main cause of cervical cancer, genetic susceptibility to HPV infection is not well understood. Tumor necrosis factor alpha (TNF-alpha), involved in the defense against HPV infection, plays an important role in cervical cancer progression and regression. The aim of this study was to investigate the relationship between the TNF-alpha rs1800629 polymorphism and risk of HPV infection or cervical cancer.

Methods

Three groups were involved in this study of Chinese women. Group 1 consisted of 285 high risk HPV positive cervical cancer patients, Group 2, 225 high risk HPV positive patients without cervical cancer, and Group 3, 318 HPV negative women with no cervical cancer. Blood samples were obtained from all patients and genotyped by PCR-RLFP. Fifty randomly selected samples were further sequenced.

Results

The allele and genotype distributions of the TNF-alpha rs1800629 polymorphism were not significantly different between each of the groups (P>0.05). There are no significant relationship between rs1800629 polymorphism and high risk HPV infection (OR  = 0.649, 95% CI: 0.253–1.670, P = 0.371), cervical cancer (OR  = 0.993, 95% CI: 0.376–2.618, P = 0.988), or cervical cancer with HPV infection (OR  = 0.663, 95% CI: 0.250–1.758, P = 0.409).

Conclusions

We demonstrated that there is no association between TNF rs1800629 polymorphism and the HPV infection, or cervical cancer with HPV infection.     

Association of TNF-α, TNFRSF1A and TNFRSF1B Gene Polymorphisms with the Risk of Sporadic Breast Cancer in Northeast Chinese Han Women

Background

The interaction of tumor necrosis factor-α (TNF-α) with its receptors: TNFRSF1A and TNFRSF1B is critical for the promotion of tumor growth, invasion and metastasis. To better understand the roles of single nucleotide polymorphisms (SNPs) in the TNF-α, TNFRSF1A and TNFRSF1B genes in the development of breast cancer, we explored the associations between SNPs in these three genes and breast cancer susceptibility in northeast Chinese Han women.

Methodology/Principal Findings

This case-control study was conducted among 1016 breast cancer patients and 806 age-matched healthy controls. Seven SNPs in the TNF-α (rs1800629, rs361525), TNFRSF1A (rs767455, rs4149577 and rs1800693) and TNFRSF1B (rs1061622 and rs1061624) genes were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In TNFRSF1B, the rs1061622 GT genotype and the G allele conferred a reduced susceptibility to breast cancer (P = 0.000662, OR = 0.706, 95% CI: 0.578–0.863; P = 0.002, OR = 0.769, 95% CI; 0.654–0.905, respectively). Moreover, the AG genotype, the AA genotype and the A allele in rs1061624 conferred an increased risk of breast cancer (P = 0.007, OR = 1.470, 95% CI:1.112–1.943; P = 0.00109, OR = 1.405 95% CI:1.145–1.724; P = 0.001, OR = 1.248 95% CI:1.092–1.426, respectively). These two SNPs also had associations with breast cancer risk under the dominant model. In haplotype analysis, the CTA (rs767455 C-rs4149577 T-rs1800693 A) haplotype in TNFRSF1A and the TA (rs1061622 T-rs1061624 A) haplotype in TNFRSF1B had higher frequencies in breast cancer patients (P = 0.00324; P = 0.000370, respectively), but the frequency of GG (rs1061622 G-rs1061624 G) haplotype in TNFRSF1B was lower in breast cancer patients (P = 0.000251). The associations of the three haplotypes remained significant after correcting for multiple testing. In addition, significant associations were also observed between TNFRSF1A polymorphisms and lymph node metastasis, P53, estrogen receptor (ER) and progesterone receptor (PR) statuses.

Conclusions

Our results suggest that rs1061622 and rs1061624 in TNFRSF1B may affect breast cancer risk, and SNPs in TNFRSF1A are associated with the clinical features of breast cancer.     

Associations between Tumor Necrosis Factor-α Polymorphisms and Risk of Psoriasis: A Meta-Analysis

Background

Tumor necrosis factor-α (TNF-α) may play an important role in the recalcitrant inflammatory and hyperproliferative dermatosis of psoriasis, and there may be a relationship between TNF-α polymorphisms and psoriasis risk.

Methods

We performed a meta-analysis to evaluate the associations between TNF-α polymorphisms and psoriasis. Electronic searches of Pubmed, Embase, and Web of Science were performed for all publications on the associations between TNF-α polymorphisms and psoriasis through September 26, 2012. The pooled odds ratios (ORs) with their 95% confidence interval (95%CIs) were calculated to assess the associations.

Results

Sixteen case-control studies with a total of 2,253 psoriasis cases and 1,947 controls on TNF-α 308 G/A polymorphism and fourteen studies on TNF-α 238 G/A polymorphism with 2,104 cases and 1,838 controls were finally included into the meta-analysis. Overall, TNF-α 308 G/A polymorphism was significantly associated with decreased risk of psoriasis under three genetic comparison models (for A versus G: fixed-effects OR 0.71, 95%CI 0.62-0.82, P < 0.001; for AG versus GG: fixed-effects OR 0.67, 95%CI 0.57-0.78, P < 0.001; for AA/AG versus GG: fixed-effects OR 0.67, 95%CI 0.58-0.78, P < 0.001). In addition, TNF-α 238 G/A polymorphism was associated with increased risk of psoriasis under three genetic models (for A versus G: fixed-effects OR 2.46, 95%CI 2.04-2.96, P < 0.001; for AG versus GG: fixed-effects OR 2.69, 95%CI 2.20-3.28, P < 0.001; for AA/AG versus GG: fixed-effects OR 2.68, 95%CI 2.20-3.26, P < 0.001). Subgroup analysis by ethnicity identified a significant association between TNF-α 308 G/A polymorphism and decreased risk of psoriasis in both Caucasians and Asians and a significant association between TNF-α 238 G/A polymorphism and increased risk of psoriasis in Caucasians.

Conclusions

The meta-analysis suggests that TNF-α 308 G/A polymorphism is associated with decreased risk of psoriasis, while TNF-α 238 G/A is associated with increased risk of psoriasis.     

Genetic Variation in the TNF Gene Is Associated with Susceptibility to Severe Sepsis,but Not with Mortality

Background

Tumor necrosis factor (TNF) and TNF receptor superfamily (TNFR)-mediated immune response play an essential role in the pathogenesis of severe sepsis. Studies examining associations of TNF and lymphotoxin-α (LTA) single nucleotide polymorphisms (SNPs) with severe sepsis have produced conflicting results. The objective of this study was to investigate whether genetic variation in TNF, LTA, TNFRSF1A and TNFRSF1B was associated with susceptibility to or death from severe sepsis in Chinese Han population.

Methodology/Principal Findings

Ten SNPs in TNF, LTA, TNFRSF1A and TNFRSF1B were genotyped in samples of patients with severe sepsis (n = 432), sepsis (n = 384) and healthy controls (n = 624). Our results showed that rs1800629, a SNP in the promoter region of TNF, was significantly associated with risk for severe sepsis. The minor allele frequency of rs1800629 was significantly higher in severe sepsis patients than that in both healthy controls (P_adj = 0.00046, odds ratio (OR)_adj = 1.92) and sepsis patients (P_adj = 0.002, OR_adj = 1.56). Further, we investigated the correlation between rs1800629 genotypes and TNF-α concentrations in peripheral blood mononuclear cells (PBMCs) of healthy volunteers exposed to lipopolysaccharides (LPS) ex vivo, and the association between rs1800629 and TNF-α serum levels in severe sepsis patients. After exposure to LPS, the TNF-α concentration in culture supernatants of PBMCs was significantly higher in the subjects with AA+AG genotypes than that with GG genotype (P = 0.007). Moreover, in patients with severe sepsis, individuals with AA+AG genotypes had significantly higher TNF-α serum concentrations than those with GG genotype (P_adj = 0.02). However, there were no significant associations between SNPs in the four candidate genes and 30 day mortality for patients with severe sepsis.

Conclusions/Significance

Our findings suggested that the functional TNF gene SNP rs1800629 was strongly associated with susceptibility to severe sepsis, but not with lethality in Chinese Han population.     

Functional Promoter -308G>A Variant in Tumor Necrosis Factor α Gene Is Associated with Risk and Progression of Gastric Cancer in a Chinese Population

Background

Tumor necrosis factor-α (TNF-α) plays a crucial role in the development and progression of gastric cancer. A functional polymorphism, -308 G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-α and influence cancer risk. In the present study, we sought to investigate whether this polymorphism has effects on the risk and progression of gastric cancer in a Chinese population.

Methods

We genotyped the TNFA -308 G>A polymorphism using the TaqMan method in a two-stage case-control study comprising a total of 1686 gastric cancer patients and 1895 cancer-free subjects. The logistic regression was used to assess the genetic associations with occurrence and progression of gastric cancer.

Results

We found a significant association between the variant genotypes and increased risk of gastric cancer [P = 0.034, odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.01–1.67, GA/AA vs. GG]. Similar results were observed in the follow-up replication study. When combined the data from the two studies, we found a more significant association (P = 0.001, OR = 1.34, 95%CI = 1.13–1.59), especially for older subjects (>65 years). Furthermore, the patients carrying the variant genotypes had a significantly greater prevalence of T4 stage of disease (P = 0.001, OR = 2.19, 95%CI = 1.39–3.47) and distant metastasis (P = 0.013, OR = 1.61, 95%CI = 1.10–2.35).

Conclusions

Our results suggest that the functional promoter -308 G>A polymorphism in TNFA influence the susceptibility and progression of gastric cancer in the Chinese population.     

Associations between TNF-α-308A/G Polymorphism and Susceptibility with Dermatomyositis: A Meta-Analysis

Background

Some surveys had inspected the effects of the tumor necrosis factor-α (TNF-α)-308A/G polymorphism on susceptibility to dermatomyositis (DM), and showed mixed results. To briefly review these consequences, a comprehensive meta-analysis was carried out to estimate the relationship between them much more accurately.

Methods

Relevant documents dated to February 2014 were acquired from the PUBMED, MEDLINE, and EMBASE databases. The number of the genotypes and/or alleles for the TNF-α-308A/G in the DM and control subjects was extracted and statistical analysis was conducted using STATA 11.2 software. Summary odds ratios (ORs) with their 95% confidence intervals (95% CIs) were used to calculate the risk of DM with TNF-α-308A/G. Stratified analysis based on ethnicity and control population source was also performed.

Results

555 patients with DM and 1005 controls from eight published investigations were finally involved in this meta-analysis. Combined analysis revealed that the overall ORs for the TNF-α-308A allele were 2.041 (95% CIs 1.528–2.725, P<0.0001) in DM. Stratification by ethnicity indicated the TNF-α-308A allele polymorphism was found to be significantly associated with DM in Europeans (OR = 1.977, 95% CI 1.413–2.765, P<0.0001). The only study conducted on TNF-α-308A/G polymorphism in Asians could not be used in ethnicity-stratified meta-analysis. Meta-analysis of the AA+AG vs. GG (dominant model) and AA vs. GG (additive model) of this polymorphism revealed a significant association with DM in overall populations and Europeans.

Conclusions

Our meta-analysis demonstrated that the TNF-α-308A/G polymorphism in the TNF gene might contribute to DM susceptibility, especially in European population. However, further studies with large sample sizes and among different ethnicity populations should be required to verify the association.     

Investigation of Variants in UCP2 in Chinese Type 2 Diabetes and Diabetic Retinopathy

Purpose

The aim of this study was to investigate variants in UCP2 genes in type 2 diabetes mellitus (DM) and diabetic retinopathy (DR) in Chinese population.

Materials and Methods

We conducted a single nucleotide polymorphism-based and haplotype-based case-control study between the variants of UCP2 and DM and between the variants of UCP2 and DR in 479 Chinese patients with type 2 DM and 479 control subjects without DM. Two SNPs (rs660339 and rs659366) were selected as genetic markers.

Results

The risk allele C at UCP2 rs660339 was closely associated with DM in Chinese population. There was significant difference in rs660339 between DM and controls (P = 0.0016; OR [95%CI]  = 1.37 (1.14–1.65)). Subjects who were homozygous of the C allele were more likely to develop DM. The frequency of C allele was higher in DM (58%) than in control (51%). But this locus didn''t have a definite effect on the onset of non-proliferative diabetic retinopathy (NPDR) (P = 0.44; OR [95%CI]  = 0.80 (0.56–1.14)) and proliferative diabetic retinopathy (PDR) (P = 1.00; OR [95%CI]  = 0.99 (0.74–1.34)) comparing to subjects with DM without retinopathy (DWR), respectively. Moreover, the UCP2 rs659366 polymorphism showed no significant difference between DM and control (P = 0.66; OR [95%CI]  = 1.10 (0.91–1.32)). However, there was a significant difference between PDR and DWR (P = 0.016; OR [95%CI]  = 0.66 (0.49–0.90)), but there was no difference between NPDR and DWR (P = 1.00; OR [95%CI]  = 0.96 (0.67–1.37)). Participants who carried the G allele at rs659366 were more likely to develop PDR. For the haplotype, C-A was present more frequently in DM than in control (16% vs 7%), indicating that it was risky, and T-A was present less in DM than in control (29% vs 35%). Haplotype frequencies in DR and DWR showed no significant difference (P = 0.068).

Conclusion

It was indicated that UCP2 may be implicated in the pathogenesis of type 2 DM and DR in Chinese population.     

Associations between TNF-α Polymorphisms and Pneumonia: A Meta-Analysis

Background

Several studies evaluated the associations of tumor necrosis factor-α (TNF-α) polymorphisms with pneumonia in different populations. However, the results were conflicting and controversial.

Methods

Databases including PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Data were extracted independently by two investigators. Crude odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated.

Results

Twelve case-control studies and one cohort study were included. Overall, no association between TNF-α −308A/G polymorphism and pneumonia risk was observed for AA +AG vs. GG (OR = 1.13; 95% CI 0.99–1.30; P = 0.07). In addition, TNF-α −308A/G polymorphism was not associated with pneumonia mortality (OR = 1.96; 95% CI 0.94–4.09; P = 0.07). Furthermore, there was no association of TNF-α −238A/G polymorphism with the risk of pneumonia (OR = 1.38; 95% CI 0.84–2.28; P = 0.20).

Conclusions

TNF-α −308A/G, −238A/G polymorphisms were not associated with pneumonia risk. Moreover, TNF-α −308A/G polymorphism did not play a role in the pneumonia mortality risk.     

Genetic Polymorphism of the Kinesin-Like Protein KIF1B Gene and the Risk of Hepatocellular Carcinoma

Background

Frequent deletions of the kinesin-like protein gene 1B (KIF1B) have been reported in neural tumors. Recently, a genome-wide association study revealed an association between polymorphisms in the KIF1B gene and the risk of hepatocellular carcinoma (HCC), and several case-control studies have further investigated this relationship. However, these studies have yielded controversial results. We therefore performed a meta-analysis to derive a more precise estimation of the association between the KIF1B gene polymorphisms and HCC risk.

Methodology/Principal Finding

PubMed, EMBASE, the ISI Web of Science and the CNKI databases were systematically searched to identify relevant studies. A total of 5 studies containing 13 cohorts with 5,773 cases and 6,404 controls were included. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the strength of the associations. Subgroup analyses were conducted based on ethnicities, sample sizes and quality scores. Overall, the G allele at rs17401966 of the KIF1B gene was associated with a significantly decreased risk for HCC (OR  = 0.81, 95%CI: 0.70–0.93; P = 0.003). Furthermore, subgroup analyses showed that the G allele at rs17401966 of the KIF1B gene significantly reduced the risk for HCC in Chinese cohorts (OR  = 0.76, 95%CI: 0.64–0.90; P = 0.002), large-sample-size cohorts (OR  = 0.80, 95%CI: 0.73–0.88, P<0.01) and high-quality cohorts (OR  = 0.78, 95%CI: 0.71–0.87, P<0.01). However, no significant associations were found in small-sample-size cohorts, studies with low-quality scores and when excluding the cohorts from the study reporting the original discovery.

Conclusion/Significance

These findings demonstrate that the presence of the G allele at rs17401966 of the KIF1B gene may decrease the risk for HCC and suggest that KIF1B may play a critical role in the development of HCC. High-quality studies with larger sample sizes and different ethnic populations will be of great value to further confirm these findings.     

TNF-α-308G/A Polymorphism Contributes to Obstructive Sleep Apnea Syndrome Risk: Evidence Based on 10 Case-Control Studies

Objective

The aim of our study was to investigate the association between the TNF-α-308G/A polymorphism and obstructive sleep apnea syndrome (OSAS).

Method

The Medline, Web of Science, EMBASE, Chinese National Knowledge Infrastructure (CNKI), and Cochrane Central Register of Controlled Trials were searched. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to study TNF-α-308G/A polymorphism and risk of OSAS.

Result

10 case-control studies were included in our meta-analysis. The results from our study showed that the TNF-α-308G/A polymorphism was significantly associated with risk of OSAS (A vs. G: OR = 1.67, 95% CI = 1.43–1.95). In the subgroup analysis by ethnicity, the statistical similar results were observed both in European (A vs. G: OR = 1.68, 95% CI = 1.35–2.08) and Asian population (A vs. G: OR = 2.02, 95% CI = 1.50–2.71). When stratified by age, a significantly increased risk was observed in adult carries A allele compared with G allele (OR = 1.79, 95% CI = 1.50–2.13), whereas no association was found in children (OR = 1.09, 95% CI = 0.70–1.69).

Conclusion

Our study suggested that the TNF-α- 308G/A polymorphism contributed to the susceptibility to the risk of OSAS. Additional well-designed large studies are needed to validate our findings.     

Effects of Common Polymorphism rs11614913 in Hsa-miR-196a2 on Lung Cancer Risk

Background

Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in microRNA-coding genes may participate in the pathogenesis of lung cancer by altering the expression of tumor-related microRNAs. Several studies were investigated in recent years to evaluate the association between hsa-miR-196a2 rs11614913 polymorphism and increased/decreased lung cancer risk. In the present study, we performed a meta-analysis to systematically summarize the possible association.

Methodology/Principal Findings

We performed a meta-analysis of 4 case-control studies that included 2219 lung-cancer cases and 2232 cancer-free controls. We evaluated the strength of the association using odds ratios (ORs) with 95% confidence intervals (CIs). In the overall analysis, it was found that the rs11614913 polymorphism significantly elevated the risk of lung cancer (CC versus (vs.) TT OR = 1.26, 95% CI 1.07–1.49, P = 0.007; CC/CT vs. TT: OR = 1.13, 95% CI 0.98–1.29, P = 0.007; C vs. T: OR = 1.12, 95% CI 1.03–1.22, P = 0.008). In the subgroup analysis by ethnicity, statistically significantly increased cancer risk was found among Asians (CC vs. TT: OR = 1.30, 95% CI 1.10–1.54, P = 0.003; CT vs. TT: OR = 1.16, 95% CI 1.01–1.34, P = 0.039; CC vs. CT/TT: OR = 1.21, 95% CI 1.04–1.41, P = 0.012; C vs. T: OR = 1.14, 95% CI 1.05–1.25, P = 0.002). For Europeans, a significant association with lung cancer risk was found in recessive model (CC vs. CT/TT: OR = 0.63, 95% CI 0.40–0.98, P = 0.040). No publication bias was found in this study.

Conclusions/Significance

Our meta-analysis suggests that the rs11614913 polymorphism is significant associated with the increased risk of lung cancer, especially in Asians. Besides, the C allele of rs11614913 polymorphism may contribute to increased lung cancer risk.     

Association of SMAD7 rs12953717 Polymorphism with Cancer: A Meta-Analysis

Background

Accumulating evidence has suggested that Mothers against decapentaplegic homolog 7 (SMAD7) rs12953717 polymorphism might be related to cancer risk. However, epidemiologic findings have been inconsistent. We therefore performed a meta-analysis to clarify the association between the SMAD7 rs12953717 polymorphism and cancer risk.

Methods

A comprehensive search was conducted to identify all eligible studies of SMAD7 rs12953717 polymorphism and cancer risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) to give a sense of the precision of the estimate. Heterogeneity, publication bias, and sensitivity analysis were also explored.

Results

A total of 14 case-control studies, including 16928 cases and 14781 controls, were included in the present meta-analysis. The overall results showed that the variant genotypes were associated with a significantly increased risk of all cancer types (homozygote comparison, OR = 1.23, 95%CI = 1.10–1.38, P<0.01; heterozygote comparison, OR = 1.12, 95%CI = 1.02–1.22, P = 0.02; recessive model, OR = 1.17, 95%CI = 1.07–1.29, P<0.01; dominant model, OR = 1.15, 95%CI = 1.06–1.25, P<0.01; allelic model, OR = 1.12, 95%CI = 1.06–1.18, P<0.01). Further sensitivity analysis confirmed the significant association. In the subgroup analysis by ethnicity, SMAD7 rs12953717 polymorphism was significantly associated with cancer risk in both Caucasians and Asians. In the subgroup analysis by cancer types, SMAD7 rs12953717 polymorphism was significantly associated with colorectal cancer.

Conclusions

Our investigations demonstrate that rs12953717 polymorphism is associated with the susceptibility of cancer. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.     

Hypoxia-Inducible Factor-1α Polymorphisms and Risk of Cancer Metastasis: A Meta-Analysis

Background

HIF-1α is a major regulator in tumor progression and metastasis which responds to hypoxia. Many studies have demonstrated that hypoxia-inducible factor1-α (HIF-1α) polymorphisms are significantly associated with cancer metastasis, but the results are inconsistent. We conducted a comprehensive meta-analysis to estimate the associations between HIF-1α C1772 T polymorphism and cancer metastasis.

Methods

Comprehensive searches were conducted on PubMed and EMBASE database. Fifteen studies were included in the meta-analysis. We used the OR and 95%CI to assess the associations between HIF-1α C1772T polymorphism and cancer metastasis. Heterogeneity and publication bias were also assessed by Q test, I ², and funnel plot.

Results

Totally, fifteen studies including 1239 cases with metastasis-positive (M+) and 2711 cases with metastasis-negative (M−) were performed in this meta-analysis. The results showed that HIF-1a C1772T polymorphism was associated with the increased risk of cancer metastasis (T allele vs. C allele, OR  = 1.36, 95% CI  = 1.12–1.64; TT+ TC vs. CC, OR  = 1.39, 95% CI  = 1.13–1.71; TT vs. TC+ CC, OR  = 1.93, 95% CI  = 0.86–4.36). In the subgroup analyses, the significant associations remained significant among Asians, Caucasians and other cancers in the dominant model. Publication bias was not observed in the analysis.

Conclusions

Our results indicate that the HIF-1αC1772T polymorphism T allele may increase the risk of cancer metastasis, which might be a potential risk factor of cancer progress.     

Association of Three Common Single Nucleotide Polymorphisms of ATP Binding Cassette G8 Gene with Gallstone Disease: A Meta-Analysis

Background

In this study, we evaluated the association between these polymorphisms and gallstone disease using meta-analysis and compared the hepatic ABCG5/G8 mRNA expression and biliary lipids composition in patients with different genotypes of T400K and Y54C.

Methods

Data were analyzed using the Stata/SE 11.0 software and a random- effects model was applied irrespective of between-study heterogeneity. Hepatic mRNA expression of ABCG5/G8 genes in 182 patients with gallstone disease and 35 gallstone-free patients who underwent cholecystectomy were determined using real-time PCR. Genotypes of Y54C and T400K in the ABCG8 gene were determined by allelic discrimination using either genomic DNA or hepatic cDNA as template by Taqman assays. Biliary compostion in gallbladder bile was assayed in these patients as well.

Results

Ten papers including 13 cohorts were included for the final analysis. In the genotype model, the overall association between genotype with gallstone was significant for D19H (OR = 2.43, 95%CI: 2.23–2.64, P<0.001), and for Y54C (OR = 1.36, 95%CI: 1.01–1.83, P = 0.044), or T400K (OR = 1.17, 95%CI: 0.96–1.43. P = 0.110). In allele model, minor alleles of D19H polymorphism (allele D: OR = 2.25, 95%CI: 2.10–2.42, P<0.001) and of T400K polymorphism (allele K: OR = 1.18, 95%CI: 1.06–1.31, P<0.001) were related with an increased risk of gallstone disease. However, minor allele of Y54C polymorphism (allele Y, OR = 1.08, 95%CI: 0.96–1.21, P = 0.146) was not related with gallstone disease. I ² statistics indicated no significant between-study heterogeneity for all genetic models for any of the three polymorphisms. Funnel plot and Egger’s test suggested the absence of publication bias as well. However, no association of T400K and Y54C polymorphism with hepatic ABCG8/G5 mRNA expression or biliary lipids composition was found.

Conclusions

Our study showed strong association of D19H polymorphism with gallstone disease. T400K and Y54C polymorphism, though to a less extent, may also relate with gallstone disease.     

Association of microRNA-499 rs3746444 Polymorphism with Cancer Risk: Evidence from 7188 Cases and 8548 Controls

Background

Owing to inconsistent and inconclusive results, we performed a meta-analysis to derive a more precise estimation of the association between miR-499 rs3746444 polymorphism and cancer risk.

Methodology/Principal Findings

A systematic search of the Pubmed, Excerpta Medica Database (Embase) and Chinese Biomedical Literature Database (CBM) databases was performed with the last search updated on May 6, 2012. The odds ratio (OR) and its 95% confidence interval (95%CI) were used to assess the strength of the association. A total of 15 independent studies including 7,188 cases and 8,548 controls were used in the meta-analysis. In the present meta-analysis, we found a significant association between miR-499 rs3746444 polymorphism and cancer risk in the overall analysis (G versus A: OR = 1.10, 95%CI 1.01–1.19, P = 0.03; GG+AG versus AA: OR = 1.15, 95%CI 1.02–1.30, P = 0.02; GG versus AG+AA: OR = 1.07, 95%CI 0.89–1.28, P = 0.50; GG versus AA: OR = 1.13, 95%CI 0.98–1.31, P = 0.09; AG versus AA: OR = 1.16, 95%CI 1.02–1.33, P = 0.03). In the subgroup analysis by ethnicity, miR-499 rs3746444 polymorphism was significantly associated with cancer risk in Asian population. In the subgroup analysis by cancer types, miR-499 rs3746444 polymorphism was significantly associated with breast cancer.

Conclusions/Significance

This meta-analysis suggests a significant association between miR-499 rs3746444 polymorphism and cancer risk. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.     

Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40∶01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients

Purpose

To assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40∶01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS).

Methods

Three-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method.

Results

HALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR = 2.43; 95%CI: 1.53–3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40∶01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/10⁶ cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p = 0.006, reference category (ref.): ‘A+A’; OR for ‘A+B’ vs. ref.: 1.39 [0.69–2.80]; OR for ‘B+A’ vs. ref.: 2.16 [1.22–3.83]; OR for ‘B+B’ vs. ref.: 3.13, 95%CI: 1.54–6.35), (b) maximum viral load ≥5 log10 (OR: 2.55, 95%CI: 1.56–4.14, P = 0.001), (c) use of EFV (1.10 [1.00–1.21], P = 0.008, per year of use).

Conclusion

HALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40∶01 carriage in Caucasian patients with long-term exposure to stavudine.     

A Meta-Analysis of Apolipoprotein E Gene ε2/ε3/ε4 Polymorphism for Gallbladder Stone Disease

Background

Numerous studies have investigated the relationship between apolipoprotein (Apo) E gene polymorphisms and gallbladder stone disease (GSD) across ethnic populations; however, the results are often inconsistent. This meta-analysis aims to comprehensively evaluate the influence of a common ε2/ε3/ε4 polymorphism in Apo E gene on the risk of gallbladder stone disease.

Method

Data were analyzed using the RevMan software (V5.1) and a random-effects model was applied irrespective of between-study heterogeneity. Publication bias was weighed using the fail-safe number.

Results

There were 17 study populations totaling 1773 cases and 2751 controls for ε2/ε3/ε4 polymorphism of Apo E gene. Overall comparison of alleles ε2 with ε3 in all study populations yielded a 16% decreased risk for GSD (95% confidence interval [95% CI]: 0.68–1.05; P = 0.31; I² = 13%), and comparison of alleles ε4 with ε3 yielded a 25% increased risk (95% confidence interval [95% CI]: 0.97–1.61; P = 0.0003; I² = 63%). Subgroup analysis by study design indicated that the magnitude of association in hospital-based studies was largely significantly strengthened for ε4 allelic model (odds ratio [OR]  = 1.46; 95% CI: 1.05–2.02; p = 0.0007; I² = 65%). Subgroup analysis by age of controls indicated a remarkably significant elevation in the magnitude of association in age >50 subgroups in ε4 allelic model (OR = 1.50; 95% CI: 1.03–2.19; p = 0.0009; I² = 72%). Moreover, subgroup analysis by cases gender indicated a reduction in the magnitude of association in male<30% studies for E2/2 genotypic model (OR = 0.32; 95% CI: 0.07–1.49; p = 0.16; I² = 45%).

Conclusions

Our results reveal that Apo E gene ε4 allele is a risk factor of gallbladder stone disease, especially in elder people and Chinese population.     

Association between CD14 Promoter -159C/T Polymorphism and the Risk of Sepsis and Mortality: A Systematic Review and Meta-Analysis

Background

Recent studies on the association between CD14-159C/T polymorphism and sepsis showed inconclusive results. Accordingly, we conducted a comprehensive literature search and a meta-analysis to determine whether the CD14-159C/T polymorphism conferred susceptibility to sepsis or was associated with increased risk of death from sepsis.

Methodology

Data were collected from the following electronic databases: PubMed, Embase, Medline, Web of Knowledge, and HuGE Navigator, with the last report up to June 15, 2012. The odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of association. We summarized the data on the association between CD14-159C/T polymorphism and sepsis in the overall population and subgroup by ethnicity and sepsis subtype.

Principal Findings

A total of 16 studies on sepsis morbidity (1369 cases and 2382 controls) and 4 studies on sepsis mortality (731 sepsis patients) met the inclusion criteria for meta-analysis. Overall analysis showed no strong evidences of association with sepsis susceptibility under any genetic model. However, slight associations were found in Asian populations (dominant model: OR = 1.38, 95%CI = 0.96–1.98, P = 0.08) and septic shock patients (dominant model: OR = 1.72, 95%CI 1.05–2.83, P = 0.03; allelic model: OR = 1.52, 95%CI 1.09–2.12, P = 0.01) in the stratified analysis. Moreover, there was borderline association between CD14-159C/T and sepsis mortality under the dominant genetic model (OR = 1.44, 95%CI = 0.98–2.11, P = 0.06).

Conclusions/Significance

This meta-analysis suggests that the CD14-159C/T polymorphism may not be a significant susceptibility factor in the risk of sepsis and mortality. Only weak associations were observed in Asian populations and septic shock patients. More studies based on larger sample sizes and homogeneous sepsis patients are needed to confirm these findings.     

Pharmacogenetics of Efficacy and Safety of HCV Treatment in HCV-HIV Coinfected Patients: Significant Associations with IL28B and SOCS3 Gene Variants

Background and Aims

This was a safety and efficacy pharmacogenetic study of a previously performed randomized trial which compared the effectiveness of treatment of hepatitis C virus infection with pegylated interferon alpha (pegIFNα) 2a vs. 2b, both with ribavirin, for 48 weeks, in HCV-HIV coinfected patients.

Methods

The study groups were made of 99 patients (efficacy pharmacogenetic substudy) and of 114 patients (safety pharmacogenetic substudy). Polymorphisms in the following candidate genes IL28B, IL6, IL10, TNFα, IFNγ, CCL5, MxA, OAS1, SOCS3, CTLA4 and ITPA were assessed. Genotyping was carried out using Sequenom iPLEX-Gold, a single-base extension polymerase chain reaction. Efficacy end-points assessed were: rapid, early and sustained virological response (RVR, EVR and SVR, respectively). Safety end-points assessed were: anemia, neutropenia, thrombocytopenia, flu-like syndrome, gastrointestinal disturbances and depression. Chi square test, Student''s T test, Mann-Whitney U test and logistic regression were used for statistic analyses.

Results

As efficacy is concerned, IL28B and CTLA4 gene polymorphisms were associated with RVR (p<0.05 for both comparisons). Nevertheless, only polymorphism in the IL28B gene was associated with SVR (p = 0.004). In the multivariate analysis, the only gene independently associated with SVR was IL28B (OR 2.61, 95%CI 1.2–5.6, p = 0.01). With respect to safety, there were no significant associations between flu-like syndrome or depression and the genetic variants studied. Gastrointestinal disturbances were associated with ITPA gene polymorphism (p = 0.04). Anemia was associated with OAS1 and CTLA4 gene polymorphisms (p = 0.049 and p = 0.045, respectively), neutropenia and thromobocytopenia were associated with SOCS3 gene polymorphism (p = 0.02 and p = 0.002, respectively). In the multivariate analysis, the associations of the SOCS3 gene polymorphism with neutropenia (OR 0.26, 95%CI 0.09–0.75, p = 0.01) and thrombocytopenia (OR 0.07, 95%CI 0.008–0.57, p = 0.01) remained significant.

Conclusions

In HCV-HIV coinfected patients treated with PegIFNα and ribavirin, SVR is associated with IL28B rs8099917 polymorphism. HCV treatment-induced neutropenia and thrombocytopenia are associated with SOCS3 rs4969170 polymorphism.     

The Pro12Ala Polymorphism in the Peroxisome Proliferator-Activated Receptor Gamma-2 Gene (PPARγ2) Is Associated with Increased Risk of Coronary Artery Disease: A Meta-Analysis

Background

Contradictory results have been reported regarding the association between Pro12Ala polymorphism of PPARγ2 and coronary artery disease (CAD). We sought to estimate the inconsistent results by performing a comprehensive meta-analysis.

Methods

Studies in English or Chinese publications were identified by screening MEDLINE, Embase, CNKI, Wanfang and CBM. 22 studies including 8948 cases and 14427 controls were selected. A random-effects model was applied to combine the divergent outcomes of the individual studies, while addressing between-study heterogeneity and publication bias.

Results

The Pro12Ala polymorphism of control population followed Hardy-Weinberg equilibrium for all studies (P>0.05). Overall, a marginal increased risk of CAD under the recessive genetic model (AlaAla vs ProAla+ProPro: P = 0.04, OR = 1.31, 95%CI 1.01–1.69, P_{heterogeneity} = 0.67, I² = 0%) and the homozygote comparison (AlaAla vs ProPro: P = 0.04,OR = 1.30, 95%CI 1.01–1.68, P_{heterogeneity} = 0.68, I² = 0%) was observed. In the subgroup analysis by ethnicity, carriers of AlaAla homozygotes had a significant increased risk for CAD among Caucasians (AlaAla vs ProAla+ProPro: P = 0.01, OR = 1.45, 95%CI 1.08–1.96, P_{heterogeneity} = 0.48, I² = 0%; AlaAla vs ProPro: P = 0.02,OR = 1.44, 95%CI 1.07–1.93, P_{heterogeneity} = 0.46, I² = 0%). After dividing into population source, the CAD risk magnitude of hospital-based studies was distinctly strengthened under the recessive model (P = 0.03,OR = 1.85,95%CI 1.07–3.19, P_{heterogeneity} = 0.87,I² = 0%) and the homozygote comparison (P = 0.03,OR = 1.83, 95%CI 1.06–3.16, P_{heterogeneity} = 0.88, I² = 0%). There was no observable publication bias as reflected by funnel plot and Egger’s linear regression test (t = -0.12, P = 0.91).

Conclusion:

Our results demonstrated that the PPARγ2 Pro12Ala polymorphism might be risk-conferring locus for the progression of CAD among Caucasians, but not among Asians.