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.     

Association between microRNA Polymorphisms and Cancer Risk Based on the Findings of 66 Case-Control Studies

MicroRNAs (miRNAs) are small non-coding RNA molecules, which participate in diverse biological processes and may regulate tumor suppressor genes or oncogenes. Single nucleotide polymorphisms (SNPs) in miRNA may contribute to diverse functional consequences, including cancer development, by altering miRNA expression. Numerous studies have shown the association between miRNA SNPs and cancer risk; however, the results are generally debatable and inconclusive, mainly due to limited statistical power. To assess the relationship between the five most common SNPs (miR-146a rs2910164, miR-196a2 rs11614913, miR-499 rs3746444, miR-149 rs2292832, and miR-27a rs895919) and the risk cancer development, we performed a meta-analysis of 66 published case-control studies. Crude odds ratios at 95% confidence intervals were used to investigate the strength of the association. No association was observed between rs2910164 and cancer risk in the overall group. However, in stratified analysis, we found that either the rs2910164 C allele or the CC genotype was protective against bladder cancer, prostate cancer, cervical cancer, and colorectal cancer, whereas it was a risk factor for papillary thyroid carcinoma and squamous cell carcinoma of the head and neck (SCCHN). Further, rs11614913 was found to be significantly associated with decreased cancer risk, in particular, for bladder cancer, gastric cancer, and SCCHN. For miR-499, a significant association was found between the rs3746444 polymorphism and cancer risk in pooled analysis. In subgroup analysis, similar results were mainly observed for breast cancer. Finally, no association was found between rs2292832 and rs895919 polymorphisms and cancer risk in the overall group and in stratified analysis. In summary, miR-196a2 rs11614913, miR-146a rs2910164, and miR-499 rs3746444 are risk factors for cancer development, whereas mir-149 rs2292832 and miR-27a rs895919 are not associated with cancer risk.     

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

Background

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

Methods

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

Results

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

Conclusions

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

The Association between Four Genetic Variants in MicroRNAs (rs11614913, rs2910164, rs3746444, rs2292832) and Cancer Risk: Evidence from Published Studies

MicroRNAs (miRNAs) participate in diverse biological pathways and may act as either tumor suppressor genes or oncogenes. Single nucleotide polymorphisms (SNPs) in miRNA may contribute to cancer development with changes in the microRNA''s properties and/or maturation. Polymorphisms in miRNAs have been suggested in predisposition to cancer risk; however, accumulated studies have shown inconsistent conslusionss. To further validate determine whether there is any potential association between the four common SNPs (miR-196a2C>T, rs11614913; miR-146aG>C, rs2910164; miR-499A>G, rs3746444; miR-149C>T, rs2292832) and the risk for developing risk, a meta-analysis was performed according to the 40 published case-control studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the extent of the association. The results demonstrated that the rs11614913TT genotype was significantly associated with a decreased cancer risk, in particular with a decreased risk for colorectal cancer and lung cancer, or for Asian population subgroup. In addition, the rs2910164C allele was associated with decreased risk for esophageal cancer, cervical cancer, prostate cancer, and hepatocellular carcinoma (HCC), in particular in Asian population subgroup. Similarly, the rs3746444G allele was observed as a risk factor for cancers in the Asian population. It is concluded that two SNPs prsent in miRNAs(rs11614913TT, and rs2910164C) may protect against the pathogenesis of some cancers, and that the rs3746444 may increase risk for cancer.     

Association of the Genetic Polymorphisms in Pre-MicroRNAs with Risk of Ischemic Stroke in a Chinese Population

microRNA (miRNA) plays a role in the pathogenesis of ischemic stroke, and single nucleotide polymorphisms in miRNA genes may contribute to disease susceptibility. However, the effect of miR-146a, miR-196a2, and miR-499 polymorphisms on ischemic stroke susceptibility has been rarely reported. Using the TaqMan assay, we evaluated the association of hsa-miR-146a/rs2910164, hsa-miR-196a2/rs11614913, and hsa-miR-499/rs3746444 polymorphisms with the risk of ischemic stroke in a Chinese population with 531 ischemic stroke patients and 531 control subjects. Rs2910164 C/G genotypes were significantly associated with increased risk of ischemic stroke in different genetic model (homozygote comparison: OR = 2.00, 95% CI, 1.29–3.12, P = 0.002; additive model: OR = 1.35, 95% CI, 1.10–1.65, P = 0.004;dominant model: OR = 1.33, 95% CI, 1.00–1.75, P = 0.049; recessive model: OR = 1.82, 95% CI, 1.20–2.74, P = 0.004). Subjects with allele G of hsa-miR-146a/ rs2910164 also showed increased risk of ischemic stroke (OR = 1.33, 95% CI, 1.09–1.62, P = 0.005). Stratification analysis showed that the association between rs2910164 and the risk of ischemic stroke was more pronounced in subjects over 60 years old, females, non-drinkers, subjects without hypertension or diabetes mellitus. There were significant combined effects between miR-146a/rs2910164 and fasting glucose/low-density lipoprotein cholesterol levels on ischemic stroke susceptibility. However, we failed to find any association between the alleles/genotypes of rs11614913 T/C and ischemic stroke, respectively (P> 0.05). In summary, this study provides evidence that miR-146a/rs2910164 might be associated with a significantly increased risk of ischemic stroke in a Chinese population, and the combined effects between miRNA polymorphism and fasting glucose /blood lipid levels may contribute to stroke pathogenesis.     

Association between microRNA-146a, -499a and -196a-2 SNPs and non-small cell lung cancer: a case–control study involving 2249 subjects

MicroRNA (miR) acts as a negative regulator of gene expression. Many literatures have suggested that miRs may be involved in the process of cell proliferation, inflammation, oxidative stress, energy metabolism and epithelial–mesenchymal transition. Thus, miRs may be implicated in the occurrence of non-small cell lung cancer (NSCLC). In the current investigation, we included 2249 subjects (1193 NSCLC patients and 1056 controls) and designed a study to identify the relationship of miR-146a rs2910164 C/G, -499a rs3746444 A/G and -196a-2 rs11614913 T/C with the risk of NSCLC. The risk factors (e.g., body mass index (BMI), sex, smoking, drinking and age) was used to adjust the odds ratios (ORs) and 95% confidence intervals (CIs). After conducting a power value assessment, we did not confirm that the miR-single nucleotide polymorphisms (SNPs) genotypic distributions were different in NSCLC cases and controls. However, the association of miR-196a-2 rs11614913 with a decreased risk of NSCLC was identified in the female subgroup (adjusted P=0.005, power = 0.809 for TC vs. TT, and adjusted P=0.004, power = 0.849 for CC/TC vs. TT). In addition, gene–gene interaction analysis showed that rs11614913 TC/3746444 AA and rs11614913 CC/rs3746444 AA could also reduce the susceptibility to NSCLC (rs11614913 TC/rs3746444 AA vs. rs11614913 TT/rs3746444 AA, P=0.001, power = 0.912 and rs11614913 CC/rs3746444 AA vs. rs11614913 TT/rs3746444 AA, P=0.003, power = 0.836). In conclusion, in overall comparisons, we did not confirm that the rs2910164, rs3746444, and rs11614913 SNPs genotypic distributions were different in NSCLC cases and controls. However, this case–control study demonstrates that miR-196a-2 rs11614913 may be a protective factor for the development of NSCLC among female patients.     

The association between common genetic variant of microRNA-499 and cancer susceptibility: a meta-analysis

Published data on the association between microRNA-499 (miR-499) rs3746444 T>C polymorphism and cancer susceptibility are inconclusive. To derive a more precise estimation of this relationship, a comprehensive meta-analysis was performed on nine published studies, with a total sample of 4,794 cases and 5,971 controls. Overall, no significant association was found between miR-499 polymorphism and cancer risk after all studies were pooled into the meta-analysis. However, in the subgroup analysis by ethnicity, significant association with an increased risk was found in Asian (CC vs. TT: OR = 1.439, 95 % CI = 1.118–1.852, P = 0.005, p-heterogeneity = 0.116). Moreover, in the the subgroup analysis by cancer type, this SNP was associated with an increased risk of breast cancer in the recessive model (OR = 1.077, 95 % CI = 1.008–1.151, P = 0.028, p-heterogeneity = 0.125). Our findings support the view that miR-499 rs3746444 T>C polymorphism is associated with breast cancer and the C allele can increase cancer susceptibility in Asian.     

Effects of common polymorphisms rs2910164 in miR-146a and rs3746444 in miR-499 on cancer susceptibility: a meta-analysis

MicroRNAs (miRNAs) are a class of new non-coding RNA, which may play a more important role in the pathogenesis of human cancers. Rs2910164 in miR-146a and rs3746444 in miR-499 are shown to be associated with increased/decreased cancer risk. We performed a meta-analysis to systematically summarize the possible association. We retrieved the relevant articles from PubMed databases. Studies were selected using specific inclusion and exclusion criteria. ORs and 95% CIs were calculated to access the strength of association between microRNA polymorphism and cancer risk. All analyses were performed using the Stata software. Twenty-nine studies were included in this meta-analysis. There were not significant associations between miR-146a rs2910164 and miR-499 rs3746444 polymorphisms with overall cancer risk. In the subgroup analysis by ethnicity, significantly affected cancer risks were found among Asians for both rs2910164 (GC vs. GG: OR = 0.89, 95% CI = 0.82–0.96; CC vs. GG: OR = 0.80, 95% CI = 0.66–0.97; GC + CC vs. GG: OR = 0.86, 95% CI = 0.76–0.97; C vs. G: OR = 0.91, 95% CI = 0.82–1.00) and rs3746444 (GG + AG vs. AA: OR = 1.21, 95% CI = 1.00–1.46). In the tumor type subgroup analysis, rs2910164 C allele decreased the risk of hepatocellular carcinoma (C vs. G: OR = 0.89, 95% CI = 0.80–1.00) and cervical squamous cell carcinoma (C vs. G: OR = 0.72, 95% CI = 0.62–0.84). The rs2910164 in miR-146a and the rs3746444 in miR-499 are likely to be associated with cancer risk.     

Polymorphisms of microRNA Sequences or Binding Sites and Lung Cancer: A Meta-Analysis and Systematic Review

Objective

Functional single nucleotide polymorphisms (SNPs) of microRNA (miRNA) sequences or binding sites (miRNA-SNPs) are associated with lung cancer risk and survival. The objective of this study was to systematically review genetic association studies about miRNA-SNPs in lung cancer.

Methods

Eligible genetic association studies were retrieved from databases of PubMed, EMBASE, China National Knowledge Infrastructure and SinoMed. Two investigators selected related studies and assessed methodological quality independently. Quantitative data synthesis was conducted for common SNPs of miRNA (miRNA-196a2 rs11614913, miRNA146a rs2910164, miRNA149 rs2292832, miRNA-605 rs2043556 and miRNA499 rs3746444). GRADE profiler was used to grade the quality of evidence for each miRNA-SNP.

Results

15 eligible studies and 27 miRNA-SNPs were retrieved and 10 miRNA-SNPs were reported with a significant association with susceptibility to or survival of lung cancer. Methodological quality of eligible studies was adequate with an average score of 8.5. miRNA-196a2 rs11614913 polymorphism was associated with increased lung cancer risk (homozygote comparison, OR = 1.299, 95% CI: 1.096–1.540; dominant model, OR = 1.217, 95% CI: 1.041–1.421) and decreased survival. And according to GRADE profiler, quality of evidence was moderate for MYCL1 rs3134615, while quality of the other significant associations was low.

Conclusions

Based on this first systematic review about miRNA-SNPs in lung cancer, quality of evidence was low for most genetic association studies. Polymorphisms of miRNA-196a2 rs11614913 and MYCL1 rs3134615 could be potential biomarkers of lung cancer.     

The correlation of microRNA-499 rs3746444 T>C locus with the susceptibility of gastric cancer: from a case–control study to a meta-analysis

The relationship between rs3746444 T>C single-nucleotide polymorphism (SNP) in microRNA (mir)-499 and risk of gastric cancer (GC) has been widely investigated. However, the association was still unconfirmed. Here, we first recruited 490 GC patients and 1476 controls, and conducted a case-control study. And we did not find any association between rs3746444 T>C SNP polymorphism and risk of GC. Subsequently, we conducted a meta-analysis to explore the association of mir-499 rs3746444 polymorphism with GC development. Two authors searched the PubMed and EMBASE databases up to October 15, 2019 independently. Finally, nine literatures involving 12 independent studies were included. In total, 3954 GC cases and 9745 controls were recruited for meta-analysis. The results suggested that allele model, homozygote model and recessive model could increase the risk of overall GC (P = 0.002, 0.009 and 0.013, respectively). When we excluded the studies violated HWE, this association was also found in allele model (P = 0.020) and dominant model (P= 0.044). In subgroup analyses, we identified that rs3746444 SNP in mir-499 increased the risk of GC in Asians and gastric cardiac adenocarcinoma (GCA) subgroups. No significant bias of selection was found (all P>0.1). Test of sensitivity analysis indicated that our findings were stable. Additionally, we found that the power value was 0.891 in the allele model, suggesting the reliability of our findings. In summary, our analysis confirmed the association between rs3746444 and the risk of GC, especially in Asians and in patients with GCA.     

miR-499 rs3746444 polymorphism is associated with cancer development among Asians and related to breast cancer susceptibility

To derive a more precise estimation of the relationship between miR-499 rs3746444 polymorphism (A>G) and cancer risk, a meta-analysis was performed. A total of 9 studies including 6,077 cases and 7,199 controls were involved in this meta-analysis. Overall, no significantly elevated cancer risk was associated with miR-499 G allele when all studies were pooled into the meta-analysis (AG vs. AA: OR?=?1.14, 95?% CI?=?0.98–1.32; GG vs. AA: OR?=?1.12, 95?% CI?=?0.95–1.33; dominant model: OR?=?1.13, 95?% CI?=?0.99–1.29; recessive model: OR?=?1.05, 95?% CI?=?0.83–1.33). In the subgroup analysis by ethnicity, significantly increased risk was only found for Asians (dominant model: OR?=?1.22, 95?% CI?=?1.02–1.46). When stratified by study design, no statistically significantly elevated risks were found in hospital-based studies or population-based studies. In the subgroup analysis by cancer type, significant cancer risk change was only found for breast cancer when miR-499 G allele was included (dominant model: OR?=?1.13, 95?% CI?=?1.01–1.26). In conclusion, this meta-analysis suggests that the miR-499 rs3746444 polymorphism (A>G) is a low-penetrant risk factor for cancer development among Asians and may contribute to breast cancer susceptibility.     

Prognostic Role of Common MicroRNA Polymorphisms in Cancers: Evidence from a Meta-Analysis

Background

The morbidity and mortality of cancer increase remarkably every year. It''s a heavy burden for family and society. The detection of prognostic biomarkers can help to improve the theraputic effect and prolong the lifetime of patients. microRNAs have an influential role in cancer prognosis. The results of articles discussing the relationship between microRNA polymorphisms and cancer prognosis are inconsistent.

Methods

We conduct a meta-analysis of 19 publications concerning the association of four common polymorphisms, mir-146a rs2910164, mir-149 rs2292832, mir-196a2 rs11614913 and mir-499 rs3746444, with cancer prognosis. Pooled Hazard Ratios with 95% Confidence Intervals for the relationship between four genetic polymorphisms and Overall Survival, Recurrence-free Survival, Disease-free survival, recurrence are calculated. Subgroup analysis by population and type of tumor are conducted.

Results

GG genotype of mir-146a may be the protective factor for overall survival, especially in Caucasian population. C-containing genotypes of mir-196a2 act as a risk role for overall survival. The same result exists in Asian population, in Non-Small Cell Lung Cancer and digestive cancer. The patients with C allele of mir-149 have a better overall survival, especially in Non-Small Cell Lung Cancer. No significant results are obtained for mir-499 polymorphisms.

Conclusions

Genetic polymorphisms in mir-146a, mir-196a2 and mir-149 may be associated with overall survival. This effect varies with different types of cancer. Genetic polymorphism in mir-499 may have nothing to do with cancer prognosis.     

Hsa-miR-499 rs3746444 Polymorphism Contributes to Cancer Risk: A Meta-Analysis of 12 Studies

Background

Single nucleotide polymorphisms (SNPs) occurred in pre-microRNAs or targets of microRNAs (miRs) may contribute to cancer risks. Since 2007, many studies have investigated the association between common SNPs located on hsa-miR-499 (rs3746444) and cancer risks; however, the results were inconclusive.

Methodology/Principal Findings

We conducted a meta-analysis of 12 studies that included 5765 cases and 7076 controls to identify the strength of association. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, individuals with the variant AG (OR = 1.215, 95% CI: 1.027, 1.437; P_{heterogeneity}<0.01) and AG/GG (OR = 1.227, 95% CI: 1.046, 1.439; P_{heterogeneity}<0.01) genotypes were associated with a significantly increased risk of cancer than those with wild AA genotype. Sub-group analysis revealed that the variant AG (OR = 1.411, 95% CI: 1.142, 1.745; P_{heterogeneity} = 0.01) and AG/GG (OR = 1.413, 95% CI: 1.163, 1.717, P_{heterogeneity} = 0.01) genotypes still showed an increased risk of cancer in Asians; however, a trend of reduced risk of cancer was observed in Caucasians (AG vs. AA: OR = 0.948, 955 CI: 0.851, 1.057, P_{heterogeneity} = 0.12; AG/GG vs. AA: OR = 0.959, 95% CI: 0.865, 1.064; P_{heterogeneity} = 0.19). Meta-regression showed that ethnicity (p = 0.048) and sample size (p = 0.02) but not cancer types (p = 0.89) or source of control (p = 0.97) were the sources of heterogeneity.

Conclusions

These meta-analysis results suggest that hsa-miR-499 polymorphism rs3746444 is associated with a significantly increased risk of cancer, especially in Asian populations.     

HIF-1α 1772 C/T and 1790 G/A Polymorphisms Are Significantly Associated with Higher Cancer Risk: An Updated Meta-Analysis from 34 Case-Control Studies

Background

HIF-1 activates various genes in cancer progression and metastasis. HIF-1α 1772 C/T and 1790 G/A polymorphisms are reportedly associated with cancer risk; however, the results are inconclusive.

Methodology/Principal Findings

A meta-analysis of 34 studies that involved 7522 cases and 9847 controls for 1772 C/T and 24 studies that involved 4884 cases and 8154 controls for 1790 G/A was conducted to identify the association of C/T and G/A polymorphisms with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association.HIF-1α 1772 C/T and 1790 G/A polymorphisms were associated with higher cancer risk in homozygote comparison (1772C/T: TT vs. CC: OR = 2.45, 95% CI: 1.52, 3.96; P _{heterogeneity} = 0.028; 1790G/A: AA vs. GG: OR=4.74, 95% CI: 1.78, 12.6; P _{heterogeneity} < 0.01), dominant model (1772C/T: TT/CT vs. CC: OR = 1.27, 95% CI: 1.04, 1.55; P _{heterogeneity} < 0.01, 1790G/A: AA/GA vs. GG: OR = 1.65, 95% CI: 1.05, 2.60; P _{heterogeneity} < 0.01), T allele versus C allele (T vs. C: OR = 1.42, 95% CI: 1.18, 1.70; P _{heterogeneity} < 0.01), and A allele versus G allele (A vs. G: OR = 1.83, 95% CI: 1.13, 2.96; P _{heterogeneity} < 0.01). On a subgroup analysis, the 1772 C/T polymorphism was significantly linked to higher risks for breast cancer, lung cancer, prostate cancer, and cervical cancer, whereas the 1790 G/A polymorphism was significantly linked to higher risks for lung cancer and prostate cancer. A significantly increased cancer risk was found in both Asians and Caucasians for 1772C/T polymorphism, whereas a significantly increased cancer risk was found in Caucasians in the heterozygote comparison and recessive model for 1790G/A polymorphism.

Conclusions

HIF-1α 1772 C/T and 1790 G/A polymorphisms are significantly associated with higher cancer risk.     

The -607C/A Polymorphisms in Interleukin-18 Gene Promoter Contributes to Cancer Risk: Evidence from A Meta-Analysis of 22 Case-Control Studies

Background

Several observational studies have investigated the association between -607 C/A polymorphism of IL-18 gene and cancer risk; however, the results were inconsistent. Therefore, we performed a meta-analysis to derive a more precise estimation of the association to help us better understand the relationship between -607 C/A polymorphism of IL-18 gene promoter and risk of cancer.

Methods

A literature search was carried out using PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) database between January 1966 and February 2013. Fixed-effect and random-effect models were used to estimate the pooled odds ratio (OR) and the corresponding 95% confidence intervals (CIs).

Results

A total of 22 case-control studies including 4100 cancer cases and 4327 controls contributed to the analysis. Significant association between -607C/A polymorphism in IL-18 gene promoter and cancer risk was observed (CA vs CC:OR =1.221, 95% CI: 1.096, 1.360; P_{heterogeneity}=0.219; AA/CA vs. CC:OR =1.203, 95% CI: 1.057, 1.369; P_{heterogeneity}=0.064). In the subgroup analysis by ethnicity, -607C/A polymorphism significantly increased risk of cancer among Asian population (AA/CA vs. CC:OR =1.197, 95% CI: 1.023,1.401; P_{heterogeneity}=0.088); however, no significant association was found in Caucasian or African population. The -607C/A polymorphism was associated with a significantly increased risk of nasopharyngeal carcinoma (CA vs CC:OR =1.330, 95% CI: 1.029,1.719; P_{heterogeneity}=0.704; AA/CA vs. CC:OR =1.323, 95% CI: 1.037,1.687; P_{heterogeneity}=0.823) and esophageal cancer (AA/CA vs. CC:OR =1.289, 95% CI: 1.002,1.658; P_{heterogeneity}=0.700).

Conclusions

The present meta-analysis suggests that the -607C/A polymorphisms in IL-18 gene promoter is associated with a significantly increased risk of cancer, especially for nasopharyngeal carcinoma and esophageal cancer and in Asian population. More studies with larger sample size, well controlled confounding factors are warranted to validate this association.     

The Association between Two Common Polymorphisms in MicroRNAs and Hepatocellular Carcinoma Risk in Asian Population

Background

Emerging evidence has shown that microRNAs (miRNAs) participate in human carcinogenesis as tumor suppressors or oncogenes. Single nucleotide polymorphism (SNP) located in the miRNAs may influence the function of mature miRNAs and then affect the processing of carcinogenesis. It has been suggested that two common SNPs rs2910164 in miR-146a and rs3746444 in miR-499 are associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. To acquire a more precise effect of the association between these polymorphisms and HCC risk, we performed this meta-analysis.

Methodology/Principal Findings

We have conducted a search of case-control studies on the associations of SNPs rs2910164 and/or rs3746444 with susceptibility to HCC in PubMed, ScienceDirect, Cochrane Central Register of Controlled Trials, and Chinese National Knowledge Infrastructure databases for the period up to Sep 10th, 2012. A total of 6 studies were identified with 2071 cases and 2350 controls for miR-146a rs2910164 polymorphism, 667 cases and 1006 controls for miR-499 rs3746444 polymorphism. It was found that neither allele frequency nor genotype distribution of the two polymorphisms was associated with risk of HCC in all genetic models. Similarly, subgroup analysis in Asian population showed no associations between the two SNPs and the susceptibility to HCC.

Conclusions/Significance

This meta-analysis suggests that miR-146a rs2910164 and miR-499 rs3746444 polymorphisms may not be associated with the risk of HCC, especially for Asian population. However, well-designed studies with larger sample size and more detailed data are needed to confirm these conclusions.     

Relationships between the Osteocalcin Gene Polymorphisms,Serum Osteocalcin Levels,and Hepatitis B Virus-Related Hepatocellular Carcinoma in a Chinese Population

Background

Available evidence has demonstrated that osteocalcin may play a role in pathogenesis of cancer, and mutation of the osteocalcin gene may be involved in the cancer development. The aim of this study is to determine whether osteocalcin gene polymorphisms are associated with hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) among Chinese population.

Methods

A total of 515 subjects were divided into four groups: 129 patients with chronic hepatitis B (CHB), 62 patients with HBV-related liver cirrhosis (LC), 154 patients with HBV-related HCC, and 170 healthy controls. The polymerase chain reaction-restriction fragment length polymorphism strategy was used to detect osteocalcin gene rs1800247 and rs1543297 polymorphisms.

Results

Compared with healthy controls, the rs1800247 HH and Hh genotypes were associated with a significantly increased susceptibility to HCC (HH versus hh: OR = 6.828, 95% CI 2.620–17.795, P <0.001; Hh versus hh: OR = 6.306, 95% CI 3.480–11.423, P <0.001, respectively). Similarly, the subjects bearing the H allele of rs1800247 had more than a 2.4-fold increased risk for development of HCC (OR = 2.484, 95% CI 1.747–3.532, P <0.001) compared with those bearing the h allele. In addition, we found significant decreased serum osteocalcin levels in HBV-related HCC patients (11.73±8.18 ng/mL) compared with healthy controls (15.3±6.06 ng/mL). Furthermore, the serum osteocalcin levels were significantly lower in HCC patients than healthy controls among the individuals with heterozygous Hh genotype (P = 0.003) and CT genotype (P <0.001). In contrast, there were no significant differences in the genotype and allele of rs1543297 polymorphisms between the groups of patients and healthy controls.

Conclusions

These findings for the first time suggest that genetic variant in osteocalcin gene rs1800247 polymorphisms may be a risk factor for HBV-related HCC. We also find an inverse association of serum osteocalcin levels with HCC.     

Variants of MIRNA146A rs2910164 and MIRNA499 rs3746444 are associated with the development of cutaneous leishmaniasis caused by Leishmania guyanensis and with plasma chemokine IL-8

Leishmania are intracellular protozoan parasites that cause a wide spectrum of clinical manifestations in genetically susceptible individuals with an insufficient or balanced Th1 immune response to eliminate the parasite. MiRNAs play important regulatory role in numerous biological processes including essential cellular functions. miR146-a acts as an inhibitor of interleukin 1 receptor associated kinase 1 (IRAK1) and tumour necrosis factor (TNF) receptor associated factor 6 (TRAF6) present in the toll-like receptors pathway while miR499a modulates TGF-β and TNF signalling pathways. Here, we investigated whether MIRNA146A rs2910164 and MIRNA499 rs3746444 variants are associated with the development of L. guyanensis (Lg)-cutaneous leishmaniasis (CL). The variants MIR146A rs2910164 and MIR499A rs3746444 were assessed in 850 patients with Lg-CL and 891 healthy controls by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Plasma cytokines were measured using the BioPlex assay. Carriers of rs2910164 CC genotype have 30% higher odds of developing CL (ORadj_age/sex = 1.3 [95%CI 0.9–1.8]; Padj_age/sex 0.14) compared to individuals with the genotype GG (ORadj_age/sex = 0.77 [95%CI 0.56–1.0]; Padj_age/sex 0.14) if exposed to Lg-infection. Heterozygous GC individuals also showed lower odds of developing CL (ORadj_age/sex = 0.77 [95%CI 0.5–1.1]; Padj_age/sex 0.09). Homozygosity for the allele C is suggestive of an association with the development of Lg-CL among exposed individuals to Lg-infection. However, the odds of developing CL associated with the CC genotype was evident only in male individuals (OR_adjage = 1.3 [95% CI = 0.9–2.0]; P_adjage = 0.06). Individuals homozygous for the G allele tend to have higher plasma IL-8 and CCL5. Similarly, for the MIR499A rs3746444, an association with the G allele was only observed among male individuals (OR = 1.4 [1.0–1.9]; P = 0.009). In a dominant model, individuals with the G allele (GG-GA) when compared to the AA genotype reveals that carriers of the G allele have 40% elevated odds of developing Lg-CL (ORadj_age = 1.4 [1.1–1.9]). Individuals with the GG genotype have higher odds of developing Lg-CL (ORadj_age/sex = 2.0 [95%CI 0.83–5.0]; P_adjage = 0.01. Individuals homozygous for the G allele have higher plasma IL-8. Genetic combinations of both variants revealed that male individuals exposed to Lg bearing three or four susceptible alleles have higher odds of developing Lg-CL (OR = 2.3 [95% CI 1.0–4.7]; p = 0.017). Both MIR146A rs2910164 and MIR499A rs3746444 are associated with the development of Lg-CL and this association is prevalent in male individuals.     

Two Functional Variants of IRF5 Influence the Development of Macular Edema in Patients with Non-Anterior Uveitis

Objective

Interferon (IFN) signaling plays a crucial role in autoimmunity. Genetic variation in interferon regulatory factor 5 (IRF5), a major regulator of the type I interferon induction, has been associated with risk of developing several autoimmune diseases. In the current study we aimed to evaluate whether three sets of correlated IRF5 genetic variants, independently associated with SLE and with different functional roles, are involved in uveitis susceptibility and its clinical subphenotypes.

Methods

Three IRF5 polymorphisms, rs2004640, rs2070197 and rs10954213, representative of each group, were genotyped using TaqMan® allelic discrimination assays in a total of 263 non-anterior uveitis patients and 724 healthy controls of Spanish origin.

Results

A clear association between two of the three analyzed genetic variants, rs2004640 and rs10954213, and the absence of macular edema was observed in the case/control analysis (P _FDR=5.07E-03, OR=1.48, CI 95%=1.14-1.92 and P _FDR=3.37E-03, OR=1.54, CI 95%=1.19-2.01, respectively). Consistently, the subphenotype analysis accordingly with the presence/absence of this clinical condition also reached statistical significance (rs2004640: P=0.037, OR=0.69, CI 95%=0.48-0.98; rs10954213: P=0.030, OR=0.67, CI 95%=0.47-0.96), thus suggesting that both IRF5 genetic variants are specifically associated with the lack of macular edema in uveitis patients.

Conclusion

Our results clearly showed for the first time that two functional genetic variants of IRF5 may play a role in the development of macular edema in non-anterior uveitis patients. Identifying genetic markers for macular edema could lead to the possibility of developing novel treatments or preventive therapies.