Associations between vitamin D receptor polymorphisms and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis

The aim of this study was to determine whether the vitamin D receptor (VDR) polymorphisms confer susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematous (SLE). A meta-analysis was conducted on the associations between the BsmI, TaqI, FokI, and ApaI polymorphisms of VDR and RA or SLE using: (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) additive model. A total of ten studies, six RA and four SLE studies, were considered in the meta-analysis. Meta-analysis of the VDR BsmI and TaqI polymorphisms showed no association between RA in all subjects, or in European or Asian subjects. In contrast, meta-analysis of the F allele, the FF genotype, and the FF vs. the ff genotype of the FokI polymorphism showed significant associations with RA in Europeans. The overall OR of the association between the F allele and RA was 1.502 (95% CI = 1.158–1.949, P = 0.002). Meta-analysis of the B allele, BB + Bb genotype, and BB genotype (additive model) of the BsmI polymorphism showed significant associations with SLE and LN in Asians. The overall ORs of the associations between the B allele and SLE and LN were 3.584 (95% CI = 1.407–9.130, P = 0.007) and 3.652 (95% CI = 1.347–9.902, P = 0.011). This meta-analysis demonstrates that the VDR FokI polymorphism may confer susceptibility to RA in Europeans. Furthermore, associations were found between the VDR BsmI polymorphism and susceptibilities to SLE and LN in Asians.     

Association of IL-10-1082 promoter polymorphism with susceptibility to gastric cancer: evidence from 22 case–control studies

Evidence suggested that interleukin-10 (IL-10) may be involved in the etiology of gastric cancer (GC). However, epidemiological studies on the association between IL-10-1082 promoter polymorphism and GC risk are still ambiguous. To quantitatively summarize the evidence for such a relationship, we performed a meta-analysis. Systemic searches of the PubMed and Medline databases were performed, with the last report up to July 2011. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. 22 independent studies including 4,289 cases and 5,965 controls were involved in this meta-analysis. Obvious association was found when all studies were pooled into the meta-analysis (A vs. G: OR = 0.489, 95% CI = 0.335–0.713, P < 0.001). In the subgroup analysis by ethnicity, we observed significant associations in Asians (A vs. G: OR = 0.651, 95% CI = 0.506–0.838, P = 0.001; AA vs. GG: OR = 0.482, 95% CI = 0.328–0.709, P < 0.001; AA/AG vs. GG: OR = 0.711, 95% CI = 0.527–0.959, P = 0.025; AA vs. AG/GG: OR = 0.701, 95% CI = 0.520–0.944, P = 0.019) and Caucasians (A vs. G: OR = 0.365, 95% CI = 0.140–0.949, P = 0.039), but not in Latino population. When stratified analysis by control sources, our results indicated that A allele decreased approximately 48% risk among population-based studies (A vs. G: OR = 0.524, 95% CI = 0.374–0.733, P < 0.001). Taken together, this meta-analysis suggests that IL-10-1082 polymorphism is associated with GC risk.     

Current evidences on vascular endothelial growth factor polymorphisms and breast cancer susceptibility

Several polymorphisms of vascular endothelial growth factor (VEGF) such as 936 C/T, −2578 C/A, −406 C/T, and −1154 G/A polymorphism have been identified. Published data on the association between VEGF polymorphisms and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude OR with 95% CI was used to assess the strength of association between them. For VEGF 936C/T polymorphism, a total of 10 studies including 7,685 cases and 7,915 controls were involved in this meta-analysis. Overall, no significant associations were found between VEGF 936C/T polymorphism and breast cancer risk when all studies pooled into the meta-analysis (TC vs. CC: OR = 0.904, 95% CI = 0.797–1.024; TT vs. CC: OR = 0.974, 95% CI = 0.786–1.205; dominant model: OR = 0.911, 95% CI = 0.811–1.024; and recessive model: OR = 0.991, 95% CI = 0.801–1.226). In the subgroup analysis by ethnicity, still no significant associations were found for all comparison models. For −2578 C/A, −406 C/T, and −1154 G/A polymorphism, there were too limited data to perform a meta-analysis. In conclusion, this meta-analysis suggests that the VEGF 936C/T polymorphism may be not associated with breast cancer development. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding.     

The association between the PTPN22 C1858T polymorphism and rheumatoid arthritis: a meta-analysis update

The aim of this study was to determine whether the protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. A meta-analysis was conducted on the PTPN22 C1858T polymorphism involving eighteen studies, which in total contained 20344 RA patients and 21828 controls. Meta-analysis revealed an association between the PTPN22 C1858T polymorphism T allele and RA in all subjects (odds ratio [OR] = 1.637, 95% confidence interval [CI] = 1.514–1.770, P < 0.001). After stratification by ethnicity, analysis indicated that the PTPN22 C1858T polymorphism T allele was significantly associated with RA in Europeans and Non-Europeans (OR = 1.587, 95% CI = 1.486–1.696, P < 0.001; OR = 1.748, 95% CI = 1.274–2.398, P < 0.001). Meta-analysis of the CT + TT genotype showed the same result patterns as that shown by the PTPN22 C1858T polymorphism T allele. Furthermore, a direct comparison between rheumatoid factor (RF)-positive and -negative subjects revealed a significant association with the T allele in RA patients with RF, but not in subjects without RF. In conclusion, this meta-analysis confirms that the PTPN22 C1858T polymorphism is associated with RA susceptibility in different ethnic groups, especially in Europeans, and the PTPN22 C1858T polymorphism T allele is significantly more prevalent in RF-positive patents than in RF-negative patients.     

Survivin promoter ?31G/C (rs9904341) polymorphism and cancer susceptibility: a meta-analysis

This study aimed to perform a meta-analysis to assess the association of survivin −31 G/C promoter polymorphism and cancer risk. Thirteen case–control studies identified through PubMed and published between 2007 and 2011 with a total of 3329 cancer cases and 3979 controls were included in this meta-analysis. Odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Overall, the pooled analysis showed that survivin −31C allele was associated with 1.27 fold increased risk of cancer compared with the −31G allele (95% CI = 1.091–1.479; random model). Subgroup analyses based on type of cancer and ethnicity were also performed, and results indicated that survivin −31G/C polymorphism was not associated with risk of gastric cancer [OR = 2.879; 95% CI = 0.553–15.004) for CC vs.GG] and esophageal cancer [OR = 1.352; 95% CI = 0.494–3.699) for CC vs.GG]. Stratification on the basis of ethnicity showed that the risk due to −31C allele was significant only in Asian population [OR = 1.894; 95% CI = 1.206–2.974 for CC vs.GG]. The present meta-analysis suggests an important role of survivin −31 G/C polymorphism with cancer risk especially in Asian population. However, further studies with larger sample size are required to draw more comprehensive conclusions and provide more precise evidence in individual cancers.     

Association of polymorphisms in the human IL-10 and IL-18 genes with rheumatoid arthritis

The decrease of anti-inflammatory cytokine and increase of pro-inflammatory cytokine was observed in rheumatoid arthritis (RA). Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, has been demonstrated to suppress joint swelling and deformation in RA animal model. Interleukin-18 (IL-18), a widely distributed pro-inflammatory cytokine, induces the production of IFN-γ, activate NK cells, and promote inflammation. Recent studies demonstrated that the serum IL-10 and IL-18 levels may be influenced by genetics and related to susceptibility to several autoimmune diseases. In the present study, using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing techniques, we analyzed the genotype and allele distributions of two single nucleotide polymorphisms (SNP) loci in the promoter region of IL-10 and IL-18 genes (IL-10-592 A/C and IL-18-607 A/C loci, respectively). Our results indicated that IL-10-592 allelic and genotypic frequencies were significantly different between the RA patients and normal subjects (P < 0.05). In addition, significant differences of IL-10-592 allelic and genotypic frequencies were also detected between the patients with or without anti-cyclic citrullinated peptide antibody (anti-CCP) (P < 0.05). In contrast, allelic and genotypic frequencies of IL-18-607 did not show significant difference between RA patients and normal subjects (P > 0.05) or between anti-CCP-positive and anti-CCP-negative RA patients (P > 0.05). Furthermore, ELISA detection of IL-10 and IL-18 serum levels revealed that the genotype of IL-10-592 was associated with IL-10 serum level (P < 0.05), but the genotype and allele frequency of IL-18-607 was not associated with IL-18 serum level (P > 0.05). Taken together, our findings provide new insight for the polymorphism of IL-10 gene in the pathogenesis of RA.     

Meta-analysis of association between cytokine gene polymorphisms and lung cancer risk

The aim of this study was to evaluate the association between various cytokine gene polymorphisms and lung cancer (LC) susceptibility. We searched Pubmed, Elsevier Science Direct, China National Knowledge Infrastructure database, Chinese Biomedical database, Google scholar. Totally, 20 studies involving 6,467 cases and 8,320 controls were included in the meta-analysis. The effects of eight polymorphisms, i.e. TNF-α 308G/A, IL-6 174G/C, IL-1β 31T/C, IL-1β 511C/T, COX-2 8473T/C, IL-10 1082G/A, IL-10 819C/T, and IL-10 592C/A were evaluated. The combined odds ratio (OR) with 95% confidence interval (95% CI) was calculated to estimate the strength of the association in a fixed or random effect model. Heterogeneity and publication bias were also assessed. We found a significant association between IL-10 polymorphism and LC. For IL-10 1082G/A, the overall ORs (95% CI) of the G versus A, GG versus AA, and GG/GA versus AA were 2.35 (1.16–4.76), 2.07 (1.16–3.70) and 3.17 (1.31–7.68), respectively. For IL-10 819C/T, the pooled ORs (95% CI) of the C versus T and CC versus TT were 1.27 (1.01–1.58) and 2.27 (1.32–3.89). For IL-10 592C/A, the comparison of subjects in the CC or CC/CA genotype versus AA homozygotes showed significant results (OR = 2.00, 95% CI: 1.24–3.23; OR = 1.80, 95% CI: 1.28–2.54). But, other gene polymorphisms did not reach statistical associations. IL-10 1082G/A, 819C/T and 592C/A polymorphisms might be risk factors for LC. TNF-α 308G/A, IL-6 174G/C, IL-1β 31T/C, IL-1β 511C/T, COX-2 8473T/C polymorphisms were not detected to be related to the risk for LC. Due to the limitation of the number of the studies, we should take the conclusion with caution. While, further studies are necessary for more precise association.     

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.     

The Ku70 ?1310C/G promoter polymorphism is associated with breast cancer susceptibility in Chinese Han population

Ku70 plays an important role in the DSBR (DNA double-strand breaks repair) and maintenance of genomic integrity. Genetic variations within human Ku70 have been demonstrated to be associated with increased risk of several types of cancers. In this hospital-based case–control study, we aimed to investigate whether a single nucleotide polymorphism (SNP) in the promoter region (rs2267437) of Ku70 gene is associated with susceptibility to breast cancer in Chinese Han population. A total of 293 patients with breast cancer and 301 age-matched healthy controls were enrolled in this study. The Ku70 −1310C/G polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) analysis. A significant difference in genotype distribution and allele frequency was observed between patients and controls. The CG or GG carries were at higher risk of breast cancer compared with the CC homozygotes (OR = 1.43, 95% CI = 1.02–2.00, P = 0.038 and OR = 3.53, 95% CI = 1.60–7.80, P = 0.002, respectively). Further stratification analysis revealed that G allele was associated with an increased risk of breast cancer among premenopausal women (OR = 1.68, 95% CI = 1.21–2.33, P = 0.002), but not in postmenopausal women (OR = 1.33, 5% CI = 0.85–2.10, P = 0.216). Our study suggests that the Ku70 −1310C/G promoter polymorphism may be a susceptibility factor for breast cancer in Chinese Han population.     

Association between the CTLA-4 +49 A/G polymorphism and susceptibility to rheumatoid arthritis: a meta-analysis

The aim of this study was to explore whether the cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 A/G polymorphism confers susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between CTLA-4 +49 A/G polymorphism and RA using; 1) allele contrast, 2) the recessive model, 3) the dominant model, and 4) an additive model. A total of 19 studies, 5,752 RA patients and 5,508 controls, encompassing 9 Caucasian, 8 Asian, 1 Mexican, and 1 Tunisian population were included in this meta-analysis. Ethnicity-specific meta-analysis was performed on Caucasian and Asian populations. Meta-analysis of the CTLA-4 +49 A/G polymorphism revealed an association between RA and the CTLA-4 +49 G allele in all 11,260 study subjects (odds ratio (OR) 1.118, 95% confidence interval (CI) 1.033–1.210, P = 0.005). Stratification by ethnicity showed an association between the CTLA-4 +49 G allele and RA in Asians (OR 1.164, 95% CI 1.056–1.283, P = 0.002), but no evidence of an association in Caucasians (OR 1.085, 95% CI 0.973–1.209, P = 0.431). Furthermore, associations were found between RA and the CTLA-4 +49 A/G polymorphism in Asians using the dominant and additive models, but not using the recessive model. On the other hand, no association was found between RA and the CTLA-4 +49 A/G polymorphism using the recessive, dominant, or additive models in Caucasians. This meta-analysis demonstrates that the CTLA-4 +49 A/G polymorphism confers susceptibility to RA in Asians, but not in Caucasians.     

Association between the IL7R T244I polymorphism and multiple sclerosis: a meta-analysis

Previously published analyses of the association between the interleukin 7 receptor (IL7R) T244I polymorphism (rs6897932) and multiple sclerosis (MS) have yielded conflicting results. We performed a meta-analysis to assess whether the combined data showed this association, and to investigate its effect size. We analyzed 10 studies identified from PubMed (12,185 MS patients and 15,855 controls) and calculated the odds ratios (ORs) and 95% confidence intervals (CIs) for the C-allele, the C/C genotype (recessive effect) and the C/C + C/T (dominant effect) genotype. Heterogeneity within and between studies was observed: allele C: Q = 30.86, P = 0.002; genotype C/C: Q = 30.28, P = 0.003. Using a random-effects model, the C-allele and the C/C genotype were associated with MS (OR = 1.11, 95% CI = 1.04–1.19, P = 0.001 for the C-allele; OR = 1.15, 95% CI = 1.06–1.24, P = 0.0009 for the C/C genotype). The C/C + C/T genotype was also associated with MS using a fixed-effects model (OR = 1.15, 95% CI = 1.05–1.26, P = 0.003). There was no significant publication bias among the selected studies according to the funnel plot. We also performed the analysis on a European subgroup. This revealed an association between IL7R T244I and MS (P < 0.00001 for the C-allele and the C/C genotype; P = 0.0004 for the C/C + C/T genotype), no heterogeneity was observed (allele C: P = 0.07; genotype C/C: P = 0.10). In conclusion, the meta-analysis demonstrated that the IL7R T244I polymorphism was associated with susceptibility to MS.     

RNASEL −1385G/A polymorphism and cancer risk: a meta-analysis based on 21 case–control studies

Polymorphisms in the endoribonuclease L (RNASEL) gene have been hypothesized to increase the incidence of cancer. The common sequence variation in RNASEL, −1385G/A (rs486907) has been involved in several types of cancer risk. However, results of the related published studies remained conflicting rather than conclusive. To clarify the role of RNASEL −1385G/A genotype in global cancer, we performed a meta-analysis of all the available published studies involving 8,732 cancer patients and 8,748 control subjects. The overall results indicated that there was no major influence of the variant on cancer risk. However, stratified analysis by ethnicity showed that the RNASEL −1385G/A polymorphism has an increased cancer risk in African descendents in the homozygote comparison (OR = 2.59, 95% CI = 1.27–5.27), although no association was found in the analysis stratified by cancer type (OR = 1.12, 95% CI = 0.94–1.35). This meta-analysis suggested that the RNASEL −1385G/A polymorphism is associated with cancer risk in African descendents. To draw more comprehensive conclusions, further prospective studies with larger numbers of participants worldwide are still required to examine associations between RNASEL −1385G/A polymorphism and cancer risk.     

Vitamin D receptor ApaI,TaqI, BsmI,and FokI polymorphisms and psoriasis susceptibility: a meta-analysis

The aim of this study was to explore whether vitamin D receptor (VDR) polymorphisms confer susceptibility to psoriasis. Meta-analyses were conducted on the associations between the VDR ApaI, TaqI, BsmI, and FokI polymorphisms and psoriasis. Nine relevant studies on VDR polymorphisms and psoriasis were included in this meta-analysis, which involved 742 psoriasis patients and 715 controls. Meta-analysis indicated an association between the VDR ApaI A allele and psoriasis in Turkish studies (OR = 0.684, 95% CI = 0.475–0.985, p = 0.041). Meta-analysis indicated an association between the BsmI B allele and psoriasis in Asians (OR = 0.636, 95% CI = 0.411–0.984, p = 0.041), and showed a significant association between the FF and ff genotypes of the FokI polymorphism and psoriasis in all study subjects and in Turkish studies (OR = 2.028, 95% CI = 1.194–3.446, p = 0.009; OR = 3.582, 95% CI = 1.602–8.009, p = 0.002). This meta-analysis suggests that the VDR ApaI polymorphism confers susceptibility to psoriasis in the Turkish population. In addition, associations were found between the BsmI polymorphism and susceptibility to psoriasis in Asians and between the Fok I polymorphism and psoriasis in the Turkish population.     

CTLA-4 and TNF-α promoter-308 A/G polymorphisms and ANCA-associated vasculitis susceptibility: a meta-analysis

The aim of this study was to explore whether the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) or tumor necrosis factor-α (TNF-α) polymorphisms contribute to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) susceptibility. The authors conducted a meta-analysis on associations between polymorphisms of the 3′ untranslated region (UTR) microsatellite at exon 3, exon 4 CT60 (A/G), exon 1 +49 (A/G), and promoter -318 (C/T) of CTLA-4, and TNF-α promoter-308 (A/G) and AAV susceptibility as determined using; (1) allelic contrast and (2) homozygote contrast, (3) recessive, and (4) dominant models. A total of 11 comparisons were considered in this meta-analysis. These studies encompassed 7 CTLA-4 studies and 4 TNF-α studies in 10 European populations and 1 Asian population. The (AT)_n repeat polymorphisms of CTLA-4 were found to be significantly associated with AAV in European populations (OR of 86 vs. xx allele = 0.402, 95% CI = 0.184–0.875, P = 0.022). The one study conducted on this polymorphism in Asians showed no significant association with AAV. Meta-analysis of the 86/86 (recessive effect), 86/86 and 86/xx (dominant effect), and 86/86 vs. xx/xx (homozygote contrast) of the (AT)_n repeat revealed a significant association with AAV in Europeans. Both the CTLA-4 CT60 and +49 polymorphisms were found to be significantly associated with AAV in European populations, and allele and genotype-based analyses showed a significant association between the CTLA-4 CT60 and +49 polymorphisms with AAV in Europeans (OR of the A allele of CT60 = 0.769, 95% CI = 0.619–0.017, P = 0.035; OR of the T allele of +49 = 1.382, 95% CI = 1.147–1.664, P = 0.001, respectively). Meta-analysis of the CTLA-4 -318 polymorphism failed to identify any association with AAV. Furthermore, meta-analysis of the AA genotype, the AA and AG genotypes, and the A allele of TNF-α failed to reveal any association with Wegener’s granulomatosis (WG). This meta-analysis demonstrates that the CTLA-4 polymorphisms confer susceptibility to AAV in Europeans. In contrast, no association was found between the TNF-α-308 polymorphism and susceptibility to WG in Europeans.     

<Emphasis Type="Italic">TGFBR1</Emphasis>*6A/9A polymorphism and cancer risk: a meta-analysis of 13,662 cases and 14,147 controls

Published data on the association between TGFBR1*6A/9A polymorphism and cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 32 studies including 13,662 cases and 14,147 controls were involved in this meta-analysis. Overall, significantly elevated cancer risks were associated with TGFBR1*6A in all genetic models (for allelic effect: OR = 1.11; 95% CI = 1.03–1.21; for 6A/6A vs. 9A/9A: OR = 1.30; 95% CI = 1.01–1.69; for 9A/6A vs. 9A/9A: OR = 1.08; 95% CI = 1.01–1.15; for dominant model: OR = 1.08; 95% CI = 1.02–1.15; for recessive model: OR = 1.29; 95% CI = 1.00–1.68). In the subgroup analysis by cancer types, significant associations were found in breast cancer (for allelic effect: OR = 1.16; 95% CI = 1.01–1.34) and ovarian cancer (for allelic effect: OR = 1.24; 95% CI = 1.00–1.54; for 6A/6A vs. 9A/9A: OR = 2.34; 95% CI = 1.03–5.33). However, no significant associations were found in colorectal cancer, bladder cancer, prostate cancer and lung cancer for all genetic models. In summary, this meta-analysis suggests that the TGFBR1*6A/9A polymorphism is associated with cancer susceptibility, increasing the risk of breast and ovarian cancer.     

IL-10R1 S138G loss-of-function polymorphism is associated with extrapulmonary tuberculosis risk development in Tunisia

There is considerable evidence that host genetic factors are important in determining susceptibility to mycobacterial infections. More recently, functional genetic mutations affecting IL-10 receptor 1 (IL-10R1) were described. In this study, we investigated the relationship of IL-10R1 S138G loss-of-function polymorphism (A536G: rs3135932) with susceptibility to active tuberculosis (TB) in Tunisian patients. A total of 168 patients with pulmonary TB, 55 with extrapulmonary TB, and 150 control subjects were studied. Genomic DNA samples were extracted from leukocytes and used to investigate S138G polymorphism in IL-10R1 gene by multiplex allele-specific polymerase chain reaction. Associations between G allele [odds ratio OR = 5.01; 95% confidence intervals CI = 2.58–9.77; P = 10⁻⁷], GG genotypes [OR=9.06; 95% CI (1.58–67.33); correcting P-values using the Bonferroni method for multiple tests Pc=0.015] and AG genotype [OR=3.75; 95% CI (1.62–8.7); Pc=0.0012] with the risk development of active extrapulmonary TB were found. In contrast, the AA genotype was found to be associated with resistance to extrapulmonary TB [OR=0.19; 95% CI (0.09–0.42); Pc=6.10⁻⁶]. No association was found between S138G SNP and pulmonary TB. In conclusion, our study suggested the possible role of IL-10R1 S138G loss-of-function polymorphism in extrapulmonary TB susceptibility-resistance in Tunisia.     

MCP-1 −2518 A/G functional polymorphism is associated with increased susceptibility to active pulmonary tuberculosis in Tunisian patients

Monocyte chemoattractant protein-1 (MCP-1) plays crucial role in protective immunity against Mycobacterium tuberculosis (MT). In this study, we examined whether single nucleotide polymorphism (SNP) −2518 A/G (rs 1024611) of MCP-1 affect the susceptibility to active tuberculosis (TB) in Tunisian populations. Genomic DNA from patients with active TB (168 cases of pulmonary TB and 55 cases of extrapulmonary TB) and ethnically controls (150 cases) was genotyped for the MCP-1 −2518 A/G SNP by polymerase chain reaction fragment length polymorphism (PCR-RFLP). We observed that −2518 G allele and GG genotype (high MCP-1 producer) frequencies were significantly more elevated in active pulmonary TB group in comparison to control group [34 vs. 22%; P = 0.0007; 15 vs. 5%, P corrected for the number of genotypes (Pc) = 0.015; respectively]. Additionally, they were associated with increased risk development of this clinical form of TB [odds ratio (OR) = 1.83, 95% confidence intervals (CI) = 1.26–2.66; OR = 3.1, 95% CI = 1.28–7.76; respectively]. However, wild type allele −2518 A and AA genotype were over-represented in control group (78 and 62%) and seem to be protective factors against TB. Moreover, −2518 AA genotype was more frequent in control group and was associated with resistance against development of active pulmonary TB (OR = 0.56, 95% CI = 0.35–0.89, Pc = 0.03). Our findings confirm the key role of −2518 A/G SNP of MCP-1 and support its association with resistance/susceptibility to the development of active pulmonary TB in the Tunisian population.     

IL-1β (−511T/C) gene polymorphism not IL-1β (+3953T/C) and LT-α (+252A/G) gene variants confers susceptibility to visceral leishmaniasis

Lymphotoxin-α (LT-α) and interleukin-1beta (IL-1β) are proinflammatory cytokines playing important roles in immunity against Leishmania infection and the outcome of the disease. As cytokine productions are under the genetic control, this study tried to find any probable relationship between these cytokine gene polymorphisms and the susceptibility to visceral leishmaniasis in Iranian pediatric patients. Ninety-five pediatric patients involved with visceral leishmaniasis and 128 non-relative healthy people, from the same area as the patients, were genotyped for LT-α (+252A/G) and IL-1β (+3953T/C and −511T/C) gene polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP). There was not found any significant differences in allele and genotype frequencies of LT-α (+252A/G) and IL-1β (+3953) among the study groups. However, the frequency of IL-1β −511TT genotype was higher in the controls (P = 0.0004) while the frequency of IL-1β −511CC genotype and C allele were higher in the patients (P = 0.008 and P = 0.00006, respectively). Furthermore, IL-1β CC (−511/+3953) haplotype was more frequent in VL patients compared with the controls (P = 0.0002) and the distribution of TT haplotype was higher in the controls compared with the patients (P = 0.003). In conclusion, based on the results, IL-1β −511C allele, CC genotype and CC (−511/+3953) haplotype could be considered as the susceptibility factors for visceral leishmaniasis while IL-1β −511TT genotype, T allele and TT haplotype (−511/+3953) might be counted as the influential factors for resistance to the disease.     

Association of C47T polymorphism in <Emphasis Type="Italic">SOD2</Emphasis> gene with coronary artery disease: a case–control study and a meta-analysis

Oxidative damage promotes atherosclerosis. SOD2 is an important antioxidant enzyme. A case–control study and a meta-analysis were performed to assess the association of C47T polymorphism in SOD2 gene with premature, late-onset and overall coronary artery disease (CAD) risk. A hospital-based case–control study was conducted with 269 premature CAD cases, 278 late-onset CAD cases and 299 healthy controls. Polymerase chain reaction (PCR) and Pyrosequencing were used to detect the polymorphism. Multinomial logistic regression model was performed to estimate odds ratio (OR) with 95% confidence intervals (CIs) and adjust potential confounders. A meta-analysis was performed using eight outcomes including our result. Fixed or random effect pooled measure was selected on the basis of homogeneity test among studies. Heterogeneity among studies was evaluated using I ². Meta-regression was used to explore potential sources of between-study heterogeneity. Publication bias was estimated using Peters’s linear regression test. In our case–control study, compared with the TT as the reference, the mutant genotype of CC + TC was significantly associated with a reduced premature CAD risk both in univariate (OR = 0.60, 95% CI = 0.41–0.87) and multivariate (OR = 0.59, 95% CI = 0.40–0.87) logistic regressions, but not with late-onset CAD risk. After excluding one article that deviated from Hardy–Weinberg equilibrium in controls, this meta-analysis showed a significant association of the C allele with reduced risk of CAD in dominant (FEM: OR = 0.69, 95% CI = 0.61–0.78), recessive (OR = 0.64, 95% CI = 0.50–0.82), and codominant (FEM: OR = 0.73, 95% CI = 0.65–0.80) models. Our study suggested that the mutant genotype of CC + TC was significantly associated with a reduced CAD risk.     

Quantitative assessment of the effect of MTHFR polymorphisms on the risk of lung carcinoma

Published studies on the relationships between 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and lung cancer risk have been conflicting. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between MTHFR C677T and A1298C polymorphisms and lung cancer risk. A total of 15 studies including 10,753 cases and 11,275 controls described C677T genotypes, among which 11 articles totalling 6,161 cases and 7,684 controls described A1298C genotypes, were also involved in this meta-analysis. Overall, no significantly elevated lung cancer risk was found in any genetic models when all studies were pooled. For C677T polymorphism: (TT vs. CC: OR = 1.17, 95% CI = 0.97–1.42; TC vs. CC: OR = 1.06, 95% CI = 0.94–1.20; dominant model: OR = 1.09, 95% CI = 0.96–1.24; and recessive model: OR = 1.08, 95% CI = 0.95–1.24); for A1298C polymorphism: (CC vs. AA: OR = 1.04, 95% CI = 0.91–1.19; AC vs. AA: OR = 0.98, 95% CI = 0.91–1.06; dominant model: OR = 0.99, 95% CI = 0.92–1.06; and recessive model: OR = 1.05, 95% CI = 0.92–1.20). In the subgroup analyses, the results showed that 677T varients could decrease lung cancer risk in female (OR = 0.63, 95% CI = 0.41–0.95, P-value = 0.03, 677CC as reference). No evidence of any associations of MTHFR A1298C polymorphism with lung cancer was found in overall or subgroup analyses. Our meta-analysis supports that the common polymorphisms of C677T and A1298C in MTHFR gene are not susceptibility gene for lung cancer from currently available evidence.