CTLA-4 polymorphisms and susceptibility to Behcet’s disease: a meta-analysis

The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) polymorphisms confer susceptibility to Behcet's disease (BD). A meta-analysis was conducted on the associations between the CTLA-4 +49 A/G, -318 C/T, CT60 A/G polymorphisms and BD using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 8 separate comparison studies on BD were considered in the meta-analysis. Meta-analysis of the CTLA-4 +49 A/G polymorphisms showed no association between BD and the CTLA-4 +49 G allele in all study subjects (odds ratio [OR] = 0.780, 95 % confidence interval [CI] = 0.491-1.240, p = 0.294). Moreover, stratification by ethnicity indicated no association between the CTLA-4 +49 G allele and BD in Turkish population. No association was found between BD and the CTLA-4 +49 A/G polymorphisms using recessive or dominant models or contrast of homozygotes. No association was found between BD and the CTLA-4 -318 C/T or CT60 A/G polymorphisms. This meta-analysis showed that no association was found between CTLA-4 +49 A/G, -318 C/T or CT60 A/G polymorphisms and BD.     

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.     

Associations between the FAS ?670?A/G and ?1,377?G/A polymorphisms and susceptibility to autoimmune rheumatic diseases: a meta-analysis

The aim of this study was to explore whether FAS ?670?A/G and ?1,377?G/A polymorphisms confer susceptibility to autoimmune rheumatic diseases. A meta-analysis was conducted on the associations between the FAS ?670?A/G and ?1,377?G/A polymorphisms and autoimmune rheumatic diseases using allele contrast, a recessive model, a dominant model, and an additive model. Thirteen articles with 21 comparison studies (16 on FAS ?670?A/G and 5 on ?1,377?G/A polymorphisms) including systemic lupus erythematosus (SLE), four systemic sclerosis, four Sjogren’s syndrome, three rheumatoid arthritis (RA), one juvenile idiopathic arthritis, and one spondyloarthropathy were available for the meta-analysis. Meta-analysis revealed an association between rheumatic diseases and the FAS ?670?A/G polymorphism in the dominant model (odds ratio [OR]?=?0.761, 95?% confidence interval [CI]?=?0.621–0.932, p?=?0.008]. Stratification by ethnicity indicated an association between the FAS ?670?G allele carrier and rheumatic diseases in Asian (OR?=?0.569, 95?% CI?=?0.409–0.791, p?=?0.001). Furthermore, stratification by disease indicated an association between the FAS ?670?G allele carrier and SLE and RA (OR?=?0.578, 95?% CI?=?0.358–0.934, p?=?0.025; OR?=?0.609, 95?% CI?=?0.398–0.934, p?=?0.023, respectively). The FAS ?670?G allele was negatively associated with SLE susceptibility. Meta-analysis of the FAS ?1,377?G/A polymorphism stratified by disease showed an association between the FAS ?1,377 A allele and SLE (OR?=?0.783, 95?% CI?=?0.613–0.997, p?=?0.047). Meta-analyses using the dominant model also showed a significant association in SLE (OR?=?0.712, 95?% CI?=?0.528–0.961, p?=?0.027). This meta-analysis demonstrates that the FAS ?670?A/G polymorphism confers susceptibility to rheumatic diseases in Asians and SLE and RA, and the FAS ?1,377?G/A polymorphism is associated with SLE susceptibility.     

Associations between TNF-α −308 A/G and lymphotoxin-α +252 A/G polymorphisms and susceptibility to sarcoidosis: a meta-analysis

Several studies have examined the effects of the tumor necrosis factor-α (TNF-α) ?308 A/G and lymphotoxin-α (LT-α) +252 A/G polymorphisms on susceptibility to sarcoidosis, showing mixed results. The purpose of this study was to examine whether the TNF-α ?308 A/G and LT-α +252 A/G polymorphisms confer susceptibility to sarcoidosis. We did a literature search from MEDLINE and EMBASE indices, and conducted a meta-analysis examining the association between TNF-α ?308 A/G and LT-α +252 A/G polymorphisms and sarcoidosis. A total of 13 separate comparisons including 1,396 patients with sarcoidosis and 2,344 controls were considered in our meta-analysis. The meta-analysis revealed a significant association between the TNF-α ?308 A allele and sarcoidosis (odds ratio [OR] = 1.480, 95 % confidence interval [CI] 1.057–2.073, p = 0.002). Stratification by ethnicity indicated an association between the TNF-α ?308 A allele polymorphism and sarcoidosis in Europeans (OR = 1.445, 95 % CI = 1.010–2.065, p = 0.044), but not Asians (OR = 4.693, 95 % CI = 0.548–40.29, p = 0.158). The results also showed a significant association between the LT-α +252 G allele and sarcoidosis (OR = 1.266, 95 % CI = 1.048–1.528, p = 0.014). Stratification by ethnicity indicated an association between the LT-α +252 G allele and sarcoidosis in Europeans (OR = 1.307, 95 % CI = 1.045–1.635, p = 0.019), but not in Asians (OR = 1.169, 95 % CI = 0.824–1.660, p = 0.381). Our meta-analysis demonstrates that the TNF-α ?308 A/G and LT-α +252 A/G polymorphisms are associated with susceptibility to sarcoidosis in an European population.     

CTLA-4 +49A/G and CT60 gene polymorphisms in primary Sjögren syndrome

CTLA-4 encodes cytotoxic T lymphocyte-associated antigen-4, a cell-surface molecule providing a negative signal for T-cell activation. CTLA-4 gene polymorphisms have been widely studied in connection with genetic susceptibility to various autoimmune diseases, but studies have led to contradictory results in different populations. This case-control study sought to investigate whether CTLA-4 CT60 and/or +49A/G polymorphisms were involved in the genetic predisposition to primary Sjögren syndrome (pSS). We analysed CTLA-4 CT60 and +49A/G polymorphisms in a first cohort of 142 patients with pSS (cohort 1) and 241 controls, all of Caucasian origin. A replication study was performed on a second cohort of 139 patients with pSS (cohort 2). In cohort 1, the CTLA-4 +49A/G*A allele was found on 73% of chromosomes in patients with pSS, compared with 66% in controls (p = 0.036; odds ratio (OR) 1.41, 95% confidence interval (CI) 1.02 to 1.95). No difference in CTLA-4 CT60 allelic or genotypic distribution was observed between patients (n = 142) and controls (n = 241). In the replication cohort, the CTLA-4 +49A/G*A allele was found on 62% of chromosomes in patients with pSS, compared with 66% in controls (p = 0.30; OR 0.85, 95% CI 0.63 to 1.16). Thus, the CTLA-4 +49A/G*A allele excess among patients from cohort 1 was counterbalanced by its under-representation in cohort 2. When the results from the patients in both cohorts were pooled (n = 281), there was no difference in CTLA-4 +49A/G allelic or genotypic distribution in comparison with controls. Our results demonstrate a lack of association between CTLA-4 CT60 or +49A/G polymorphisms and pSS. Premature conclusions might have been made if a replication study had not been performed. These results illustrate the importance of case-control studies performed on a large number of patients. In fact, sampling bias may account for some contradictory results previously reported for CTLA-4 association studies in autoimmune diseases.     

TNF promoter ?308 A/G and ?238 A/G polymorphisms and juvenile idiopathic arthritis: a meta-analysis

The aim of this study was to determine whether the tumor necrosis factor (TNF) promoter polymorphisms confer susceptibility to juvenile idiopathic arthritis (JIA). A meta-analysis was conducted on the A allele of the TNF -308 A/G and -238 A/G polymorphisms. The nine comparison studies including 1,132 JIA patients and 1,663 controls were included in the meta-analysis and consisted of 7 European, 1 Mexican, and 1 Turkish population. No association was found between JIA and the TNF -308 A allele and the TNF -238 A allele (odds ratio [OR] = 1.211, 95 % confidence interval [CI] = 0.917-1.598, P = 0.177; OR = 1.135, 95 % CI = 0.603-1.861, P = 0.615, respectively). Stratification by ethnicity did not show the association of the TNF -308 and -238 polymorphisms with JIA in Europeans. Mexicans were found to have lower prevalences of A alleles (2.9, 4.1 %) of the TNF -308 A/G and -238 A/G polymorphisms than any other population studied, and the Turkish population the highest (31.2, 26.9 %). This meta-analysis shows no association between the A alleles of the TNF -308 A/G or -238 A/G polymorphisms and JIA in Europeans, but that the prevalences of these alleles are ethnicity dependent.     

Apolipoprotein A1 −75 G/A and +83 C/T polymorphisms: susceptibility and prognostic implications in breast cancer

Apolipoprotein A1 (ApoA1) is the major apoprotein constituent of high-density lipoprotein that can play important roles in tumor invasion and metastasis. In the current report, we evaluated the role of the functional ApoA1 polymorphisms (−75 G/A and +83 C/T) as genetic markers for breast cancer susceptibility and prognosis. We used the polymerase chain reaction and restriction enzyme digestion (RFLP-PCR) to characterize the variations of the ApoA1 gene in 295 unrelated Tunisian patients with breast carcinoma and 197 healthy control subjects. No association was found between the +83 C/T genetic variation in ApoA1 gene and the risk of breast cancer occurrence. The presence of the (+83) T allele appeared however to be associated with an increased risk of lymph node metastasis occurrence (OR = 2.94; P = 0.01). Furthermore, a positive association was found between ApoA1 −75 A allele carriers and breast cancer risk (OR = 1.57; P = 0.02). Regarding prognostic indicators, a significant association was found between ApoA1 (−75) A allele carriers and the premenopausal status of breast cancer patients (OR = 1.73; P = 0.03). Additionally, the presence of the −75 A allele was correlated with the oestrogen receptor status among premenopausal women (OR = 2.45; P = 0.02). This is the first report on the studies of ApoA1 single nucleotide polymorphisms (SNPs) in breast carcinomas. Our data suggest that these genetic variations of ApoA1 may represent a marker for the increased risk of breast cancer.     

The association between IFN-γ and IL-4 genetic polymorphisms and childhood susceptibility to bronchial asthma

The present study aims to investigate the association between the genetic polymorphisms of interferon (IFN)-γ and interleukin (IL)-4 with childhood susceptibility to asthma and the levels of IFN-γ, IL-4, and immunoglobulin (Ig) E among asthmatic children. A total of 100 asthmatic children and 122 control children were enrolled in the present study. The genotypes of the IFN-γ gene at the − 179G/T locus and the IL-4 gene at the − 33C/T and − 589C/T loci were detected using polymerase chain reaction with restriction fragment length polymorphism. The IFN-γ gene at the + 874A/T locus and the IFN-γ CA repeats were tested using allele-specific and capillary electrophoresis, respectively, whereas the IFN-γ, IL-4, and total IgE levels were measured using enzyme-linked immunosorbent assays. The 100 asthmatic children and the 122 control children were all GG homozygous in the − 179 locus of the IFN-γ gene, which shows that the IFN-γ gene is not mutated at the − 179 locus. No significant differences were found in terms of genotypic and allelic frequency distribution in the IFN-γ gene or the CA repeat at the + 874A/T locus between the asthmatic children and the control (P > 0.05). An association was found between the polymorphism of the IFN-γ gene at + 874A/T and IFN-γ levels. IFN-γ expression was lower among patients with the AA genotype than those with the AT genotype (P < 0.05); the genotypic and allelic frequency distributions of the IL-4 gene at − 33C/T and − 589C/T were significantly different between the asthmatic children and the control (P < 0.05). The levels of IL-4 and IgE among children with TT genotype at the − 33 and − 589 loci were higher than those with the CT genotype, but only the polymorphism at − 33C/T was associated with IL-4 levels (P < 0.05). The polymorphisms of the IFN-γ gene at + 874A/T or the CA repeats are not correlated with susceptibility to asthma. Thus, the polymorphism at + 874A/T is correlated with IFN-γ level. The TT genotypes of the IL-4 gene at the − 33 and − 589 loci are associated with asthma susceptibility in children, and polymorphism at the − 33 locus may be associated with IL-4 level.     

The ?159C/T polymorphism in the CD14 gene and the risk of asthma: a meta-analysis

The -159C/T polymorphism in the CD14 gene has been implicated in susceptibility to asthma, but a large number of studies have reported inconclusive results. The aim of this study is to investigate the association between the -159C/T polymorphism in the CD14 gene and the risk of asthma by meta-analysis. We searched Pubmed, Embase, CNKI database, Wanfang database, Weipu database, and Chinese Biomedical database, covering all publications (last search been performed on April 20, 2010). Statistical analysis was performed by using the softwares Revman 4.2 and STATA 10.0. A total of 17 case-control studies in 17 articles (4,246 cases and 3,631 controls) were included in this meta-analysis. There was no association between this polymorphism and asthma risk in combined analyses (odds ratio (OR)?=?0.86 and 95% confidence interval (95% CI)?=?0.72-1.02, P?=?0.09 for TC?+?TT vs. CC). In the subgroup analysis by age, ethnicity, and atopic status, no significant associations of asthma risks were obtained from age groups, ethnic groups, and atopic groups for TC?+?TT vs. CC comparison. For atopic population, significant decreased atopic asthma risks were found among Asian population (OR?=?0.69, 95% CI 0.52-0.92, P?=?0.01) and children population (OR?=?0.69, 95% CI 0.54-0.89, P?=?0.0004) for TC?+?TT vs. CC comparison. This meta-analysis suggests that CD14 is a candidate gene for atopic asthma susceptibility. The -159C/T polymorphism may be a protective factor for atopic asthma in Asian and children. More studies are needed to validate these associations.     

Interleukin 1 beta −511 C/T gene polymorphism and susceptibility to febrile seizures: a meta-analysis

One previous meta-analysis found no evidence that interleukin 1 beta (IL-1β) −511 gene polymorphism was associated with febrile seizures (FS) by pooling a limited number of studies. However, it is necessary for the meta-analysis to reevaluate the relationship with more recent findings. Electronic databases were systematically searched for studies published before June 2011. Pooled odds ratios (OR) and 95% confidence interval (CI) were estimated by means of a genetic model free approach. Subgroup and sensitivity analyses were also performed. All statistical analyses were conducted using Stata 9.0. A total of eight studies, 728 FS cases and 1,223 controls, met the selection criteria. The results show a significant association between IL-1β −511 C/T gene polymorphism and FS (recessive genetic model TT vs. CC + CT: OR = 1.361, 95% CI: 1.065–1.738, P = 0.014). Subgroup analyses show a significant association in Asia (OR = 1.394, 95% CI: 1.005–1.935, P = 0.047), but not in Europe (OR = 1.387, 95% CI: 0.750–2.565, P = 0.298). IL-1β −511 C/T gene polymorphism may play a role in susceptibility to FS, especially in Asia. Geographic differences may be a critical factor in the risk of FS.     

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.     

CTLA-4 exon 1 +49 polymorphism alone and in a haplotype with ?318 promoter polymorphism may confer susceptibility to chronic HBV infection in Chinese Han patients

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) plays a pivotal role in regulating T cell activation, which is believably critical for the outcome of hepatitis B virus (HBV) infection. The expression and function of CTLA-4 may be affected by gene polymorphisms. This study investigated the influence of CTLA-4 polymorphisms on disease susceptibility in Chinese Han patients with chronic HBV infection. CTLA-4 +49A/G and -318C/T polymorphisms were evaluated by DNA amplification with polymerase chain reaction followed by the restriction fragment length polymorphism analysis. The patients with chronic HBV infection had higher frequencies of genotype AA and allele A of CTLA-4 +49A/G polymorphism. The haplotype +49A-318C was significantly over-represented (P < 0.001) and haplotype +49G-318C under-represented (P = 0.006) in the patients. The +49GG genotype was more frequent (P = 0.009) and +49A allele was less frequent in patients with lower ALT levels (P = 0.012) in HBeAg positive chronic hepatitis B. It is indicated that CTLA-4 +49A/G polymorphism alone and in a haplotype with -318C allele may confer susceptibility to chronic HBV infection in Chinese Han patients.     

Association of TGF-β1 +869C/T promoter polymorphism with susceptibility to autoimmune diseases: a meta-analysis

Many case–control studies have investigated the role of TGF-β1 gene +869C/T promoter polymorphism in autoimmune diseases, but the results are inconsistent. To clarify this point, we performed a meta-analysis based on all available studies in Pubmed, Elsevier Science Direct, Google Searching, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure. Crude odds ratios (ORs) with 95 % confidence intervals were calculated to estimate the strength of the association. A fixed or random effects model was used on the basis of heterogeneity. A total of 21 papers including 2,693 cases and 3,036 controls were considered in the current meta-analysis. These studies encompass two ankylosing spondylitis (AS), eight rheumatoid arthritis (RA), four systemic lupus erythematosus (SLE), and seven systemic sclerosis (SSc). The results showed that TGF-β1 +869C/T promoter polymorphism were associated with susceptibility to RA (CC vs. TT: OR = 0.65, 95 % CI = 0.48–0.88, P = 0.005; CC vs. CT + TT: OR = 0.56, 95 % CI = 0.45–0.69, P = 0.000; C vs. T: OR = 0.81, 95 % CI = 0.71–0.93, P = 0.003). When stratified by race, significant association was observed only in Asian population. However, we failed to reveal the association between this gene promoter polymorphism and AS, SLE, and SSc. Therefore, this meta-analysis suggests a possible association between TGF-β1 +869C/T promoter polymorphism and RA, especially in Asian population.     

Association between the −1438G/A and T102C polymorphisms of 5-HT2A receptor gene and obstructive sleep apnea: a meta-analysis

The serotonin 2A (5-HT2A) receptor has been implicated in obstructive sleep apnea (OSA). Single nucleotide polymorphisms (SNPs) in the 5-HT2A gene have been found in OSA, the most common being ?1438G/A and T102C; however, studies of the association between 5-HT2A SNPs and OSA risk have reported inconsistent findings. A meta-analysis was performed to quantitatively review the association between ?1438G/A and T102C SNPs and OSA. Five studies, including 791 subjects for ?1438G/A genotype and 1,068 subjects for T102C genotype, were selected. Pooled data analysis of the ?1438G/A genotype indicated a significantly increased OSA risk was associated with two variant genotypes (AA vs. AG+GG: OR 3.023, 95 % CI 2.169–4.213, P = 0.506 for heterogeneity; A allele carriers vs. GG: OR 1.938, 95 % CI 0.879–4.274, P = 0.012 for heterogeneity). Stratification analysis by gender supported the association in males, but not females. For the T102C genotype, no significantly increased OSA risk was associated with the two variant genotypes (CC vs. CT+TT: OR 1.065, 95 % CI 0.787–1.442, P = 0.361 for heterogeneity; C allele carriers vs. TT: OR 0.979, 95 % CI 0.737–1.3, P = 0.9 for heterogeneity).In conclusions, meta-analysis indicated that the ?1438G/A, and not T102C, polymorphism of 5-HT2A is a positive risk factor of OSA, especially in males.     

The β1-adrenoreceptor gene Arg389Gly and Ser49Gly polymorphisms and hypertension: a meta-analysis

The gene encoding β1-adrenoreceptor is regarded as a hypertension-susceptibility candidate gene. The association of β1-adrenoreceptor gene Arg389Gly and Ser49Gly polymorphisms with hypertension has been exhaustively investigated; however, the studies have yielded inconsistent results. We sought to shed some light on this inconsistency by performing a systemic meta-analysis. Data were extracted from 17 articles (cases/controls: 7,586/8,441) for Arg389Gly, and eight articles (3,582/2,998) for Ser49Gly. The random-effects model was applied irrespective of between-study heterogeneity. Overall results indicated significance for Ser49Gly under both allelic (odds ratio = 1.13; 95 % confidence interval [95 % CI] 1.03–1.26; P = 0.011) and dominant (1.19; 1.04–1.28; 0.011) models, without evidence of heterogeneity (I ² = 0.0 %). Grouping studies by ethnicity observed marginally significant association for Arg389Gly (0.82; 0.66–1.0; 0.049) and Ser49Gly (1.3; 1.0–1.68; 0.048) polymorphisms in Caucasians under allelic model. Association was strikingly potentiated for both polymorphisms after restricting analyses to studies published in English journals. When only large studies (≥500 subjects) were considered, 389Gly allele decreased the odds of developing hypertension by 16 % (0.84; 0.74–0.95; 0.007). There was no observable publication bias for both polymorphisms. Taken together, our results provide clarification to the logical candidacy of β1-adrenoreceptor gene in the development of hypertension.     

Interferon gamma +874 T/A polymorphism contributes to cancer susceptibility: a meta-analysis based on 17 case–control studies

Interferon gamma (IFN-γ) plays a pivotal role in antiproliferative, antitumor and antiviral activities. The +874 polymorphism in IFN gene region reportedly affects cancer risk. However, pertinent studies offer conflicting results. To derive a more precise estimation, we performed a meta-analysis based on 1,929 cases and 2,830 controls from 17 published case–control studies, assessing the strength of the association using odds ratios with 95% confidence intervals. Our meta-analysis showed the evidence that IFN-γ +874 T/A was not associated with increased cancer risk in ethnicity and source of controls. However, stratified analysis by cancer type indicated a significantly increased risk of cervical cancer (AT vs. TT: OR = 1.10, 95% CI = 1.02–1.19, P = 0.961 for heterogeneity). Further prospective researches with a larger single study are required to evaluate any association with other types of cancer or in other populations.     

The association of IL1α and IL1β polymorphisms with susceptibility to systemic lupus erythematosus: A meta-analysis

Many epidemiological studies have investigated IL1α and IL1β polymorphisms with SLE risk, but no conclusions are available because of conflicting results. This meta-analysis was performed to more precisely estimate the relationships. The databases of PubMed updated to September 1st, 2012 were retrieved. Odds ratio (OR) and corresponding 95% confidence interval (95% CI) as effect size were calculated by a fixed- or random-effect model. In total, six case–control studies for IL1β − 511C/T, four studies for IL1β + 3953C/T, three studies for IL1α − 889C/T and three studies for IL1α + 4845G/T were involved in this analysis. The results indicated that for IL1α − 889C/T polymorphism T allele was associated with decreased risk of SLE (OR (95% CI)) (T vs. C: 0.802 (0.679–0.949); TT + CT vs. CC: 0.615 (0.380–0.995); TT vs. CC: 0.679 (0.466–0.989)). However, when analysis for TT vs. CT + CC was conducted, the result indicated that IL1α − 889C/T polymorphism was not associated with SLE (OR (95% CI): 0.847 (0.595–1.205)). Combined analysis indicated that IL1β − 511C/T polymorphism was not overall associated with risk of SLE (OR (95% CI)) (T vs. C: 1.113 (0.954–1.298); TT vs. CT + CC: 1.146 (0.889–1.447); TT + CT vs. CC: 1.145 (0.903–1.452); TT vs. CC: 1.255 (0.928–1.698)). When subgroup analysis for Asian ethnicity was conducted, the results indicated that IL1β − 511C/T polymorphism was associated with SLE only for TT vs. CT + CC (OR (95% CI): 1.468 (1.001–2.152)), but was not associated for T vs. C (OR (95% CI): 1.214 (0.955–1.544)), TT + CT vs. CC (OR (95% CI): 1.112 (0.765–1.615)) and TT vs.CC (OR (95% CI): 1.411 (0.896–2.222)). In addition, overall analyses indicated that IL1β + 3953C/T and IL1α + 4845G/C polymorphisms were also not associated with risk of SLE (OR (95% CI)) (for IL1β + 3953C/T T vs. C: 0.996 (0.610–1.626), TT vs. CT + CC: 0.658 (0.318–1.358), TT + CT vs. CC: 1.021 (0.618–1.687), TT vs. CC: 0.640 (0.309–1.325); for IL1α + 4845G/T T vs. G: 1.067 (0.791–1.440), TT + GT vs. GG: 0.934 (0.646–1.351)).This study inferred that IL1α − 889C/T polymorphism might be moderately associated with SLE, but no sufficient evidence was available to support any associations between IL1β + 3953C/T or IL1α + 4845G/C polymorphisms and SLE. We could not draw a definite conclusion between IL1β − 511C/T polymorphism and risk of SLE owing to the limited data. Further large sample-sized studies should be required.     

Association between tumor necrosis factor-α promoter −308 A/G, −238 A/G, interleukin-6 −174 G/C and −572 G/C polymorphisms and periodontal disease: a meta-analysis

The aim of this study was to determine whether tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) promoter polymorphisms confer susceptibility to periodontitis in ethnically different populations. A literature search was performed using PubMed and Embase and a meta-analysis of the identified studies was conducted to explore the associations between TNF-α ?308 A/G, ?238 A/G, IL-6 promoter ?174 G/C and ?572 G/C polymorphisms and periodontitis. Seventeen comparison studies for the TNF-α ?308 A/G polymorphism and three studies for the TNF-α ?238 A/G polymorphism were included in the meta-analysis. And 16 separate studies for the IL-6 ?174 G/C polymorphism and 10 studies for the IL-6 ?572 G/C polymorphism were considered in our meta-analysis. Analysis after stratification by ethnicity indicated that the TNF-α ?308 A allele was associated with periodontitis in Brazilian, Asian, and Turkish populations (OR = 0.637, 95 % CI = 0.447–0.907, p = 0.013; OR = 0.403, 95 % CI = 0.204–0.707, p = 0.009; OR = 1.818, 95;  % CI = 1.036–3.189, p = 0.037). The meta-analysis showed no association between the TNF-α ?238 A/G polymorphism and periodontitis. The meta-analysis indicated an association of the IL-6 ?174 G/C polymorphisms with periodontitis in Brazilian populations (OR for GG + GC = 2.394, 95 % CI = 1.081–5.302, p = 0.031). Stratification by ethnicity and disease type indicated an association between the IL-6 ?572 G allele and chronic periodontitis (OR = 1.585, 95 % CI = 1.030–2.439, p = 0.036), and periodontitis in Europeans (OR = 2.118, 95 % CI = 1.254–3.577, p = 0.005). This meta-analysis demonstrates that the TNF-α ?308 A/G polymorphism confers susceptibility to periodontitis in Brazilian, Asian and Turkish populations. The IL-6 ?174 G/C polymorphism may confer susceptibility to periodontitis in Brazilians, and the IL-6 ?572 G/C polymorphism may be associated with susceptibility to periodontitis in Europeans, and chronic periodontitis.     

Genetic polymorphism of interleukin 1β −511C/T and susceptibility to sporadic Alzheimer’s disease: a meta-analysis

A large number of epidemiological studies have been performed to investigate the association between Alzheimer’s disease (AD) risk and interleukin-1β ?511C/T genetic polymorphism, however, inconsistent results have been reported. The effect of the IL-1β ?511C/T polymorphism on AD susceptibility was evaluated by a meta-analysis. Series of databases were researched. 14 studies involving 2640 AD case and 3493 control subjects were identified. The pooled results showed there were no statistical associations of interleukin-1β ?511C/T genetic polymorphism with susceptibility to AD for five analysis models in all subjects. However, obvious heterogeneity among studies was detected. When stratifying for age at onset, ethnicity and geographic distribution of population to explore the original source of heterogeneity, the meta-analysis results based on geographic distribution of population showed the significant difference (CC vs CT, OR 1.26, 95 % CI: 1.03, 1.54, z = 2.25, P = 0.025; CC vs CT+TT, OR 1.24, 95 % CI: 1.03, 1.50, z = 2.24, P = 0.025) only in non-Europe. These findings indicate that the IL-1β ?511C/T polymorphism might be associated with AD risk, and individuals with IL-1β ?511C/C genotype might be at higher risk of AD in non-Europe. Further larger sample research would be warranted to confirm these conclusions.     

The −319C/+49G/CT60G Haplotype of CTLA-4 Gene Confers Susceptibility to Rheumatoid Arthritis in Mexican Population

Several single nucleotide polymorphisms (SNPs) within the CTLA-4 gene and elevated serum levels of soluble CTLA-4 (sCTLA-4) have been associated with autoimmunity including rheumatoid arthritis (RA). In this case–control study, we evaluated the relationship between the ?319C/T (rs5742909) and CT60 G/A (rs3087243) SNPs and sCTLA-4 levels in 200 RA patients and 200 control subjects (CS) from Western Mexico. Both SNPs were genotyped with the polymerase chain reaction–restriction fragment length polymorphism technique and the sCTLA-4 levels were quantified using an enzyme-linked immunosorbent assay kit. In addition, we performed a haplotype analysis, including our previous data of the +49A/G (rs231775) SNP. The G/A genotype of the rs3087243 SNP was associated with a decreased risk of RA [odd ratio (OR) 0.61, 95 % confidence interval (CI) 0.38–0.96, p = 0.024]. This protection was also observed in the negative anti-cyclic citrullinated peptide group of RA carriers of the A allele (OR 0.48, 95 % CI 0.22–1.05, p = 0.042). On the contrary, we identified the ?319C/+49G/CT60G haplotype of CTLA-4 gene as a risk factor for RA (OR 1.69, 95 % CI 1.13–2.52, p = 0.01). The sCTLA-4 levels were not associated with RA (p = 0.377), but were correlated with the functional disability of these patients (r = 0.282, p = 0.012). However, in CS the C/T genotype of the rs5742909 SNP, as well as the G/G and G/A genotypes of the rs3087243 SNP were associated with higher sCTLA-4 levels (p < 0.001). In conclusion, our results suggest that the ?319C/+49G/CT60G haplotype of CTLA-4 gene is a genetic marker of susceptibility to RA in Western Mexico, whereas the rs3087243 SNP confers protection against this disease. Moreover, both SNPs showed an effect on the sCTLA-4 production in our control population. However, further studies are required to evaluate the role of sCTLA-4 in RA, as well as the molecular and functional basis of the association between both CTLA-4 gene SNPs and soluble levels of CTLA-4 in CS.