PTPN22 1858C > T polymorphism and susceptibility to systemic lupus erythematosus: a meta-analysis update

Studies performed in the past years showed PTNP22 1858?C?>?T (rs2476601) polymorphism as associated with systemic lupus erythematosus susceptibility, although conflicting findings are still found. In this context, a powerful statistical study, such as meta-analysis, is necessary to establish a consensus. The aim of this study was to evaluate association studies between the PTPN22 1858?C?>?T polymorphism and SLE by a meta-analysis update, including three recently published studies in the last three?years. A total of 3868 SLE patients and 7458 healthy individuals were considered herein, enclosing 19 studies from Asian, American, European and Latin ethnic groups. Odds ratio (OR) was performed for allelic, dominant and recessive genetic models. Statistically significant association was found between the PTPN22 1858?C?>?T polymorphism and susceptibility to SLE in all inheritance models. Allelic genetic model data (OR?=?1.54, 95% confidence interval (CI)?=?1.38–1.72, p value=.000) shows that T allele confers increased SLE susceptibility. As well as recessive genetic model (OR?=?2.04, 95% CI?=?1.09–3.82, p value?=?.030) for T/T genotype. Instead, dominant genetic model shows that C/C genotype confers lower susceptibility for SLE development (OR?=?0.62, 95% CI?=?0.54–0.72, p value?=?.000). In addition, we provided an ethnicity-derived meta-analysis. The results showed association in Caucasian (OR?=?1.47, p value?=?.000) and Latin (OR?=?2.41, p value?=?.000) ethnic groups. However, rs2476601 polymorphism is not associated nor in Asian (OR=?1.31; p value?=?.54) and African (OR?=?2.04; p value=.22) populations. In conclusion, present meta-analysis update confirms that T allele and T/T genotype in PTPN22 1858?C?>?T polymorphism confers SLE susceptibility, particular in Caucasian and Latin groups, suggesting PTPN22 1858?C?>?T as a potential genetic marker in SLE susceptibility.     

PTPN22 Gene Polymorphism (C1858T) Is Associated with Susceptibility to Type 1 Diabetes: A Meta‐Analysis of 19,495 Cases and 25,341 Controls

The protein tyrosine phosphatase N22 (PTPN22) gene C1858T polymorphism has been reported to be associated with susceptibility to type 1 diabetes (T1D) in relatively small sample sizes. This study aimed at investigating the pooled association by carrying out a meta‐analysis on the published studies. The Medline, EBSCO, and BIOSIS databases were searched to identify eligible studies published in English before June 2012. The association was assessed by odds ratio (OR) with 95% confidence intervals (CI). The presence of heterogeneity and publication bias was explored by using meta‐regression analysis and Begg's test, respectively. A total of 28 studies were involved in this meta‐analysis. Across all populations, significant associations were found between the PTPN22 C1858T polymorphism and susceptibility to T1D under genotypic (TT vs. CC [OR = 3.656, 95% CI: 3.139–4.257], CT vs. CC [OR = 1.968, 95% CI: 1.683–2.300]), recessive (OR = 3.147, 95% CI: 2.704–3.663), and dominant models (OR = 1.957, 95% CI: 1.817–2.108). In ethnicity‐ and sex‐stratified analyses, similar associations were found among Caucasians and within Caucasian male and female strata. The meta‐analysis results suggest that the PTPN22 C1858T polymorphism was associated with susceptibility to T1D among the Caucasian population, and males who carried the ‐1858T allele were more susceptible to T1D than females.     

Association of PTPN22 C1858T polymorphism and type 1 diabetes: a meta-analysis

Recently, protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism has been identified as a susceptibile gene for type 1 diabetes (T1D), but studies are inconsistence, In order to assess the association between PTPN22C1858T polymorphism and T1D based on different ethnicities, a meta-analysis was performed, including 26 studies, total of 16,240 patients and 17,997 controls. Meta-analysis was performed on T versus C, T/T+T/C versus C/C (dominant model) and T/T versus T/C+C/C (recessive model) in a fixed/random effects model. The results indicated an association between the PTPN22 C1858T polymorphism and T1D in all subjects. The overall odds ratio (OR) of T versus C using the fixed effects model was 1.948 (95% CI = 1.859～2.041, P < 0.001). After stratification by ethnicity, analysis revealed that the PTPN22 C1858T polymorphism T allele was significantly associated with T1D in Europeans, Americans (OR = 1.946, 95% CI = 1.852~2.045, P < 0.001; OR = 1.946, 95% CI = 1.690~2.242, P < 0.001, respectively). Meta-analysis of the T/T+T/C genotype and the T/T genotypes showed the same results as that shown by the PTPN22 C1858T polymorphism T allele. This meta-analysis suggests a possible association between the PTPN22 C1858T polymorphism and T1D, especially in European and American populations.     

Interleukin-6-174G > C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: A case-control study and meta-analysis

The association of interleukin-6 (IL-6)-174G?>?C (rs1800795) single nucleotide polymorphism (SNP) with the risk of acquiring rheumatoid arthritis (RA) is a relevant issue because of conflicting and consensus lacking reports published in literature. We investigated IL-6-174G?>?C promoter polymorphism in 34 RA patients, attending a tertiary care hospital in north India. We also performed a meta-analysis, of the previously published studies reporting this genetic relationship, in overall population, and independently in Asian and Caucasian ethnicities to further elucidate this association. A total of 13 studies, including the current one, involving 3291 RA cases and 3812 controls were analyzed. Out of the 13 studies, 6 were from Asian, 6 from Caucasian and 1 from a mixed population. Our case-control study showed significant association of IL-6-174G?>?C SNP with increased RA risk: allelic (OR?=?3.750, 95% CI?=?1.800–7.813, p?<?0.001); dominant (OR?=?2.800, 95% CI?=?1.167–6.721, p?=?0.021); and recessive (OR?=?36.72, 95% CI?=?2.004–672.7, p?=?0.015). The meta-analysis revealed the increased RA risk associated with IL-6-174G?>?C SNP in overall population: allelic (OR?=?1.650, 95% CI?=?1.169–2.329, p?=?0.004); homozygous (OR?=?1.380, 95% CI?=?0.906–2.101, p?=?0.133); heterozygous (OR?=?1.559, 95% CI?=?1.001–2.428, p?=?0.049); dominant (OR?=?1.663, 95% CI?=?1.078–2.567, p?=?0.022); and recessive (OR?=?1.366, 95% CI?=?0.964–1.935, p?=?0.079). Subgroup analysis also showed this polymorphism to be associated with increased RA risk in Asian population: allelic (OR?=?3.724, 95% CI?=?1.361–10.190, p?=?0.010); dominant (OR?=?3.823, 95% CI?=?1.320–11.074, p?=?0.013); and recessive (OR?=?4.357, 95% CI?=?1.634–11.623, p?=?0.003), but not in Caucasian population. This meta-analysis shows that IL-6-174G?>?C SNP is significantly associated with increased RA risk in overall, and specifically in Asian population.     

Association of PTPN22 single nucleotide polymorphism with rheumatoid arthritis but not with allergic asthma

PTPN22 gene encodes a lymphoid tyrosine phosphatase (LYP), an important negative regulator of T-cell responses. The 1858C>T (Arg620Trp) single nucleotide polymorphism (rs2476601) was found associated with autoimmune diseases, including rheumatoid arthritis (RA). Allergic diseases are similar to autoimmune diseases, by an exaggerated immune response to an antigen (allergen in this case) normally not invoking such response in healthy individuals. We investigated whether polymorphism 1858C>T in PTPN22 gene is associated with susceptibility to allergic asthma and RA in a Polish population. PTPN22 was genotyped in 173 patients with RA, in 198 patients with allergic asthma, and in 543 controls using PCR-RFLP. The patients with RA differed from healthy controls in frequencies of PTPN22 1858C>T alleles (P=0.0004; odds ratio (OR), 1.8; 95% CI, 1.33-2.55) and genotypes (P=0.0009). Strong associations of 1858T allele with RA limited to joints (0.21 vs 0.12, P=0.0002; OR, 2.1; 95% CI, 1.44-3.00), with erosive disease (0.20 vs 0.12, P=0.0003; OR, 1.92; 95% CI, 1.34-2.71), with a lack of rheumatoid factor (RF; 0.23 vs 0.12, P=0.0008; OR, 2.29; 95% CI, 1.44-3.63), and weak association with the presence of RF (0.17 vs 0.12, P=0.02; OR, 1.6; 95% CI, 1.10-2.40) in comparison with healthy controls were observed. Very strong association of 1858T allele (P<0.0001; OR, 2.72; 95% CI, 1.9-3.9) and T phenotype (P<0001; OR, 3.2; 95% CI, 2.1-4.9) with antibodies to cyclic citrullinated peptide (CCP) was found. When patients with allergic asthma were typed for PTPN22 1858C>T polymorphism, no difference with control was found. Subdivision of patients into those with mild, moderate, or severe asthma did not reveal any associations. In conclusion, we confirmed associations between several clinical manifestations of RA and PTPN22 1858T allele. However, no association with 1858C>T polymorphism was found for susceptibility to allergic asthma or for severity of the disease.     

CTLA-4 +49 A/G and −318 C/T polymorphisms and susceptibility to multiple sclerosis: a meta-analysis

Objective: The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 A/G, and ?318?C/T polymorphisms confer susceptibility to multiple sclerosis (MS).

Methods: A meta-analysis of the associations between the CTLA-4 +49?A/G and ?318?C/T polymorphisms and MS.

Results: A total of 23 separate comparisons from 19 studies of the CTLA-4 +49 A/G polymorphism and 10 comparisons (8 studies) of the CTLA-4 ?318?C/T polymorphism were considered. Meta-analysis showed no association between MS and the CTLA-4 +49G allele in the analysis of all study subjects (OR?=?1.026, 95% CI?=?0.967–1.089, p?=?0.395). Stratification by ethnicity indicated no association between the CTLA-4 +49G allele and MS in Caucasians, Asians, or Arabs. Meta-analysis showed no association between RA and the CTLA-4 ?318C allele in all study subjects (OR?=?0.909, 95% CI?=?0.704–1.175, p?=?0.467). In addition, meta-analysis stratified by ethnicity revealed no association between MS and the CTLA-4 ?318 C/T polymorphism in Caucasian, Asian, or Arab populations.

Conclusions: This meta-analysis of published studies did not find an association between the CTLA-4 +49?A/G and ?318?C/T polymorphisms and susceptibility to MS in Caucasian, Asian, and Arab populations.     

Association of PTPN22 C1858T Polymorphism and Type 1 Diabetes: A Meta-analysis

Recently, protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism has been identi?ed as a susceptibile gene for type 1 diabetes (T1D), but studies are inconsistence, In order to assess the association between PTPN22C1858T polymorphism and T1D based on different ethnicities, a meta-analysis was performed, including 26 studies, total of 16,240 patients and 17,997 controls. Meta-analysis was performed on T versus C, T/T+T/C versus C/C (dominant model) and T/T versus T/C+C/C (recessive model) in a ?xed/random effects model. The results indicated an association between the PTPN22 C1858T polymorphism and T1D in all subjects. The overall odds ratio (OR) of T versus C using the fixed effects model was 1.948 (95% CI = 1.859～2.041, P < 0.001). After strati?cation by ethnicity, analysis revealed that the PTPN22 C1858T polymorphism T allele was signi?cantly associated with T1D in Europeans, Americans (OR = 1.946, 95% CI = 1.852～2.045, P < 0.001; OR = 1.946, 95% CI = 1.690～2.242, P < 0.001, respectively). Meta-analysis of the T/T+T/C genotype and the T/T genotypes showed the same results as that shown by the PTPN22 C1858T polymorphism T allele. This meta-analysis suggests a possible association between the PTPN22 C1858T polymorphism and T1D, especially in European and American populations.     

The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status

We have recently described the association between rheumatoid arthritis and a coding single-nucleotide polymorphism in the intracellular protein tyrosine phosphatase, PTPN22. The disease-associated polymorphism, 1858 C/T (rs2476601), encodes an amino-acid change (R620W) in one of four SH3 domain binding sites in the PTPN22 molecule. We have now extended our initial studies to address three questions: (1) Is the association with rheumatoid arthritis limited to rheumatoid factor (RF) positive disease? (2) Does homozygosity for PTPN22 R620W substantially increase disease susceptibility? (3) Is there an interaction between PTPN22 and the rheumatoid arthritis (RA)-associated HLA-DRB1 shared epitope alleles? A total of 1413 Caucasian rheumatoid arthritis patients and 1401 Caucasian controls were genotyped. The results support the view that PTPN22 was strongly and preferentially associated with RF positive disease (OR=1.75, 95% CI 1.46-2.10, P=1.3 x 10(-9)). The PTPN22 risk allele was not significantly associated with RF negative disease (OR=1.19, 95% CI 0.92-1.53, P=0.18), although a very weak association cannot be completely excluded. There was a strong dose effect on disease risk; two copies of the PTPN22 R620W allele more than doubles the risk for RF positive RA (OR=4.57, 95% CI 2.35-8.89). There was no evidence of a genetic association between PTPN22 and HLA susceptibility alleles.     

Association Between CD24-P226-C/T Polymorphism and Multiple Sclerosis: A Meta-Analysis

Background: Multiple sclerosis (MS) is a progressive inflammatory and neurodegenerative disease of the central nervous system (CNS), the etiology of which is still uncertain. Several case-control studies investigated the association between CD24-P226-C/T polymorphism and MS risk, and these studies have shown inconsistent results.

Objective: To address the association of CD24-P226-C/T polymorphism with MS risk by meta-analysis.

Methods: A comprehensive search was conducted to identify all eligible studies of CD24-P226-C/T polymorphism and MS risk up to July 2013. The odds ratios (ORs) of CD24 allele distributions in MS were analyzed against controls.

Results: In total, seven case-control studies with 949 cases of MS and 1177 controls were included in this meta-analysis. The overall results showed a significant association between CD24-P226-C/T polymorphism and MS susceptibility under homozygote comparison model (OR?=?2.496, 95% CI?=?1.813–3.435, p?<?0.0005), dominant model (OR?=?1.367, 95% CI?=?1.147–1.629, p?<?0.0005), recessive model (OR?=?2.305, 95% CI?=?1.700–3.126, p?<?0.0005) and allelic model (OR?=?1.422, 95% CI?=?1.244–1.625, p?<?0.0005). However, no significant association was observed under heterozygous comparison model (OR?=?1.182, 95% CI?=?0.982–1.423, p?=?0.078).

Conclusions: This meta-analysis indicates that CD24 P266-C/T polymorphism is more associated with the risk of MS than healthy controls. However, due to the small sample size in most of the included studies, additional large-scale and well-designed case-control studies were required for the validation of this association.     

The association between interleukin-6 polymorphisms and rheumatoid arthritis: a meta-analysis

Objective

The aim of this study was to determine whether the functional interleukin-6 (IL-6) promoter ?174 G/C and ?572 G/C polymorphisms confer susceptibility to rheumatoid arthritis (RA) in ethnically different populations.

Methods

Meta-analysis was conducted on the associations between these IL-6 polymorphisms and RA.

Results

A total of nine studies involving 3,851 subjects (RA 2,053 and controls 1,798) were considered in this study and ethnicity-specific meta-analysis was performed on European subjects. In all study subjects, meta-analysis revealed a trend toward to an association between RA and the IL-6 ?174 G allele (odds ratio [OR]?=?0.699, 95?% confidence interval [CI]?=?0.463–1.054, p?=?0.088). Stratification by ethnicity indicated a significant association between RA and the IL-6 ?174 G/C polymorphism in Europeans using the dominant (OR?=?0.329, 95?% CI?=?0.155–0.699, p?=?0.004) and recessive (OR?=?0.823, 95?% CI?=?0.679–0.997, p?=?0.047) models. Meta-analysis of the IL-6 ?572 G/C polymorphism showed no association between RA and the IL-6 ?572 G allele in all study subjects (OR?=?1.641, 95?% CI?=?0.613–4.397, p?=?0.324).

Conclusions

This meta-analysis shows that the IL-6 ?174 G/C polymorphism may confer susceptibility to RA in Europeans.     

PTPN22 Polymorphism is Related to Autoimmune Disease Risk in Patients with Turner Syndrome

Individuals with Turner syndrome (TS) clearly have an increased risk for autoimmune diseases. Recently, an allelic variation (C1858T) of the PTPN22 gene was revealed to be associated with the development of autoimmunity. Thus, the aim of this study was to determine the frequency of the PTPN22 C1858T polymorphism in women with Turner syndrome (TS) compared to controls. Case–control study comprises 142 women with TS (cases) and 180 healthy and fertile women without a history of autoimmune disease (controls). Detection of the PTPN22 C1858T polymorphism (rs2476601) was performed by TaqMan real‐time PCR. The chi‐square test was used to compare allele and genotype frequencies between groups and to estimate the Hardy–Weinberg equilibrium. All P‐values were two‐tailed, and 95% confidence intervals (CIs) were calculated. A P‐value <0.05 was considered statistically significant. Genotypes CC, CT and TT of the PTPN22 C1858T polymorphism presented frequencies of, respectively, 67.6%, 28.2% and 4.2% in the TS, and 82.8%, 16.1% and 1.1% in the control group (P = 0.0043). Alleles C and T were present in, respectively, 81.7% and 18.3% of the patients with TS (P = 0.001, OR = 2.22, 95% CI = 1.39‐3.54) and in 90.8% and 9.2%, respectively, of the controls. The data suggest that in Brazilian patients with TS, the PTPN22 C1858T polymorphism may be an important genetic factor predisposing to autoimmune disease risk.     

Association of IFIH1 rs1990760 polymorphism with susceptibility to autoimmune diseases: A meta-analysis

Abstract

Published data on the association between the IFIH1 rs1990760 polymorphism and multiple autoimmune diseases are controversial and inconclusive. To more precisely estimate the association between the IFIH1 rs1990760 polymorphism and susceptibility to autoimmune diseases, a meta-analysis was conducted. Studies examining the association of the IFIH1 rs1990760 polymorphism with autoimmune diseases were exhaustively searched using PubMed, Web of Science and a review of the references. A total of 19 studies with 26 comparisons including 8 type 1 diabetes (T1D), 5 systemic lupus erythematosus (SLE), 5 Graves’ disease (GD), 2 multiple scleorosis (MS), 2 rheumatoid arthritis (RA), 2 Hashimoto's thyroiditis (HT), 2 autoimmune Addison’s disease (AAD) were available for this meta-analysis. Meta-analysis was performed for genotype T/T?+?T/C (dominant model), genotype T/T (recessive model) and T-allele in fixed or random-effects models. The overall odds ratios (ORs) and 95% confidence intervals (CIs) for T-allele were T1D (OR?=?1.184, 95% CI?=?1.142–1.229), SLE (OR?=?1.143, 95% CI?=?1.073–1.217), MS (OR?=?1.181, 95% CI?=?1.062–1.313) and RA (OR?=?1.115, 95% CI?=?1.004–1.239), respectively. For T1D and SLE, significant association was observed in the population of European ancestry, but not in the Asian population. This meta-analysis demonstrates that the IFIH1 rs1990760 T-allele confers susceptibility to T1D, SLE, MS and RA and suggests that the IFIH1 rs1990760 polymorphism might have no effect on GD and AAD. Our result provides further evidence for the notion of common gene underlying multiple autoimmune diseases.     

Association of the PTPN22 gene polymorphism with autoantibody positivity in Turkish rheumatoid arthritis patients

The PTPN22 C1858T gene polymorphism has been recently reported to be associated with rheumatoid arthritis (RA) in European and North American ancestry. In contrast, the frequency of PTPN22 C1858T polymorphism is extremely rare in Asian and African populations. As the genetic heterogeneity between populations is clearly present in RA, we wanted to investigate whether the PTPN22 C1858T polymorphism is associated with RA in Turkey and with autoantibody positivity. A total of 323 RA patients and 426 healthy controls were genotyped by polymerase chain reaction restriction fragment length polymorphism for the PTPN22 C1858T polymorphism (rs2476601). The frequencies of heterozygote genotype (CT) were 8.4% in RA patients and 5.4% in the healthy controls, respectively [odds ratio (OR): 1.6, P = 0.14]. The homozygote genotype (T/T) was absent in both RA patients and the healthy controls. When compared with the healthy controls, we found the significant associations between the frequency of PTPN22 heterozygote (CT) polymorphism and RA patients with RF positivity and anti-CCP positivity, respectively (OR: 2.05, P = 0.04 and OR: 2.1, P = 0.03, respectively). Our study suggests that the PTPN22 C1858T polymorphism acts as a susceptibility gene for autoantibody-positive RA in Turkey.     

The PTPN22 promoter polymorphism -1123G>C association cannot be distinguished from the 1858C>T association in a Norwegian rheumatoid arthritis material

The protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene has, during the last 2 years, been recognized as a susceptibility gene for numerous autoimmune diseases, including rheumatoid arthritis (RA) and type 1 diabetes. An association between the exonic 1858C>T single nucleotide polymorphism (SNP) and RA has repeatedly been replicated in several Caucasian populations. The SNP is not associated with autoimmune diseases in Asian populations, as the 1858T allele is almost absent. Recently, a promoter polymorphism -1123G>C was proposed to be associated with acute-onset type 1 diabetes in Japanese and Korean populations. Furthermore, in Caucasian populations, the presence of additional PTPN22 risk variants has been suggested, indicating that the 1858C>T risk variant cannot explain the entire disease association observed in the region. In this study, we wanted to jointly address and integrate these separate findings to further elucidate the association between the PTPN22 gene and RA in a Norwegian material of 861 RA patients and 559 healthy controls. Our results revealed that the strength of the association with the PTPN22 promoter polymorphism, -1123G>C, is analogous to that observed for 1858C>T. As the -1123G>C variant is also polymorphic in Asian populations, our data underpin the need to further explore the association between this variant and autoimmune diseases in different populations.     

Interaction analysis between BLK rs13277113 polymorphism and BANK1 rs3733197 polymorphism,MMEL1/TNFRSF14 rs3890745 polymorphism in determining susceptibility to rheumatoid arthritis

Two pairwise genetic interactions (B cell lymphocyte kinase (BLK) rs13277113,B cell scaffold protein with ankyrin repeats 1 (BANK1) rs3733197and BLK rs13277113 membrane metalloendopeptidase like 1 (MMEL1)/ tumor necrosis factor receptor superfamily member 14 (TNFRSF14) rs3890745) have been demonstrated in determining susceptibility to rheumatoid arthritis (RA) without replication, thus this study was performed to examine whether abovementioned genetic polymorphisms were associated with RA and further tests were performed to see whether aforementioned genetic interactions existed in RA among Chinese population. A total of 328 patients with RA and 449 healthy control subjects were included in the current study. The polymorphisms were genotyped using the ligase detection reaction-polymerase chain reaction (LDR-PCR) technology. The association of RA with each polymorphism was analyzed by multivariate logistic regression model. Interaction analysis was done by multiple methods. Significant difference in genotype distribution of BLK rs13277113 polymorphism between RA patients and healthy controls was found (p?=?1.01?×?10^?2). The major allele A of BLK rs13277113 polymorphism was significantly increased in RA patients compared with controls (OR?=?1.36, 95% CI?=?1.08–1.71, p?=?9.27?×?10^?3). Significant association of RA with the major allele A of BLK rs13277113 polymorphism under dominant model was also detected (OR?=?2.74, 95% CI?=?1.42–5.29, p?=?2.73?×?10^?3). However, we did not find significant association between neither BANK1 rs3733197 polymorphism nor MMEL1/TNFRSF14 rs3890745 polymorphism and RA. Non-significant evidence was found for neither additive nor multiplicative interaction for these two pairwise genetic polymorphisms (BLK rs13277113-BANK1 rs3733197; BLK rs13277113-MMEL1/TNFRSF14 rs3890745). Significant association of RA with G allele of BANK1 rs3733197 polymorphism was only found among individuals carrying A/A genotype of the BLK rs13277113 polymorphism (OR?=?1.49, 95% CI?=?1.01–2.18, p?=?.04). In summary, our results indicated that the BLK rs13277113 polymorphism was involved in the genetic background of RA in Chinese population and the association of BANK1 rs3733197 polymorphism with RA was dependent on the genotype of BLK rs13277113 polymorphism, highlighting B-cell response implicated in the pathogenesis of RA.     

Associations between TNFSF15 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: A meta-analysis

Abstract

Aims: Several polymorphisms have been identified in TNFSF15, while their roles in the incidence of ulcerative colitis (UC) and Crohn's disease (CD) are conflicting. This meta-analysis was aimed to clarify the impact of these polymorphisms on UC and CD risk. Method: Databases were searched until 31 January 2014 for eligible studies on TNFSF15 polymorphisms. Data were extracted, and pooled odd ratios (ORs) as well as 95% confidence intervals (95% CIs) were calculated. Results: Fifteen studies with 8903 CD patients, 4687 UC patients and 12?606 controls were included. Except for rs4263839 polymorphism, significant associations were found between the rest six TNFSF15 polymorphisms and CD risk (rs3810936: OR?=?2.10, 95% CI, 1.47–3.00; rs6478108: OR?=?2.19, 95% CI, 1.53–3.13; rs4979462: OR?=?1.89, 95% CI, 1.42–2.52; rs6478109: OR?=?2.00, 95% CI, 1.39–2.88; rs7848647: OR?=?1.54, 95% CI, 1.15–2.06; rs7869487: OR?=?1.51, 95% CI, 1.06–2.17). And we found rs3810936, rs6478108 and rs6478109 polymorphism were significantly associated with UC risk (rs3810936: OR?=?1.19, 95% CI, 1.06–1.34; rs6478108: OR?=?1.16, 95% CI, 1.06–1.26; rs6478109: OR?=?1.16, 95% CI, 1.03–1.32). According to the subgroup analysis by ethnicity, except for rs4263839 in Caucasian and rs4979462 in Asian, all the rest investigated TNFSF15 polymorphisms were associated with CD risk and rs3810936 and rs7848647 polymorphism in Asian as well as rs6478108 polymorphism in Caucasian were associated with UC risk. Conclusion: This meta-analysis indicated that most of the seven TNFSF15 polymorphisms (except for rs4263839) were risk factors contributed to CD and UC susceptibility. The differences in ethnicity did not influence the risk obviously.     

Susceptibility to type 1 diabetes conferred by the PTPN22 C1858T polymorphism in the Spanish population

Background

The protein tyrosine phosphatase N22 gene (PTPN22) encodes a lymphoid-specific phosphatase (LYP) which is an important downregulator of T cell activation. A PTPN22 polymorphism, C1858T, was found associated with type 1 diabetes (T1D) in different Caucasian populations. In this study, we aimed at confirming the role of this variant in T1D predisposition in the Spanish population.

Methods

A case-control was performed with 316 Spanish white T1D patients consecutively recruited and 554 healthy controls, all of them from the Madrid area. The PTPN22 C1858T SNP was genotyped in both patients and controls using a TaqMan Assay in a 7900 HT Fast Real-Time PCR System.

Results

We replicated for the first time in a Spanish population the association of the 1858T allele with an increased risk for developing T1D [carriers of allele T vs. CC: OR (95%) = 1.73 (1.17–2.54); p = 0.004]. Furthermore, this allele showed a significant association in female patients with diabetes onset before age 16 years [carriers of allele T vs. CC: OR (95%) = 2.95 (1.45–6.01), female patients vs female controls p = 0.0009]. No other association in specific subgroups stratified for gender, HLA susceptibility or age at onset were observed.

Conclusion

Our results provide evidence that the PTPN22 1858T allele is a T1D susceptibility factor also in the Spanish population and it might play a different role in susceptibility to T1D according to gender in early-onset T1D patients.     

Gender-specific association of the PTPN22 C1858T polymorphism with achalasia

The protein tyrosine phosphatase N22 (PTPN22) gene encodes a lymphoid-specific phosphatase (LYP), a downregulator of T-cell activation. Because a functional PTPN22 polymorphism, C1858T, has been found to be associated with different autoimmune diseases, we aimed to elucidate the role of this variant in predisposition to achalasia. We performed a case-control study with 231 nonrelated Spanish patients of white ethnicity diagnosed with achalasia and in 554 healthy control subjects, all genotyped for PTPN22 C1858T using TaqMan chemistry. The frequency of the 1858T allele was higher in the achalasia patients than in the healthy controls (carriers of allele T vs CC: OR = 1.38, 95% confidence interval [95% CI] 0.88-2.16, p = 0.13). Moreover a different genotype distribution was found between female and male patients (carriers of allele T vs CC: OR = 2.06, 95% CI 0.96-4.42, p = 0.04) and also between female patients and controls (OR = 1.94, 95% CI 1.12-3.36, p = 0.01), but not between male patients and controls (OR = 0.94, 95% CI 0.50-1.77, p = 0.85). We conclude that the PTPN22 1858T allele is a susceptibility factor for Spanish women with achalasia.     

Meta-Analysis of Associations Between Interleukin-10 Polymorphisms and Susceptibility to Vasculitis

Objective: This study determined whether interleukin-10 (IL-10) polymorphisms are associated with susceptibility to vasculitis.

Methods: A meta-analysis was conducted of the associations between the IL-10 -1082 G/A, -819 C/T, and -592 C/A polymorphisms and the haplotype of the IL-10-1082 G/A, -819 C/T, -592 C/A polymorphisms and vasculitis.

Results: A total of 21 comparative studies involving 4121 patients and 5504 controls were considered in the meta-analysis. Meta-analysis revealed no association between the IL-10-1082 G allele and vasculitis in all study subjects (OR?=?0.927, 95% CI?=?0.780–1.102, p?=?0.389). However, disease-specific meta-analysis showed an association between Wegener’s granulomatosis (WG) and the IL-10-1082 G allele (OR?=?0.729, 95% CI?=?0.547–0.971, p?=?0.031). Meta-analysis revealed an association between vasculitis and the IL-10-819 C allele (OR?=?0.804, 95% CI?=?0.706–0.916, p?=?0.001) in all study subjects and Behcet’s disease (BD) (OR?=?0.724, 95% CI?=?0.679–0.781, p?<?1.0?×?10^?9). Meta-analysis of the IL-10-592 C allele showed an association with vasculitis in all study subjects (OR?=?0.805, 95% CI?=?0.619–0.938, p?=?0.005) and BD (OR?=?0.718, 95% CI?=?0.661–0.781, p?<?1.0?×?10^?9). Meta-analysis of the IL-10 haplotype revealed an association between the GCC haplotype and vasculitis in Europeans (OR?=?1.239, 95% CI?=?1.105–1.513, p?=?0.035).

Conclusions: This meta-analysis showed that IL-10 polymorphisms are associated with vasculitis susceptibility, especially in WG and BD.     

Meta-Analysis: The Relationship Between CTLA-4 +49 A/G Polymorphism and Primary Biliary Cirrhosis and Type I Autoimmune Hepatitis

Objectives: CTLA-4 exon-1 +49A?>?G (rs231775) polymorphism has been reported to influence the risk for primary biliary cirrhosis (PBC) as well as type I autoimmune hepatitis (AIH-1) in many studies; however, the results still remain controversial and ambiguous. This study aimed to determine more precise estimations for the relationship between CTLA-4 +49 A?>?G polymorphism and the risk for PBC and AIH-1 by using a meta-analysis.

Design and Methods: PubMed, EMBASE and MEDLINE were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association.

Results: Fifteen studies including 3661 patients with PBC and 4427 controls as well as seven studies including 1270 patients with AIH-1 and 1614 controls were identified. Our pooled analysis revealed that G allele of CTLA-4 gene +49A/G polymorphism may confer an increased risk of PBC in overall (p?=?0.001, OR?=?1.29; 95% CI?=?1.13–1.47) and Caucasians (p?=?0.001, OR?=?1.32; 95% CI?=?1.21–1.44). At genotypic level, the codominant, dominant and recessive models showed no significant association with PBC. With respect to AIH-1, the AG genotype demonstrated a trend for association with increased risk of AIH-1 (p?=?0.04, AG vs. AA, OR?=?1.20; 95% CI?=?1.01–1.43). However, the CTLA-4 alleles as well as genotypes in dominant and recessive models were not associated with a risk for AIH-1 in both Caucasians and Asians.

Conclusions: This meta-analysis concluded that the CTLA-4 G allele and the AG genotype were associated with an increased risk for PBC and AIH-1, respectively, suggesting the CTLA-4 +49 A/G polymorphism as a candidate of susceptibility locus to PBC and AIH-1.