Association between CTLA-4 polymorphisms and susceptibility to Celiac disease: A meta-analysis

Objective

The study explored whether cytotoxic T lymphocyte antigen-4 (CTLA-4) polymorphisms confer susceptibility to Celiac disease (CD).

Methods

A meta-analysis was conducted on the associations between the CTLA-4 CT60 A/G, +49 A/G, −318 C/T polymorphisms and CD using allele contrast, a recessive model, a dominant model, and homozygote contrast.

Results

Thirteen separate comparison studies were considered in the meta-analysis consisting of 5072 patients with CD and 13,462 controls. All subjects were Europeans. Meta-analysis of the CTLA-4 CT60 A/G polymorphism showed an association between CD and the CTLA-4 CT60 G allele in all subjects [Odds ratio (OR) = 1.160, 95% Confidence interval (CI) = 1.104–1.219, p < 1.0 × 10⁻⁹). Meta-analysis using the recessive model also revealed an association between CD and the CTLA-4CT60 GG genotype (OR = 1.331, 95% CI = 1.093–1.620, p = 0.004). Furthermore, analyses using the dominant model and homozygote contrast showed the same pattern as that shown by the CTLA-4CT60 G allele. Meta-analysis of the CTLA-4 +49 A/G polymorphism showed no association between CD and the CTLA-4 +49 G allele in all subjects (OR = 0.992, 95% CI = 0.872–1.129, p = 0.907). Meta-analysis using the recessive, dominant model, and homozygote contrast showed the same pattern as that shown by the CTLA-4 +49 Gallele. Meta-analysis of the CTLA-4 −318 C/T polymorphism showed no association between CD and the CTLA-4 −318 T allele in all subjects (OR = 1.018, 95% CI = 0.813–1.275, p = 0.877).

Conclusions

The CTLA-4 CT60 A/G polymorphism was associated with CD susceptibility, but no association was found between CTLA-4 +49 A/G and −318 C/T polymorphisms and CD in Europeans.     

CTLA-4 polymorphisms and susceptibility to inflammatory bowel disease: A meta-analysis

Objective

The aim of this study was to explore whether the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) polymorphisms are associated with susceptibility to ulcerative colitis (UC) and Crohn’s disease (CD).

Methods

The authors conducted a meta-analysis on associations between CTLA-4 +49 A/G, −318 C/T, CT60 A/G polymorphisms, and (AT)n repeat in the 3′ untranslated region (UTR) and UC and CD susceptibility.

Results

A total of 15 comparison studies were considered in our meta-analysis. Meta-analysis revealed no association between UC and the CTLA-4 +49 G and CTLA-4 −318 T alleles in all subjects (OR = 0.982, 95% CI = 0.851–1.1339, p = 0.804; OR = 0.500, 95% CI = 0.223–1.124, p = 0.094). No association was found between UC and the CTLA-4 CT60 A/G polymorphism in Europeans. However, a significant association was observed between the longer allele (?118 bp) of the (AT)n and UC in Asian population (OR = 6.073, 95% CI = 4.246–8.684, p = 1.0 × 10⁻⁹). Meta-analysis of the CTLA-4 +49 A/G, −318 C/T, CT60 A/G polymorphisms showed no association with CD.

Conclusions

This meta-analysis demonstrates that the CTLA-4 (AT)n repeat in 3′ UTR may be associated with susceptibility to UC in Asians, while no association was found between the CTLA-4 +49 A/G, −318 C/T, and CD60 A/G polymorphism and susceptibility to UC and CD.     

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.     

Association of CTLA-4 variants with susceptibility to inflammatory bowel disease: A meta-analysis

Objective

The aim of this study was to determine whether CTLA-4 gene variants were associated with susceptibility to inflammatory bowel disease (IBD).

Methods

Meta-analysis was conducted on the association between CTLA-4 variants and IBD using: (1) allelic contrast, (2) the recessive model, and (3) the dominant model.

Results

A total of 9 relevant studies including 1739 Crohn’s disease (CD) cases, 10 relevant studies containing 1017 ulcerative colitis (UC) cases and 2685 healthy controls were involved in this meta-analysis. Overall, CTLA-4+49A/G, −318C/T and CT60 variants were not associated with IBD susceptibility in all genetic models (P > 0.05). Stratification by ethnicity indicated a significant association between the CTLA-4+49A/G variant and CD in Caucasian group (GG vs. GA + AA: OR = 0.723, 95% CI = 0.564–0.926, P = 0.010). In Asian group, meta-analysis showed a significant association between the CTLA-4 CT60 variant and UC (AA vs. AG + GG: OR = 0.375, 95% CI = 0.163–0.861, P = 0.021).

Conclusions

Based on the published literature, this meta-analysis suggests that the CTLA-4+49A/G variant may be related to CD susceptibility in Caucasians, and the CTLA-4 CT60 variant may be associated with UC susceptibility in Asians.     

Association of the CTLA-4 gene with rheumatoid arthritis in Chinese Han population

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is important for downregulation of T-cell activation, and CTLA-4 gene polymorphisms have been implicated as risk factors for rheumatoid arthritis (RA). Previous studies of the association between the +49 polymorphism of the CTLA-4 gene in RA have provided conflicting results. In order to determine association of the CTLA-4 gene with RA in Chinese Han population, we used denaturing gradient gel electrophoresis (DGGE) to genotype polymorphisms of four SNPs (MH30, +49, CT60 and JO31) of the CTLA-4 gene in 326 RA patients and 250 healthy controls. Furthermore, meta-analysis of all available studies relating +49 polymorphism to the risk of RA was performed to confirm the disease association. Among the SNPs examined, the genotype frequencies of CTLA-4 +49 and CT60 in RA patients differed significantly from controls (P=0.028 and 0.007). In addition, the distribution of four haplotypes constructed by these two SNPs was significantly different between patients and controls (chi(2)=10.58, d.f. =3, P=0.014). The meta-analysis also revealed that in both European and Asian populations, the CLTA-4 +49 G allele was associated with the risk of RA. These results suggested that the CTLA-4 gene might be involved in the susceptibility to RA in the Chinese Han population and both +49 and CT60 of CTLA-4 gene might be the causal variants in RA 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 between CTLA-4 gene polymorphism and ankylosing spondylitis: a case-control study

Aims: The aim of our study was to evaluate the association between CTLA-4 polymorphisms (+49A/G, -318C/T and CT60A/G) and ankylosing spondylitis (AS) susceptibility. Methods: A total of 120 AS cases and healthy controls, matched on the age and gender, were enrolled in the study. Polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) were used to determine the gentypes of +49A/G, -318C/T and CT60A/G polymorphisms. Genotype distribution in control group was assessed by Hardy Weinberg Equilibrium (HWE) test. Odds ratio (OR) with 95% confidence interval (95% CI) were adopted to evaluate the relationship of CTLA-4 polymorphisms and AS susceptibility. Results: In our study, genotype distribution of the three polymorphisms in control group was consistent with the HWE (P > 0.05). The genotype analysis showed that AA genotype of + 49A/G polymorphism could increase the risk for AS (OR=2.357, 95% CI=1.127-4.930). Moreover, the frequency of A allele was also presented as a risk factor for AS. Additionally, AA genotype and A allele of CT60A/G appeared to be related with AS susceptibility (OR=2.610, 95% CI=1.047-6.510; OR=1.751, 95% CI=1.160-2.641). However, the T allele of -318C/T appeared to be a protective factor for AS (OR=0.383, 95% CI=0.228-0.643). Conclusion: In summary, there existed significant association between CTLA-4 gene polymorphisms and increased or decreased risk for AS.     

CTLA-4 gene polymorphisms and their influence on predisposition to autoimmune thyroid diseases (Graves’ disease and Hashimoto's thyroiditis)

Introduction

Autoimmune thyroid disease (AITD) is associated with both genetic and environmental factors which lead to the overactivity of immune system. Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) gene polymorphisms belong to the main genetic factors determining the susceptibility to AITD (Hashimoto''s thyroiditis, HT and Graves'' disease, GD) development. The aim of the study was to evaluate the relationship between CTLA-4 polymorphisms (A49G, 1822 C/T and CT60 A/G) and HT and/or GD in Polish patients.

Material and methods

Molecular analysis involved AITD group, consisting of HT (n=28) and GD (n=14) patients, and a control group of healthy persons (n=20). Genomic DNA was isolated from peripheral blood and CTLA-4 polymorphisms were assessed by polymerase chain reaction-restriction fragment length polymorphism method, using three restriction enzymes: Fnu4HI (A49G), BsmAI (1822 C/T) and BsaAI (CT60 A/G).

Results

Statistical analysis (χ² test) confirmed significant differences between the studied groups concerning CTLA-4 A49G genotypes. CTLA-4 A/G genotype was significantly more frequent in AITD group and OR analysis suggested that it might increase the susceptibility to HT. In GD patients, OR analysis revealed statistically significant relationship with the presence of G allele. In controls, CTLA-4 A/A genotype frequency was significantly increased suggesting a protective effect. There were no statistically significant differences regarding frequencies of other genotypes and polymorphic alleles of the CTLA-4 gene (1822 C/T and CT60 A/G) between the studied groups.

Conclusions

CTLA-4 A49G polymorphism seems to be an important genetic determinant of the risk of HT and GD in Polish patients.     

Association between the SUMO4 M55V (A163G) polymorphism and susceptibility to type 1 diabetes: A meta-analysis

Objective

The aim of this study was to determine whether the SUMO4 M55V (A163G) polymorphism confers susceptibility to type 1 diabetes (T1D).

Methods

A meta-analysis was conducted on the association between the SUMO4 M55V polymorphism and T1D using; (1) allelic contrast (G vs. A), and the (2) recessive (GG vs. GA+AA), (3) dominant (GG+GA vs. AA), and (4) additive models (GG vs. AA).

Results

Thirteen separate studies were considered in the meta-analysis, which in total included 5915 patients and 6660 controls, and five European and eight Asian sample populations. Europeans had a higher prevalence of the G allele than Asians (50.4% vs. 30.2%). Meta-analysis of the SUMO4 M55V polymorphism showed an association between T1D and the SUMO4 G allele in all study subjects (OR = 1.236, 95% CI = 1.112–1.373, p = 7.9 × 10⁻⁶), and stratification by ethnicity indicated a highly significant association between the SUMO4 G allele and T1D in Asians (OR = 1.303, 95% CI = 1.169–1.452, p = 1.78 × 10⁻⁷) and a marginal association with T1D in Europeans (OR = 1.177, 95% CI = 1.000–1.386, p = 0.050). Furthermore, significant associations were found between the SUMO4 M55V polymorphism and T1D and all study subjects, Europeans, and Asians using the dominant model (OR = 1.239, 95% CI = 1.144–1.342, p = 1.4 × 10⁻⁸; OR = 1.156, 95% CI = 1.051–1.271, p = 0.003; OR = 1.461, 95% CI = 1.262–1.691, p = 3.8 × 10⁻⁸, respectively).

Conclusions

This meta-analysis indicates that the SUMO4 M55V polymorphism confers susceptibility to T1D in Asians and Europeans.     

Associations between interleukin-10 polymorphisms and susceptibility to psoriasis: a meta-analysis

Objective

The aim of this study was to determine whether three specific interleukin-10 (IL-10) polymorphisms confer susceptibility to psoriasis.

Methods

A meta-analysis was conducted on the associations between the IL-10-1082 G/A, -592 C/A polymorphisms and haplotypes of the IL-10-1082 G/A, -592 C/A, -819 C/T polymorphisms and psoriasis.

Results

A total of eight studies involving 1,018 psoriasis patients and 1,186 controls were considered in the meta-analysis. No association was found between psoriasis and the IL-10-1082 G allele in all study subjects [odds ratio (OR)?=?1.098, 95?% confidence interval (CI)?=?0.923?1.306, p?=?0.291] or between this allele and psoriasis in Europeans (OR?=?0.990, 95?% CI?=?0.809?1.214, p?=?0.925), but a significant association was found in Asians (OR?=?1.785, 95?% CI?=?1.144?2.76, p?=?0.011). Three polymorphisms at the promoter region of IL-10 (-1082 G/A, -819 C/T, -592 C/A) are known to be in complete linkage disequilibrium, but no association was found between the haplotype and psoriasis.

Conclusions

This meta-analysis shows that the IL-10-1082 G/A polymorphism confers susceptibility to psoriasis in Asians, and suggests that the IL-10 promoter -1082 polymorphism has an ethnicity-specific effect.     

CTLA-4 Gene and the Susceptibility of Multiple Sclerosis: An Updated Meta-analysis Study Including 12,916 Cases and 15,455 Controls

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a cell surface molecule involved in the regulation of T cells. Single-nucleotide polymorphisms (SNPs) of CTLA-4 gene are known to be associated with susceptibility to several autoimmune diseases, including multiple sclerosis (MS). This study aimed to evaluate the association between CTLA-4 and the risk of MS. Comprehensive meta-analysis was applied to case-control studies of the association between MS and CTLA-4 to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. The authors searched PubMed, MEDLINE, Cochrane Library, and reference lists of relevant studies to September 2013. In all, the allele or genotype analysis showed no significant association between + 49A/G, ? 318C/T, or CT60A/G and MS. And the subgroups of the three polymorphisms divided into Americas, Europe, and Asia showed no significant association with MS. The sensitivity analysis or publication bias analysis showed no significance. In conclusion, this comprehensive meta-analysis suggested that + 49A/G, ? 318C/T, or CT60A/G polymorphism, either in total analysis or in subgroup analyses, has no significant association with MS disease.     

Associations between PXK and TYK2 polymorphisms and systemic lupus erythematosus: a meta-analysis

Objective

The aim of this study was to determine whether phox homology domain containing serine/threonine kinase (PXK) and tyrosine kinase 2 (TYK2) confer susceptibility to systemic lupus erythematosus (SLE).

Materials and methods

The authors conducted meta-analyses on associations between SLE susceptibility and the rs6445975 polymorphism of PXK and the rs2304256, rs12720270, rs280519, and rs1272036 polymorphisms of TYK2.

Results

A total of 13 separate comparisons studies were included in this meta-analysis. Meta-analysis identified an association between SLE and the 2 allele of the rs6445975 polymorphism in the overall population [odds ratio (OR)?=?1.151, 95?% confidence interval (CI)?=?1.086–1.291, P?=?1.8E?06]. Stratification by ethnicity identified a significant association between this polymorphism and SLE in Europeans (OR?=?1.198, 95?% CI?=?1.118–1.285, P?=?3.4E?07), but not in Asians. Meta-analysis identified a significant negative association between SLE and the 2 allele of the rs2304256 polymorphism in the overall population (OR?=?0.808, 95?% CI?=?0.659–0.990, P?=?0.040), and a significant negative association was found in Europeans, but not in Asians.

Conclusions

This meta-analysis shows that the rs6445975 polymorphism of PXK and the rs2304256 polymorphism of TYK2 are associated with the development of SLE in Europeans.     

The CTLA4+49A/G and CT60 polymorphisms and chronic inflammatory arthropathies in Northern Ireland

Rheumatoid and juvenile idiopathic arthritis (RA, JIA) are chronic inflammatory arthropathies with an autoimmune background. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) protein plays a key role in the down-regulation of T cell activation. We analyzed the CTLA4 +49A/G and CT60 polymorphisms in cohorts of Northern Irish RA and JIA patients and healthy control subjects using restriction fragment length polymorphism methods. The +49 A allele was increased in RA (61.2%; P=0.02; OR=1.28; 95% C.I.=1.04-1.58) and JIA (61.8%; P=0.14) patients compared to the control population (55.3%). No significant association was observed for the CT60 polymorphism. Haplotype analysis revealed a significantly different distribution of +49 A/G-CT60 haplotypes in RA and JIA patients compared to controls (P value<0.00001 and 0.030 for comparison of RA and JIA patients with controls, respectively). Our results suggest that the CTLA-4 gene is involved in predisposition to inflammatory arthropathies in the Northern Irish population.     

Functional genetic variants of CTLA-4 and risk of tobacco-related oral carcinoma in high-risk North Indian population

Single nucleotide polymorphisms (SNPs) of the CTLA-4 gene have been implicated in susceptibility to different cancer in different ethnic populations. We assessed the association of five SNPs [−1722C/T, −1661A/G and −318C/T in the promoter region49A/G in exon 1 and CT60A/G in the 3′untranslated region (UTR)] with tobacco-related oral squamous cell carcinoma (OSCC) in North Indian subjects. We genotyped 130 OSCC patients and 180 normal subjects by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) using BbvI, MseI, NcoI and BstEII restriction endonucleases. Among these SNPs, −1722CC, −1661AG and CT60AA genotypes were more prevalent in OSCC patients as compared to controls and in the logistic regression analysis with odd ratio (OR) 2.85, 95% CI (0.69–11.68); OR 2.48, 95% CI (1.29–4.78) and OR 3.0, 95% CI (1.43–6.28) respectively, these genotypes showed strong association with OSCC risk. With higher prevalence in controls 49GG genotype and G allele (OR 0.57, 95% CI 0.40–0.81) appeared to be protective. Moreover, TACAG, TACGA and TATAG appeared as susceptible while TACGG and CACGG appeared as protective haplotypes. These results suggest significant risk modifying effects of CTLA-4 −1722C/T, −1661A/G, −318T/C, CT60 A/G and 49A/G SNPs in tobacco-related OSCC in North Indian population.     

Interleukin-18 promoter polymorphisms and plasma levels are associated with increased risk of periodontitis: a meta-analysis

Objective

Emerging evidence has showed that interleukin-18 (IL-8) promoter polymorphisms and plasma IL-18 levels may be associated with increased risk of periodontitis, but individually published results are inconclusive. The aim of this meta-analysis was to derive a more precise estimation of these associations.

Methods

A literature search of PubMed, Cochrane Library, Embase, Web of Science, SpringerLink, China BioMedicine and China National Knowledge Infrastructure databases was conducted on articles published before April 1st, 2013. Crude odds ratio (OR) or standardized mean difference (SMD) with 95 % confidence intervals (CI) were calculated.

Results

Nine case–control studies were included with a total of 576 periodontitis patients and 458 healthy controls. Two common polymorphisms (?607A > C and ?137G>C) in the IL-18 gene were addressed. Our meta-analysis results indicated that the C variant of IL-18 ?607A>C polymorphism was associated with increased periodontitis risk (C allele vs. A allele: OR = 1.86, 95 % CI: 1.30–2.65, P = 0.001; AC+CC vs. AA: OR = 2.64, 95 % CI: 1.34–5.21, P = 0.005). There was also a significant association between the C variant of IL-18 ?137G>C polymorphism and an increased periodontitis risk (C allele vs. G allele: OR = 1.47, 95 % CI: 1.13–1.91, P = 0.004; GC+CC vs. GG: OR = 1.66, 95 % CI: 1.21–2.29, P = 0.002). Furthermore, the mean levels of plasma IL-18 of periodontitis patients were also higher than those of healthy controls (SMD = 1.18, 95 % CI: 0.51–1.85, P = 0.001).

Conclusion

The current meta-analysis suggests that IL-18 promoter polymorphisms and plasma IL-18 levels are associated with increased risk of periodontitis. IL-18 promoter polymorphisms and elevated plasma IL-18 levels may be useful biomarkers for predicting the development of periodontitis.     

Mental health and resiliency following 44 months of terrorism: a survey of an Israeli national representative sample

Background

Genetic variation in the innate immune system of the host may play a role in determining the risk of developing infection, as well as outcome from infection.

Methods

Infectious complications were retrospectively determined in 293 (233 African-American (AA), 57 Caucasian and 3 Hispanic) mechanically ventilated very low birth weight (VLBW) infants (<1500 grams at birth) who were genotyped for the IL-6 -174 G/C, IL-10 -1082 G/A and CD14 -260 C/T single nucleotide polymorphisms (SNPs).

Results

The IL-6 -174C allele was associated with an increased incidence of late blood stream infection (BSI) in AA but not Caucasian infants. In AA infants with the C allele the incidence of late BSI was 20/29 (69%) compared to 94/204 (46%) in homozygous GG infants (RR 2.6, 95% CI: 1.1–6.0, p = 0.021). The IL-10 -1082A allele was associated with an increased incidence of late BSI. One or more episodes of late BSI developed in 14 (35%) of 40 infants with the GG genotype, 71 (49%) of 145 infants with the GA genotype and 63 (58%) of 108 infants with the AA genotype (p = 0.036). Infants with the A allele (AA or GA genotypes) had an incidence of late BSI that was 134/253 (53%) compared to 14/40 (35%) in homozygous GG infants (RR 2.1, 95% CI: 1.04–4.19, p = 0.035). The CD14 -260 C/T SNP did not alter the overall risk for BSI in ventilated VLBW infants. Multiple BSI episodes were more common in the TT genotype group (CC: 17%, CT: 11%, TT: 30%, p = 0.022). This effect was due to the strong effect of the TT genotype on the incidence of multiple BSI in AA infants (CC: 15%, CT: 11%, TT: 39%, p = 0.003).

Conclusion

The IL-6 -174 G/C, IL-10 -1082 G/A and CD14 -260 C/T SNPs may alter risk for BSI in ventilated VLBW infants.     

Associations Between Autoimmune Thyroid Disease Prognosis and Functional Polymorphisms of Susceptibility Genes, CTLA4, PTPN22, CD40, FCRL3, and ZFAT, Previously Revealed in Genome-wide Association Studies

Purpose

Genome-wide association studies have revealed several susceptibility genes among patients with autoimmune thyroid disease (AITD), including CTLA4, PTPN22, FCRL3, and ZFAT. However, any possible association between these genes and AITD prognosis remains unknown. The objective of this study was to identify associations between polymorphisms of these genes and AITD prognosis.

Methods

We genotyped functional polymorphisms, including CTLA4 CT60, CTLA4 +49A/G, CTLA4 -1147C/T, CTLA4 -318C/T, PTPN22 -1123C/G, PTPN22 SNP37, CD40 -1C/T, FCRL3 -169C/T, ZFAT Ex9b-SNP10, and ZFAT Ex9b-SNP2, in 197 AITD patients carefully selected from 456 registered AITD patients, and 86 control subjects. The restriction fragment length polymorphism method was used for genotyping.

Results

The CD40 -1CC genotype and C allele were significantly more frequent in patients with Graves’ disease (GD) in remission than in those with intractable GD (P?=?0.041 and P?=?0.031, respectively). The FCRL3 -169TT genotype was significantly less frequent in patients with intractable GD than in those with GD in remission (P?=?0.0324). For a ZFAT Ex9b-SNP10 polymorphism, the TT genotype and T allele were significantly more frequent in patients with severe Hashimoto’s disease (HD) than in those with mild HD (P?=?0.0029 and P?=?0.0049, respectively). For a CTLA4 CT60 polymorphism, the antithyrotropin receptor antibody levels at the onset of GD were significantly higher in those with the GG genotype than in those with other genotypes (P?=?0.0117).

Conclusions

CD40 and FCRL3 gene polymorphisms were associated with GD intractability, and ZFAT polymorphism was associated with HD severity but not its development.     

CTLA-4, CD28, and ICOS gene polymorphism associations with non-small-cell lung cancer

Polymorphisms in genes encoding CD28, ICOS, and CTLA-4 were demonstrated to be associated with susceptibility to malignancies. To the best of our knowledge, no study on this association has been performed in a Caucasian population for non-small-cell lung cancer (NSCLC). In the present work, we investigated the polymorphisms CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA-4g.*642AT(8_33), CTLA-4g.*6230G>A (CT60) (rs3087243), CTLA-4g.*10223G>T (Jo31) (rs11571302), CD28c.17+3T>C (rs3116496), and ICOSc.1554+4GT(8_15) in 208 NSCLC patients and 326 controls. The distributions of the allele and genotype were similar in both groups for CTLA-4, CD28, and ICOS gene polymorphisms. However, we noted a tendency toward overrepresentation of individuals possessing the CTLA-4c.49A>G[A] allele in NSCLC patients compared with controls (0.84 vs 0.79, p = 0.09). The association became significant compared with controls in women for the CTLA-4c.49A>G[A] allele and CTLA-4c.49A>G[AA] genotype (0.67 vs 0.54, p = 0.01, and 0.47 vs 0.30, p = 0.02; respectively). Moreover, the constellation of alleles CTLA-4c.49A>G[A]/CT60[G]/CD28c.17+3T>C[T]/ICOSc.1554+4GT(8_15)[>10] increased the risk of NSCLC about 2-fold (p = 0.002). The same constellation of alleles combined with smoking, CTLA-4g.319C>T[T], and ICOSc.1554+4GT(8_15)[>10] was associated with a decreased overall survival rate. In conclusion, the constellation of specific alleles in CTLA-4, CD28, and ICOS genes contributes to the susceptibility and clinical course of NSCLC.     

Association of the A/G polymorphism at position 49 in exon 1 of CTLA-4 with the susceptibility to unexplained recurrent spontaneous abortion in the Chinese population

PROBLEM: To investigate whether the A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte antigen-4 (CTLA-4) gene, which delivers a negative signal to T-cell activation, confers the susceptibility to unexplained recurrent spontaneous abortion in the Chinese population. METHOD OF STUDY: A total of 168 patients with unexplained recurrent spontaneous abortion (RSA), who were treated in the Renji Hospital affiliated to the Shanghai Second Medical University, were matched against 117 women with normal pregnancy history. Case-control study to compare the frequency of G/A alleles, AA/AG/GG genotypes and A + (AA + AG) /G+ (GG + AG) phenotypes of CTLA-4 between RSA patients and controls were performed. After amplification of CTLA-4 exon-1 region by polymerase chain reaction (PCR), restriction fragment-length polymorphism (RFLP) was used to detect the polymorphism at position 49 in exon-1 of CTLA-4 gene. Statistical significance was tested by SPSS software. RESULTS: There were dissimilar distributions of G/A alleles, AA/AG/GG genotypes and A+/G+ phenotypes of CTLA-4 between RSA patients and controls. The frequencies of G allele (P = 0.032) and GG genotype (P = 0.011) in RSA patients were significantly higher than those in controls, while the frequencies of AG genotype (P = 0.039) and A + (AA + AG) phenotype in RSA patients were decreased significantly (P = 0.011). CONCLUSIONS: Our findings suggest that A/G polymorphism in exon-1 of CTLA-4 is associated with the immunopathogenesis of RSA, and it confers susceptibility to RSA in Chinese population.     

Association between functional Fc receptor-like 3 (FCRL3) −169 C/T polymorphism and susceptibility to seropositive rheumatoid arthritis in Asians: A meta-analysis

Objective

The aim of this study was to determine whether the functional Fc receptor like-3 (FCRL3) −169 C/T polymorphism confers susceptibility to rheumatoid arthritis (RA).

Methods

A meta-analysis was conducted on the associations between the FCRL3 −169 C/T polymorphism and RA.

Results

A total of 17 comparison studies including 11,170 patients and 11,142 controls were considered in the meta-analysis. The meta-analysis showed no association between RA and the FCRL3 −169 C allele in study subjects (OR = 1.046, 95% CI = 0.997–1.098, p = 0.068). Stratification by ethnicity indicated an association between the FCRL3 −169 C allele and RA in Asians (OR = 1.101, 95% CI = 1.035–1.174, p = 0.002), but not in Europeans. Stratification of patients according to the presence of rheumatoid factor (RF) revealed a different significant association between the C allele and RA in RF-positive and RF-negative RA patients. Stratification by ethnicity indicated an association between the FCRL3 −169 C allele and RF-positive RA in Asians (OR = 1.093, 95% CI = 1.004–1.189, p = 0.040), but not in Europeans.

Conclusions

This meta-analysis demonstrates that the FCRL3 −169 C/T polymorphism may confer susceptibility to seropositive RA in Asians.