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.     

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.     

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.     

Association of CTLA-4 and CD28 Gene Polymorphisms with Type 1 Diabetes in South Indian Population

Each functional gene illustrates the complexity of genetic predisposition to disease; however, it is difficult to bring out these traits with reference to autoimmune diseases like type 1 diabetes (T1D). To find out the genetic contribution of CTLA-4 + 49A/G, CTLA-4 ?318C/T and CD28 + 17T/C polymorphisms toward T1D, the present study was performed with 124 T1D patients, 54 siblings and 125 parents including 39 trios in South Indian population. The association and linkage of CTLA-4 + 49A/G, CTLA-4 ?318C/T and CD28 + 17T/C polymorphisms with T1D were analyzed and transmission disequilibrium test was performed. CTLA-4 G allele carrying genotypes (GG+AG) showed a higher risk association and can be considered as susceptible to develop T1D among patients with age at diagnosis from 0 to 10 years as compared to siblings (OR = 2.9; p_c = 0.047) and parents (OR = 2.7; p_c = 0.036). On the other hand, a strong protection against the disease (age at diagnosis; 0–10 years) was observed with CTLA-4 + 49AA genotype (OR = 0.37; p_c = 0.036) and combined AA/CC genotype (OR = 0.31; p_c = 0.034) of CTLA-4 + 49A/G and CTLA-4 ?318C/T polymorphisms. However, a significant association was not observed between CTLA-4 ?318C/T and CD28 + 17T/C polymorphisms and T1D. This family-based study reports a strong association between possible genotypes of CTLA-4 gene polymorphism and T1D in South Indian population, particularly in younger individuals.     

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.     

Association of -318 C/T and +49 A/G cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms with a clinical subset of Italian patients with systemic sclerosis

Systemic sclerosis (SSc) is a complex and heterogeneous autoimmune disorder with a multi-factorial pathogenesis. Like other autoimmune disorders, the possible role of specific cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms in predisposing to SSc has been hypothesized, but it remains controversial. CTLA-4 promoter (-318C/T) and exon 1 (+49 A/G) polymorphisms have been analysed in 43 Italian females with SSc and in 93 unrelated matched healthy controls by a newly designed tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) method. No significant association has been found with either polymorphisms.Nevertheless, SSc patients without concomitant Hashimoto's thyroiditis (HT) were carrying both the -318T allele (P = 0.031) and the +49 G allele (P = 0.076) more frequently than SSc patients with HT [defined by positivity for anti-thyroperoxidase (TPO) and anti-thyroglobulin (TGA) autoantibodies] than controls. Haplotype analysis confirms this association (P = 0.028), and suggests the predominant role of the -318T, whereas that of the +49 G, if any, seems weak. Thus, in Italian SSc patients the CTLA-4 -318C/T promoter polymorphism appears to be associated with the susceptibility to develop SSc without thyroid involvement. Larger studies are needed to confirm these findings and to clarify whether the -318C/T polymorphism is the functional responsible or whether it reflects the presence of another linked genetic element in the same chromosomal region.     

中国人自身免疫性肝病相关性 CTLA-4基因多态性研究

目的　探讨细胞毒性 T细胞相关抗原 - 4 (cytotoxic T lymphocyte- associated antigen- 4 ,CTL A- 4 )基因启动子 - 318和第 1外显子区第 4 9位基因多态性与中国人自身免疫性肝炎 (autoimmunehepatitis,AIH)、原发性胆汁性肝硬化 (primary biliary cirrhosis,PBC)发病的相关性。方法　应用限制性片段长度多态性方法分析 6 2例 AIH和 77例 PBC患者外周血单核细胞基因组 DNA CTL A- 4启动子 -318T/ C、第 1外显子区第 4 9位基因 A/ G多态性 ,并与 16 0名正常对照比较。结果　 AIH组 CTL A- 4启动子 - 318位 T/ C基因型分布与对照组比较差异无显著性 ,但 C等位基因频率明显高于正常对照组 (P=0 .0 2 ,OR=2 .4 3)。 PBC患者 CTL A- 4第 1外显子区第 4 9等位基因分布与正常对照组比较差异非常显著(P=0 .0 0 6 ) ,PBC患者 G等位基因频率明显高于正常组 (P=0 .0 0 4 6 ,OR=1.8)。联合分析 CTL A- 4启动子与第 1外显子的基因多态性分布 ,虽然 AIH组和 PBC组 GG- CC型携带率均比正常人高 (AIH组 :32 .3% ,PBC组 :37.7% ,对照组 :2 2 .5 % ) ,但是统计学分析结果均显示两组患者与正常人差异无显著性。结论　 CTL A- 4启动子 - 318和第 1外显子区第 4 9位基因多态性可能与中国人 AIH、PBC易感性相关。     

Genetic analysis and functional evaluation of the C/T(-318) and A/G(-1661) polymorphisms of the CTLA-4 gene in patients affected with Graves' disease

In this study, we evaluated the A/G(-1661), C/T(-318), A/G49 and A/G6230 single nucleotide polymorphisms (SNPs) of the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene for association with Graves' disease (GD) in 126 Russian simplex families. The conditional TDT analysis revealed significant overtransmission of the A(-1661)G(-318) haplotype (P = 0.033) and undertransmission of the GT haplotype (P = 0.0043) from parents homozygous for both +49 and +6230 polymorphisms. Parents homozygous for both (-1661) and (-318) markers significantly overtransmitted the G49G6230 haplotype (P = 0.0013) and undertransmitted the AG haplotype (P = 0.035) to affected offspring. This suggests in favor of the independent genetic effects of the 3' and 5'ends of CTLA-4 in conferring the susceptibility to GD. Both SNPs located at the 5' untranslated region of CTLA-4 were functionally analyzed using the luciferase reporter assay. We observed differential activation of the C/T(-318) promoter variant when Jurkat T cells and HeLa cells were cotransfected with a plasmid expressing lymphoid enhancing factor 1 (LEF1) and various CTLA-4 promoter constructs. The (-318) SNP modifies a putative binding site for LEF1 so that it alters the stimulating effect of LEF1 on the expression ability of the CTLA-4 promoter. The (-1661) dimorphism modifies a potential binding site for myocyte enhancer factor 2 (MEF2). No significant correlation between the (-1661) SNP and MEF2 activity in cotransfection experiments was found. Observed data help for further understanding a functional role of CTLA-4 promoter polymorphisms in the pathogenic mechanism of GD.     

中国人群脂联素基因+45T/G多态性与冠心病相关性的Meta分析

目的:对中国人apMl基因+45T/G多态性与冠心病相关性的研究进行Meta分析。方法:通过文献检索收集2009年12月以前完成或发表的中国人apMl基因+45T/G多态性与CHD相关性的病例对照研究,剔除不符合要求的文献。采用ReviewManager4.2软件进行Meta分析,根据各入选文献的同质性检验结果进行数据合并,计算总OR值。绘制漏斗图和Egger’s回归分析检验发表偏倚,并通过改变样本含量进行敏感性分析。结果:共纳入符合条件的8组研究,包括CHD患者1929例,对照1641例;Meta分析结果显示中国人apMl基因+45T/G多态性与CHD易感性无明显相关性(P0.05);发表偏倚和敏感性分析显示本次Meta分析结果稳定可靠。结论:尚无足够证据表明中国人apMl基因+45T/G多态性与CHD易感性相关。     

Association of the CTLA-4 gene with Vogt-Koyanagi-Harada syndrome

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a critical negative regulator of the T cell response, has been shown to be associated with a variety of autoimmune diseases. In this study, we investigated the association of CTLA-4 gene polymorphisms (- 1661A/G; - 318C/T; + 49G/A, and CT60) with Vogt-Koyanagi-Harada (VKH) syndrome in Chinese Han patients and normal controls. The results showed that the frequency of the G allele at the + 49 site was significantly higher in VKH patients than that observed in healthy controls (71.6% versus 62.8%, P = 0.0046, Pc = 0.037). Three haplotypes were identified from the four SNPs. The frequency of haplotype - 1661A:- 318C:+ 49G:CT60G, the most prevalent haplotype both in patients and controls, was significantly higher in patients than that in controls (70.1% versus 60.0%, P= 0.0013, n= 16, Pc = 0.021). These results suggest that CTLA-4 genetic polymorphisms are associated with the susceptibility to VKH syndrome.     

Effect of donor CTLA-4 alleles and haplotypes on graft-versus-host disease occurrence in Tunisian patients receiving a human leukocyte antigen-identical sibling hematopoietic stem cell transplant

The CTLA-4 genetic variation, such as single nucleotide polymorphisms (SNPs) may be critical and can affect the functional activity of cells that initiate the graft-versus-host disease (GVHD) effects. The aim of this study is to examine the effect of donor CTLA-4 alleles and haplotypes for the -318C>T and the 49A>G polymorphisms on the occurrence of GVHD in Tunisians recipients of HSCs. A total of 112 patients and their 112 respective sibling donors of HSCs were enrolled in this study. All patients had either grades 0-I or grades II-IV acute GVHD, or chronic GVHD. The SNPs genotyping assay was performed using sets of sequence specific primers (SSP-PCR). The single marker association analysis showed that the 49G allele, in a genetic recessive model, may be a potential risk factor only for the chronic GVHD (p = 0.032, odds ratio [OR] = 2.58, 95% confidence interval = 1.05-6.32). The haplotypes analyses showed that the CTLA-4 -318C49G nucleotide combination is significantly associated with the incidence of chronic GVHD (p = 0.043, χ2 = 3.27). Donor CTLA-4 -318C49G haplotype may be a significant risk factor for developing chronic GVHD after allo-stem cell transplantation. We suppose that donor T cells expressing this haplotype in a homozygous state have higher proliferation than those expressing other haplotypes, especially after recognition of the recipient's minor histocompatibility antigens.     

Polymorphisms in the CTLA-4 Gene and Rheumatoid Arthritis Susceptibility: A Meta-analysis

Introduction

The +49A/G polymorphism and CT60 polymorphism in the CTLA-4 gene have been extensively examined for the association with rheumatoid arthritis (RA); however, results of different studies have been inconclusive. The aim of this study is to comprehensively evaluate the genetic risks of +49A/G and CT60 polymorphisms in the CTLA-4 gene for RA.

Methods

A meta-analysis was carried out to analyze the association of +49A/G and CT60 polymorphisms with RA risk.

Results

A total of 30 case?Ccontrol studies in 20 articles were included in this meta-analysis. The results indicated that the variant G allele carriers (GG + GA) of +49A/G polymorphism had an 18% increased risk of RA when compared with the homozygote AA (odds ratio (OR)?=?1.18, 95% confidence interval (CI): 1.04?C1.34 for GG + AG vs. AA). In addition, the variant CT60 A allele carriers of CT60 polymorphism had a 14% decreased risk of RA when compared with the homozygote GG (OR?=?0.86, 95%CI?=?0.78?C0.95 for AA + AG vs. GG). In the subgroup analysis by ethnicity, significant elevated RA risks were associated with +49G allele carriers in Asians, but not in Europeans. However, for CT60 polymorphism, significant decreased RA risks were associated with CT60 A allele carriers in Europeans, but not in Asians.

Conclusions

This meta-analysis suggested that the +49A/G and CT60 polymorphisms in the CTLA-4 gene may be risk factors for RA.     

Investigation of CTLA-4 and CD28 gene polymorphisms in a group of Turkish patients with colorectal cancer

Colorectal cancer (CRC), also called colon cancer or bowel cancer, includes cancerous growths in the colon, rectum and appendix. The immune system is an important defence mechanism against cancer and is often dysfunctional in patients with malignancies. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and CD28 genes encode receptors that provide negative and positive signals, respectively. Polymorphisms in these genes can affect their functions. In this study, we aimed to investigate the association of cancer with the frequencies and roles of CTLA-4/+49A > G (exon 1) and -318C > T (promoter), and CD28/IVS3 + 17T > C (intron 3 position + 17). These polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 218 Turkish subjects (56 patients with CRC and 162 healthy controls). No statistically significant differences in the genotype distributions of CTLA-4/+49GG (1.8% vs. 6.8%, odds ratio (OR) = 0.250, P = 0.305) and CTLA-4/-318TT (0% vs. 0.6%, OR = 1.006, P = 1.000), and CD28/IVS3 + 17CC (8.9% vs. 3.7%, OR = 0.2411, P = 0.155) between patients with CRC and healthy controls, were observed. We also found that there were no significant differences in the frequencies of CTLA-4/+49G (18.8% vs. 20.1%, OR = 0.920, P = 0.891) and CTLA-4/-318T (7.1% vs. 4.3%, OR = 1.653, P = 0.314), and CD28/IVS3 + 17C alleles (25.9% vs. 19.1%, OR = 1.353, P = 0.139) between two study groups. Present results suggested that CTLA-4 and CD28 gene polymorphisms did not play an important role in Turkish patients with CRC.     

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.     

Study of the CTLA-4 gene polymorphisms in systemic lupus erythematosus (SLE) samples from Malaysia

Abstract

In this study, we investigated the polymorphisms of the exon 1 (+49A/G), promoter sites (–1722T/C, –1661A/G, –318C/T), and 3′-untranslated region (3′-UTR) (+6230 A/G) of the CTLA-4 gene in systemic lupus erythematosus (SLE) affected patients. Polymerase chain reaction-restriction fragment length polymorphism was used to determine genotypes of these five markers in 130 SLE patients and 130 healthy controls. Of the five tested polymorphisms, there was no statistical significant difference between the genotypic and allelic frequencies of patients with SLE and controls. Hence, we propose that the CTLA-4 gene does not play a major role in the genetic susceptibility to the development of SLE in the Malaysian population.     

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.     

Promoter region -318 C/ T and -1661 A/G CTLA-4 single nucleotide polymorphisms and type 1 diabetes in North Indians

Single nucleotide polymorphisms (SNPs) of the CTLA-4 gene have been associated with manifestation of type 1 diabetes in several populations. We assessed the association of five SNPs present in the CTLA-4 gene [-318C/T, -1661A/G and -1722C/T in the promoter region, +49A/G in exon 1 and CT60 in the 3' untranslated region (UTR) region] with type 1 diabetes in North Indian subjects. Genotyping was performed in the patients (n = 130) and the healthy control (n = 180) subjects by polymerase chain reaction-fragment length polymorphism analysis using MseI, BbvI, BstEII and NcoI restriction endonucleases for the -318, -1661, -1722, +49 and CT60 SNPs, respectively. The frequency of G alleles at -1661 locus was significantly higher in the patient group compared with the control subjects. Although the frequency of T alleles at -318 SNP was significantly higher in patients with type 1 diabetes compared with the controls, it did not remain significant after Bonferroni correction for the number of alleles tested. The frequencies of C/T alleles and genotypes at -1722C/T and G allele at +49A/G and CT60 SNPs were not significantly different between the patient and the control groups. Of the various possible haplotypes constructed using the five genetic loci tested (-318, -1661, -1722, +49, CT60), the frequency of 'TGTAG' haplotype was significantly higher in the patients when compared with the controls. The results of the present study indicate that the presence of G allele at -1661 locus at the CTLA-4 gene (IDDM12 locus) is associated with increased susceptibility to type 1 diabetes in North Indians, whereas A allele is protective.     

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.     

CTLA-4 gene polymorphisms and natural soluble CTLA-4 protein in psoriasis vulgaris

CTLA-4 molecule is an important inhibitor of T-lymphocyte activation. Several single nucleotide polymorphisms (SNPs) in the CTLA-4 gene were found, and their associations with many human diseases were described. So far, however, such studies have not been performed in psoriasis vulgaris in Caucasoids. Therefore, we examined the distribution of three CTLA-4 SNPs: -1147C/T, -318C/T and +49 A/G in 116 patients with psoriasis vulgaris and 123 healthy blood donors using the polymerase chain reaction-restriction fragment length polymorphism method. For all three SNPs, the frequencies of alleles, genotypes and three-point haplotypes were very similar in patients and controls, suggesting no contribution of these genetic variants to psoriasis.