CTLA-4 Gene Polymorphisms Research Articles

Association of CTLA4 Gene Polymorphism in Iranian Patients with Ankylosing Spondylitis

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a costimulatory molecule expressed by activated T cells. This study was performed to investigate the allele and genotype frequencies of CTLA4 gene polymorphisms in Iranian patients with ankylosing spondylitis (AS). One hundred and fifty-seven patients with AS and 103 controls were included in this study. Polymorphisms of CTLA4 gene at positions +49 (in exon 1), -318, and -1,147 (in the promoter region) were studied on the genomic DNA using PCR restriction fragment-length polymorphism method. The frequencies of the T allele at position -1147 in the patients with AS was significantly increased in comparison with the control group (11% vs. 5%, P = 0.004); whereas the frequencies of C allele at the same position were significantly decreased in the patient group (89% vs. 95%, P = 0.004). Comparison of genotype frequencies at this position showed that the frequency of CT genotype in comparison with other genotypes was overrepresented in the patient group (20% vs. 8%, P = 0.012), while the CC genotype in comparison with other genotypes was decreased (79% vs. 91%, P = 0.012). There was no significant difference on frequencies of genotypes at the positions -318 and +49. This study could suggest an association between specific allele in the promoter region of CTLA4 gene and AS disease.

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

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.

Functional polymorphism in CTLA4 gene influences the response to therapy with inhaled corticosteroids in Slovenian children with atopic asthma

We genotyped CTLA4 CT60 (rs3087243) functional single nucleotide polymorphism (SNP) in children with asthma and in healthy controls and correlated the genotype data with asthma clinical data, including treatment response with inhaled corticosteroids measured by forced expiratory volume in the first second (FEV1). FEV1 increased by 21.7% after 4 weeks of therapy in atopic asthmatics with the A/A genotype compared with an 8.6% increase in heterozygotes and a 5.8% increase in G/G homozygotes (p <0.01). Genotype and allele frequencies in asthmatics did not differ significantly from those in the control group. SNP CT60 in the CTLA4 gene is significantly associated with the response to treatment with inhaled corticosteroids in children with atopic asthma and could be a useful biomarker for personalized therapy in asthmatic children. SNP CT60 in the CTLA4 gene plays only a minor role in genetic susceptibility to childhood asthma in the Caucasian population.

Genetic Polymorphisms of Immunoregulatory Proteins in Acute Renal Allograft Rejection

CTLA-4 and CD28 are T lymphocyte receptors involved in the regulation of T-cell activation. Allograft rejection is an alloimune response which is strongly dependent on T-cell proliferation. Thus, we examined the relationship between CTLA-4 and CD28 gene polymorphisms and renal transplant outcomes. We genotyped 141 renal recipients and 229 healthy controls using PCR-SSP methods for the (−318) C/T polymorphism in the promoter region of the CTLA-4 gene and IVS3 (+17) T/C on intron 3 of the CD28 gene, and by PCR-RFLP method for exon 1 (+49) A/G and CT60 G/A within the 3′-untranslated region (UTR) of the CTLA-4 gene. Patients were classified into two groups: Group I included 23 HLA-identical haplotype allograft recipients and group II, 118 recipients with one or more mismatches in HLA haplotypes. Thirty-six patients developed at least one acute rejection episode (ARE). No significant differences were observed between the genotypes or the allele distribution between ARE and non-ARE patients. However, in group I, (+49) A and CT60 (G) allele frequencies were lower in patients with ARE than those without ARE (0.100 and 0.400 vs 0.361 and 0.722 respectively). However, the difference was not significant. Our study suggested that these alleles may confer protection against renal allograft loss.

CTLA‐4 gene polymorphism of exon 1(+49 A/G) in Turkish systemic lupus erythematosus patients

Cytotoxic T lymphocyte-associated antigen-4 is a cell-surface molecule providing a negative signal for T cell activation. CTLA-4 gene polymorphisms are known to be related with genetic susceptibility to various autoimmune diseases, including systemic lupus erythematosus (SLE). However, the effects of this polymorphism on clinical features of SLE have not been defined. We analysed the CTLA-4 gene +49 A/G polymorphisms in patients with SLE by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and investigated the effect of polymorphisms on clinical outcomes. Blood was collected from 47 unrelated Turkish SLE patients, all fulfilling the American College of Rheumatology criteria for SLE, and 100 ethnically matched healthy volunteers. The AA genotype was a predominant genotype in the Turkish population and genotype frequencies of CTLA-4 AA were significantly higher in SLE patients (70%) than healthy controls (47%) (P = 0.015). There was a statistically significant difference in the AA genotype [odds ratio (OR): 2.66, confidence interval (CI) 95%: 1.27-5.56, P = 0.014] distribution among patients and controls. There was also an increase in A allele frequency in SLE and controls, but the difference was not statistically significant (81% vs. 70%, P = 0.068, OR = 1.8, CI 95%: 0.99-3.28). Interestingly, mean age and mean age of onset disease was higher in AA homozygote SLE patients compared to non-AA (39.2 +/- 11.5 vs. 31.6 +/- 10.6, P = 0.044; 32.38 vs. 24.31, P = 0.046, respectively). There was no association between genotype and the other clinical features of SLE. Our results suggested that CTLA-4 +49 AA genotype might be a risk factor for the development of SLE in Turkish population and G allele might be involved in early development of SLE. No association with clinical features was found for polymorphism of the promoter region in CTLA-4 +49.

Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis

Recent advances have led to novel identification of genetic polymorphisms that are associated with susceptibility to rheumatoid arthritis (RA). Currently, 5 loci (HLA, PTPN22, TRAF1/C5, TNFAIP3, and STAT4) have been consistently reported, whereas others have been observed less systematically. The aim of the present study was to independently replicate 3 recently described RA susceptibility loci, STAT4, IL2/IL21, and CTLA4, in a large Dutch case-control cohort, and to perform a meta-analysis of all published studies to date and investigate the relevance of the findings in clinically well-defined subgroups of RA patients with or without autoantibodies. The STAT4, IL2/IL21, and CTLA4 gene polymorphisms (rs7574865, rs6822844, and rs3087243, respectively) were genotyped in 877 RA patients and 866 healthy individuals. A meta-analysis of all published studies of disease association with these polymorphisms was performed using the Mantel-Haenszel fixed-effects method. An association of STAT4, IL2/IL21, and CTLA4 with RA was detected in Dutch patients (odds ratio [OR] 1.19 [P=0.031], OR 0.84 [P=0.051], and OR 0.87 [P=0.041], respectively). Results from the meta-analysis confirmed an association of all 3 polymorphisms with RA in Caucasians (OR 1.24 [P=1.66x10(-11)], OR 0.78 [P=5.6x10(-5)], and OR 0.91 [P=1.8x10(-3)], respectively). The meta-analysis also revealed that STAT4 predisposed to disease development equally in patients with autoantibodies and those without autoantibodies, and that CTLA4 enhanced the development of anti-citrullinated protein antibody (ACPA)-positive RA as compared with ACPA-negative RA. Our results replicate and firmly establish the association of STAT4 and CTLA4 with RA and provide highly suggestive evidence for IL2/IL21 loci as a risk factor for RA. Given the strong statistical power of our meta-analysis to confirm a true-positive association, these findings provide considerable support for the involvement of CTLA4 in distinct subsets of RA patients.

CTLA4 gene polymorphisms are associated with chronic bronchitis

Chronic obstructive pulmonary disease (COPD) is characterised by chronic and progressive dyspnoea, cough and sputum production. T-lymphocytes may play a key role in the pathogenesis of COPD and chronic bronchitis. Cytotoxic T-lymphocyte antigen (CTLA) 4 is a potential candidate gene because it modulates T-cell activation. Genetic association between nine CTLA4 single nucleotide polymorphisms (SNPs) and chronic bronchitis was assessed in 606 pedigrees (1,896 individuals) from the International COPD Genetics Network (ICGN) population. We then replicated the associations in 342 COPD subjects with chronic bronchitis and 511 COPD subjects without chronic bronchitis from Bergen, Norway. Family-based association tests were used to analyse the ICGN cohort, and a logistic regression model was used for the Bergen cohort. Six CTLA4 SNPs were significantly associated with chronic bronchitis in the ICGN cohort (0.0079< or = p < or =0.0432), with three being replicated with the same directionality of association in the Bergen cohort (0.0325< or = p < or =0.0408). One of these replicated SNPs (rs231775) encodes the Thr to Ala substitution at amino acid position 17. Haplotype analyses supported the results of single SNP analyses. Thus, CTLA4 is likely to be a genetic determinant of chronic bronchitis among COPD cases.

Influence of CTLA-4 gene polymorphism in autoimmune and infectious diseases

Cell-mediated immunity requires costimulatory activity to initiate or inhibit antigen-specific T-cell responses. CTLA-4 is an inhibitory receptor expressed by activated and regulatory T cells. The single nucleotide polymorphism (SNP) +49 A/G of the CTLA-4 gene alters intracellular distribution of CTLA-4, interleukin-2 production, and, as a consequence, T-cell proliferation. The aim of this study was to analyze the only coding SNP CTLA-4 +49 A/G polymorphism in patients with either infectious (Chagas's, Dengue, and American cutaneous leishmaniasis) or autoimmune diseases (myasthenia gravis, pemphigus, and psoriasis). No statistically significant differences were reported when all patients of each disease group were compared with healthy individuals. However, the +49 G/G genotype was moderately increased in pemphigus and myasthenia gravis. Patients with diffuse cutaneous leishmaniasis (DCL) exhibited an increased frequency of the A/G +49 genotype compared with patients with localized cutaneous leishmaniasis (LCL; p = 0.009; odds ratio [OR] = 4.25; 95% confidence interval [CI] = 1.245–14.501) and intermediate cutaneous leishmaniasis (ICL; p = 0.027; OR = 4.44; 95% CI = 1.273–15.516), indicating that the heterozygous genotype, associated with overactivation of T-cell proliferation, could confer susceptibility to the development of the more severe clinical form of cutaneous leishmaniasis. The A/A +49 genotype was increased in LCL patients compared with DCL patients ( p = 0.019; OR = 0.25; 95% CI = 0.067–0.953), indicating that this genotype, which has been associated with normal proliferation of T cells, could confer protection to the development of DCL. The results indicate that the polymorphism of CTLA-4 is an important genetic factor associated with risk or protection for the development of diffuse cutaneous leishmaniasis and has influence in the pathogenesis of autoimmune diseases. However, other closely linked candidate genes in linkage disequilibrium with CTLA4, such as CD28 and ICOS, could be associated with the development of autoimmune and infectious disease.

CTLA4/ICOS gene variants and haplotypes are associated with rheumatoid arthritis and primary biliary cirrhosis in the Canadian population

The co-occurrence of different autoimmune diseases in patients and their families suggests the presence of shared genetic risk factors. Two compelling candidate autoimmune disease susceptibility genes are those that encode CTLA4 and inducible costimulator (ICOS), immunoregulatory proteins. Associations of CTLA4 polymorphisms with various autoimmune diseases have been reported, but for rheumatoid arthritis (RA) and primary biliary cirrhosis (PBC), the association data are inconsistent and have largely excluded analysis of polymorphisms in the ICOS gene adjacent to CTLA4. We undertook this study to examine whether CTLA4 and ICOS influence RA and PBC susceptibility by testing CTLA4/ICOS polymorphisms for association with these diseases in Canadian subjects. Caucasian RA patients (n = 1,140), PBC patients (n = 481), and controls (n = 1,248) were typed for 21 biallelic polymorphisms across the CTLA4/ ICOS genes using a multiplex genotyping array, and the results were analyzed using a false discovery rate method to correct for multiple testing. Significant associations of multiple CTLA4 and ICOS gene polymorphisms with RA and PBC were observed, with the strongest association signals for both diseases coming from a CTLA4/ICOS intergenic single-nucleotide polymorphism, rs17268364 (corrected P [P(corr)] = 6.0 x 10(-4) and P(corr) < 1.0 x 10(-4), respectively). Significant associations, which were common to both diseases, were also observed with other alleles and haplotypes across 3 linkage disequilibrium blocks within the CTLA4 gene, the intergenic region, and the ICOS gene. Our results provide evidence for RA and PBC association with the CTLA4/ICOS locus and suggest that the risk allele(s) within this region may be common to both diseases.

Combination of CTLA-4 and TGFβ1 gene polymorphisms associated with dengue hemorrhagic fever and virus load in a dengue-2 outbreak

The pathogenesis of dengue hemorrhagic fever (DHF) has been considered to be massive immune activation of T cells. Abnormal expression of the immune regulatory molecules, CTLA-4 and TGFbeta1, leads to disturbances of regulatory T cell immune response. We investigate the contribution of CTLA-4 and TGFbeta1 in DHF by analyzing them for association with virus load in blood and polymorphisms of CTLA-4 +49A/G, and TGFbeta1 -509C/T in a DEN-2 outbreak. The increased frequency of the TGFbeta1 -509 CC genotype in patients with DHF was compared to those with dengue fever (OR=1.9, p=0.034). Moreover, the presence of the CTLA-4 +49 G allele and TGFbeta1 -509 CC genotype increased the susceptibility to risk of DHF (OR=2.1, p=0.028) and significantly higher virus load (p=0.013). This finding suggests that a combination of CTLA-4 and TGFbeta1 polymorphisms is associated with the susceptibility of DHF and higher virus load.

Association of the T-cell Regulatory Ggene CTLA-4 with Suscep-tibility to Autoimmune Thyroid Disease in Population of Novosibirsk

Autoimmune thyroid disease (AITD) is caused by an immune response to self-thyroid antigen. The cytotoxic T-lymphocyte antigen-4 (CTLA4) gene, encoding a negative regulator of the T-lymphocyte immune response, had been reported to be associated and/or linked to AITD. The aim of the study was to investigate the association between the exon 1 CTLA-4 gene polymorphism A(49)G and susceptibility to graves’ disease (GD) and Hashimotos thyroiditis (HT). Materials and methods. We analyzed the A(49)G exon 1 CTLA-4 gene polymorphism in 105 unrelated Novosibirsk patients with GD, in 101 patients with HT and 150 matched healthy subjects. Results. The distribution of genotype frequencies differed significantly between patients with GD and controls (p = 0.039). The allele G and the genotype GG were associated with the increased risk for GD (odds ratio OR = 1,55, 95% CI, 1,09—2,21, OR = 2,43, 95% CI, 1,17—5,01 respectively). In contrast, no differences in genotype frequencies were observed between HT patients and controls for the A(49)G exon 1 CTLA-4 gene polymorphism. Conclusion: This suggests that the CTLA-4 gene might play a role in the development of DTS in the Novosibirsk population.

Identification of CTLA-4 isoforms produced by alternative splicing and their association with myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness induced by autoantibodies against the acetylcholine receptor. CTLA-4 (CD152) plays an inhibitory role in the immune response and has been suggested to be involved in the pathophysiology of MG. In this study, we focused on alternative CTLA-4 mRNA expression in PBMCs from MG patients. We defined two new isoforms of CTLA-4 mRNA that arise due to alternative splicing. By semi-quantitative RT-PCR analysis, we observed a lower expression of sCTLA-4 mRNA relative to the membrane form in MG patients. In addition, the MG patients had lower levels of sCTLA-4 mRNA in PBMCs compared to healthy controls, as assessed by real-time PCR. One of the spliced isoforms (LCTLA-4) was more prevalent in MG patients compared to healthy controls. The alternative splicing was not associated with sex, thymectomy, serum levels of anti-AChR, immunosuppressive treatment or the four CTLA-4 gene polymorphisms analyzed. This study reveals an abnormal spectrum of mRNA expression of CTLA-4 in MG patients, which marks the importance of studying gene expression of alternative splicing.

Pharmacogenetic analysis of CTLA4 gene polymorphisms and response to tremelimumab in patients with advanced melanoma

14003 Background: Tremelimumab is a fully-human, immune-enhancing, monoclonal antibody targeted against CTLA4 in clinical development for the treatment of solid tumors. In recognition of the fact t...

Possible Association of CTLA-4 Gene Polymorphism With Cyclosporine-Induced Gingival Overgrowth in Kidney Transplant Recipients

T-lymphocytes may play a role in the pathogenesis of inflammatory periodontal diseases and cyclosporine (CsA)-induced gingival overgrowth (GO). The gene encoding CTLA-4 (Cytotoxic T-lymphocyte antigen 4, a molecule influencing T-cell activation), is known to have a single nucleotide polymorphism (SNP) in promoter C>T −318; an exon 1 A>G 49, and a microsatellite dinucleotide repeat polymorphism (AT) n in exon 4. The purpose of this study was to analyze the possible influence of polymorphisms of CTLA-4, interleukin (IL)-2, and tumor necrosis factor (TNF)-α on GO incidence in eighty two renal transplant recipients. 34 CsA-treated with significant GO (CsAGO+); 22, CsA-treated with no GO (CsAGO−), and 26 tacrolimus (Tac)-treated without GO (TacGO−). The SNPs of CTLA-4 (−318 C>T and +49 A>G), IL-2 (−330T>G), and TNF-α (−308 G>A) were determined by SSP-PCR methods. The CTLA-4 (AT) n genotype was determined using polymerase chain reaction and fluorescence-based analysis with capillary electrophoresis. Allele frequencies in all patient groups were similar for CTLA-4 −318C>T, IL-2, and TNF-α. However, patients with CsAGO+ showed differences from CsAGO− for allele and genotype frequencies in position +49A>G of the CTLA-4 gene. The +49G allele was two times less frequent among CsAGO+ than CsAGO− ( P = .0052; P corrected = .008). Slight differences between CsAGO+ and CsAGO− were noticed for the genotype distribution of CTLA-4 (AT) n ( P = .056). The results suggested that appearance of an adenosine allele(A) in position +49 of the CTLA-4 gene may be a permissive element for CsA-induced GO.

145-P: Association of CTLA-4 gene polymorphisms and susceptibility to type 1 diabetes in Greek population

145-P: Association of CTLA-4 gene polymorphisms and susceptibility to type 1 diabetes in Greek population

CTLA4 gene polymorphisms and multiple sclerosis in Northern Ireland

Four CTLA4 polymorphisms were investigated in a Northern Irish collection of relapsing–remitting (RR) and primary-progressive (PP) multiple sclerosis (MS) patients. The CTLA4 promoter (− 318 C/T), exon 1 (+ 49 A/G) and intergenic CT60 SNPs, as well as a microsatellite found in the 3′ UTR (AT n) were analysed in 246 RRMS, 84 PPMS and 158 healthy controls. The A allele of the exon 1 + 49 A/G SNP (OR = 1.36; 95% CI = 1.11–1.81; P = 0.038), and more so the AA genotype (OR = 1.70; 95% CI = 1.11–2.60; P = 0.015) were associated with RR, but not PPMS. In the PPMS population, overall allele distribution of the AT n microsatellite was significantly different from that in the healthy controls. We did not find any association with the promoter (− 318 C/T) or intergenic CT60 SNPs in either of the disease cohorts. In concordance with several recent studies, we detected a trend toward higher carriage rates of the + 49 G allele in PP vs RR MS patients (66.7% vs 58.9%), though this was not significant. Our data highlight the CTLA4 + 49 A/G and 3′UTR polymorphisms as potential modifiers of disease course in MS.

CTLA-4 gene polymorphisms in patients with Turner syndrome

Immunological disturbances have previously been described in Turner syndrome (TS) that were associated with reduced levels of serum IgG and IgM, increased IgA and a decrease of circulating T- and B lymphocytes. The cytotoxic T-lymphocyte antigen 4 (CTLA-4; CD152) is expressed on activated T cells and inhibits further activation by binding to costimulatory molecules B7.1 and B7.2 of antigen-presenting cells. In order to evaluate the role of CTLA-4 gene in TS disease we analysed five single nucleotide polymorphisms (SNPs) within the CTLA-4 gene [MH30 (C/G n=19), -1661 (A/G n=23), -319 (C/T n=23), +49 (A/G=36) and CT60 (G/A n=19)] in patients with TS and in healthy controls (n=167). Additionally, haplotypes in both patients and controls were constructed and compared. The polymorphisms -319, MH30 and -1661 were genotyped by restriction fragment length polymorphisms, the +49 polymorphism by single strand conformation polymorphism and the CT-60 polymorphism by real time PCR. Patients and controls were compared using genotype-wise Chi2. The CTLA4 MH30 (C/G) heterozygosity rate (57.9% vs. 40.1%) was higher in patients with TS than in healthy controls while the variant C was less frequent (5.3% vs. 22.8%). However, the differences did not reach the level of statistical significance (p=0.1). Furthermore, no significant differences in the distribution of the polymorphisms -1661 (A/G), +49 (A/G) CT60 (G/A) and CTLA4–319 (C/T) were observed between TS and healthy controls. Our data suggest that the CTLA-4 MH30 polymorphism could be associated with TS disease whereas the polymorphisms -1661, +49, CT60 and -319 within the CTLA-4 gene are probably not related to the TS disease. An association with CTLA4 variants in a subgroup of TS patients may contribute to the frequently coobserved autoimmune disorders. To confirm this hypothesis the sample size will be increased and functional studies of the CTLA-4 gene performed that are focused on the underlying signal transduction pathway in order to elucidate the role of these SNPs in TS.

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.

Distribution of CTLA-4 Polymorphisms in Allergic Asthma

Background: The CTLA-4 molecule is an important negative regulator of T cell activation. It is encoded on chromosome 2q33 and found to be associated with several allergic phenotypes including asthma. However, the association of CTLA-4 gene polymorphisms with allergic asthma is still controversial and therefore was the subject of this study. Methods: By PCR-RFLP, the distribution of three single nucleotide polymorphisms (SNPs), –1147 C/T, –318 C/T, and +49 A/G, was examined in 219 Polish Caucasoid patients diagnosed with allergic asthma and in 102 ethnically matched healthy control individuals. (AT)_n microsatellite polymorphism was also tested in the same individuals. Results:No statistically significant differences in SNPs or microsatellite allele, genotype or haplotype frequencies between patients and controls were found. Conclusion:CTLA-4 polymorphisms do not seem to be a risk factor for allergic asthma in Poles.

Association of T-Cell Regulatory Gene Polymorphisms With Susceptibility to Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Helicobacter pylori infection and host susceptibility interact to develop gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and activation of specific T cells might play a crucial role in this process. Recent investigations show that the CTLA4, CD28, and ICOS genes are located on chromosome 2q33 and their polymorphisms confer susceptibility to infectious and immune diseases through deregulation of T-cell stimulation. We aimed to determine the role of CTLA4, CD28, and ICOS polymorphisms in gastric MALT lymphoma. Genotyping for CTLA4 (49 A/G, -318 C/T, and CT60 A/G), CD28 (IVS3+ 17T/C), and ICOS (c.602 A/C and c.1624C/T) was performed for 62 patients with gastric MALT lymphoma and compared with 250 unrelated healthy controls. H pylori infection was significantly higher in patients with gastric MALT lymphoma (90.3%) compared with controls (66.4%; P < .001). The CTLA4 -318 C/T genotype was associated with a lower risk of developing gastric MALT lymphoma (odds ratio [OR] = 0.3; P = .022), whereas CTLA4 49 G/G genotype was linked to a higher risk (OR = 4.1; P = .044). In patients with H pylori infection, CTLA4 49 G/G genotype was associated with an even higher risk (OR = 6.4; P = .047). Carriage of the tightly linked -318C -49G haplotype conferred a four-fold higher susceptibility to MALT lymphoma (OR = 4.2; P = .042). Complete remission after H pylori eradication was related to tumor stage but not to genotypes or haplotypes. These results indicate a genetic link of CTLA4 gene polymorphisms to development of gastric MALT lymphoma and indirectly support the crucial role of host activated T cells in the MALT lymphomagenesis.