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

Tsu-Yao Cheng, Jaw-Town Lin, Li-Tzong Chen, Chia-Tung Shun, Hsiu-Po Wang, Ming-Tsang Lin, Tsang-En Wang, Ann-Lii Cheng, Ming-Shiang Wu

From the Department of Laboratory Medicine, Division of Gastroenterology, Department of Internal Medicine, and Departments of Pathology, Surgery, and Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine; Division of Cancer Research, National Health Research Institute; and the Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan

Address reprint requests to Ming-Shiang Wu, MD, PhD, Departments of Internal Medicine and Primary Care Medicine, National Taiwan University Hospital, 7, Chung-Shan South Rd, Taipei, Taiwan; e-mail: stanley{at}ha.mc.ntu.edu.tw

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: 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.

PATIENTS AND METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

	INTRODUCTION

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Mucosa-associated lymphoid tissue (MALT) lymphoma is a histologically distinct malignancy characterized by lymphoepithelial lesions infiltrated by monoclonal B cells.¹ It usually arises from MALT that has been acquired as a result of chronic inflammatory conditions at sites normally devoid of MALT, such as the stomach, salivary gland, lung, thyroid, and ocular adnexa.² Gastric MALT lymphoma accounts for at least 50% of primary gastric lymphoma.¹ Recently, several lines of epidemiologic, clinical, and laboratory evidence have suggested that the gastric MALT lymphoma is linked to chronic Helicobacter pylori infection.³ However, the majority of H pylori–infected patients remain in asymptomatic gastritis, and only less than 0.01% of patients with H pylori gastritis progress to gastric MALT lymphoma.⁴ Such variable outcomes after infection are dependent on the interaction of H pylori and immune reaction of the host. It was assumed that additional microbial virulence, environmental cofactors, and host genetic makeup might contribute to the process of gastric lymphomagenesis.⁵

Previous studies have demonstrated that H pylori can directly stimulate the proliferation of tumor-infiltrating T cells rather than MALT lymphoma B cells.⁶ The H pylori–specific T cells then provide contact-dependent help to promote the survival and proliferation of the lymphoma cells.⁷ These H pylori–specific T cells thus play a key role in assisting development of gastric MALT lymphoma.⁸ Accordingly, factors regulating T-cell function may influence the susceptibility to MALT lymphomagenesis. In this respect, cytotoxic T-lymphocyte antigen 4 (CTLA4), which is expressed mainly on activated T cells, is currently regarded to be crucial in the regulation of T-cell stimulation. CTLA4 binds to B7 molecules present on antigen-presenting cells and functions as a negative regulator of T-cell activation.⁹ The inhibitory role of CTLA4 in maintaining homeostasis of inflammatory and immune reactions made it a potential candidate gene in determining the genetic predisposition of infectious and autoimmune diseases. It has been documented that CTLA4-deficient mice could develop lymphoproliferative disorders characterized by polyclonal T-cell proliferation and early lethality.¹⁰ Furthermore, CTLA4 polymorphisms (49 A/G, –318 C/T, and CT60) were associated with susceptibility to autoimmune disorders, such as Graves' disease, autoimmune hypothyroidism, and type 1 diabetes.¹¹ Recent reports also revealed that polymorphisms in CTLA4 genes have a role in the occurrence of multiple myeloma¹² and non-Hodgkin's lymphoma (NHL).^13,14

In addition to CTLA4, CD28 and inducible costimulator (ICOS) are also potential candidates for investigations of immune-mediated diseases. CD28 provides a costimulatory signal necessary for T-cell activation, which is counterbalanced by CTLA4. ICOS plays a role in regulating cytokine production in recently activated and effector T cells.¹⁵ There is growing evidence that CD28, CTLA4, and ICOS genes are located on chromosome 2q33, which contains a locus or loci for autoimmune and immune-mediated diseases.¹⁶ CD28 IVS3+ 17T/C allele polymorphism was associated with early-onset type 1 diabetes,¹⁷ whereas ICOS polymorphisms (c.602 A/C and c.1624 C/T) were related to celiac disease.¹⁸ However, whether genetic polymorphisms of the CD28-CTLA4-ICOS region play a role in gastric MALT lymphoma remains unknown.

There are only a few reports concerning host genetic factors in gastric MALT lymphoma. Rollinson et al¹⁹ first reported that both the IL-1RN 2/2 and GST T1 null genotypes were strongly associated with risk of gastric MALT lymphoma. Nevertheless, Hellmig et al²⁰ could not confirm the results, and they reported that toll-like receptor 4 (TLR4) Asp299Gly was associated with decreased risk of gastric MALT lymphoma.²¹ However, TLR4 polymorphism was rarely present in the Chinese population.²² We previously reported that the influence of TNF-857 T allele and GST T1 null genotype may modify the risk of gastric MALT lymphoma.^23,24 In this study, we aimed to investigate the relationship between genetic polymorphisms of T-cell regulatory genes (CTLA4, CD28, and ICOS) and gastric MALT lymphoma.

	PATIENTS AND METHODS

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Study Patients
Since January 1998, blood samples have been prospectively collected from individuals who participated in the national project on risk factors and natural history of gastric MALT lymphoma. Study protocol was approved by the Department of Health, Executive Yuan, Taiwan and the Taiwan Cooperative Oncology Group for gastric MALT lymphoma. A full verbal explanation of the study was given to all participants. They consented to participate on a voluntary basis. Patients with newly diagnosed gastric MALT lymphoma were enrolled from inpatient units and outpatient cancer clinics of four major medical centers in Taiwan. Inclusion and exclusion criteria, along with the diagnostic criteria for tumor grading and staging, were defined previously.²⁵ In brief, high-grade MALT lymphoma was defined as the presence of confluent clusters or sheets of large cells resembling centroblasts or lymphoblasts within predominantly low-grade centrocyte-like cell infiltrate or a predominance of high-grade lymphoma with only small, residual, low-grade foci and/or the presence of lymphoepithelial lesions. Patients with primary, pure, large-cell lymphoma of the stomach, without evidence of a low-grade component, were excluded. In total, we studied 62 patients with gastric MALT lymphoma, for whom a DNA sample and complete clinical data were available. All patients were Han Chinese, and none had a family history of gastric malignancy. For the control group, we randomly screened participants from health-examination clinics. They did not have malignancy or any autoimmune or immune-mediated disease such as type 1 diabetes, Graves' disease, and autoimmune hypothyroidism.

H pylori infection was screened with serology test using a standard enzyme-linked immunosorbent assay and confirmed by histologic examination, biopsy urease test, or bacterial culture. Patients were scheduled for regular follow-up as stated previously.²⁵ Complete histologic remission was defined as a Wotherspoon's score of 2 or less on every histologic section of the biopsy specimens. Systemic chemotherapy would be administered to those with grossly stable or progressive disease during follow-up courses.

Genotyping Method
Genomic DNA was isolated from cryopreserved WBCs by a standard proteinase K digestion and phenol-chloroform method. Polymorphism analyses for CTLA4, CD28, and ICOS were performed according to modified protocols from previously reported assays. Polymerase chain reaction (PCR) amplification of the promoter or coding regions of the genes was performed using specifically designed pairs of oligonucleotide primers. Polymorphisms were then identified by restriction enzyme length polymorphism for CTLA4, CD28, and ICOS. The individual genotype was confirmed by PCR with subsequent direct sequencing (ABI Prism 377 DNA sequencer; PE Biosystems, Foster City, CA). Primer sequences, annealing temperatures for PCR, and detection methods used in assays are listed in Table 1. All laboratory assays were conducted and interpreted blindly, without the knowledge of case or control status.

	RESULTS

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Demographic Features of the Patients and Controls
The demographic characteristics of patients and controls are listed in Table 2. There were no statistical differences in the distributions of age and sex between patients with gastric MALT lymphoma and controls. The positive rate of H pylori was significantly higher for patients with gastric MALT lymphoma (90.3%) than controls (66.4%; P < .001).

Genotype Distribution of the Patients and Controls
Table 3 lists the genotype frequencies of the CD28-CTLA4-ICOS gene region in patients with gastric MALT lymphoma and controls. The frequencies of all the genotypes approximated Hardy-Weinberg equilibrium, and the allele frequencies were comparable with those previously reported.²⁶ No statistical significance was noted in the overall risk of developing gastric MALT lymphoma for CTLA4 CT60, CD28 IVS3+ 17, ICOS c.602 and ICOS c.1624 genotypes. CTLA4 –318 C/T genotype was associated with a significantly lower risk of developing gastric MALT lymphoma (OR = 0.3; P = .022), whereas CTLA4 49 G/G genotype was associated with a significantly higher risk (OR = 4.1; P = .044). The reported high-risk polymorphism (CT60) with Graves' disease in the study be Ueda et al¹¹ showed no association in our analysis.

	DISCUSSION

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The genetic associations between CTLA4 promoter –318C/T and exon 1 49A/G polymorphisms have been extensively investigated in many autoimmune diseases,^27-31 including type 1 diabetes, Graves' disease, autoimmune hypothyroidism, Addison's disease, celiac disease, primary biliary sclerosis, systemic lupus erythematosus, primary progressive multiple sclerosis, and rheumatoid arthritis. In addition, B-cell lymphoproliferative disorders, such as multiple myeloma and NHL, were also related to CTLA4 polymorphisms.^12-14 Most of the reported disease associations showed that there were significantly higher frequencies of CTLA4 49G allele (susceptible variant) in patients than in controls, except that the 49A allele was found significantly more frequently in patients with celiac disease and NHL.²⁸ Previous studies have also shown that the CTLA4 promoter –318T allele is tightly linked to the 49A allele.^29,30 In this study, we found that carriers of the CTLA4 49G variant were over-represented among gastric MALT lymphoma patients with a four-fold increase of risk, whereas CTLA4 –318T allele carriers were significantly under-represented. Moreover, CTLA4 49G/G genotype was associated with a six-fold increase of risk in patients with H pylori infection. Thus, our results suggest that CTLA4 gene polymorphisms might play an important role in affecting development of gastric MALT lymphoma, particularly in those with previous H pylori infection.

Defective immunoregulation after T-cell activation can favor the development of B-cell lymphoproliferative disorders.^32,33 Gastric MALT lymphoma is a lymphoproliferative disorder characterized by monoclonal B-cell infiltration and lymphoepithelial lesions. A number of studies have implicated the pathogenic role of H pylori in gastric MALT lymphoma. However, H pylori stimulation of lymphoma B cells is not direct but, instead, occurs through tumor-infiltrating T cells. These H pylori–specific T cells provide contact-dependent stimulus to tumor B cells via CD40-mediated signaling, so the tumor B cells could continue to proliferate.⁷ Because CTLA4 acts specifically as a negative regulator of T-cell activation, it is plausible that variant CTLA4 alleles might contribute to interindividual differences in inflammatory and immune responses and account for genetic susceptibility to gastric MALT lymphoma after an infectious event.

Previous studies have revealed that the susceptible allele (CTLA4 49G) found in the current study has a functional effect on the expression level of CTLA4.^34-36 CTLA4 49G introduces a hydrophobic amino acid (threonine to alanine) in a highly conserved position and changes glycosylation in one of the two possible sites. Anjos et al³⁷ have demonstrated that persons with homozygous G/G have one third less CTLA4 on their T-cell surface than people with homozygous A/A. Moreover, CTLA4 blockade with soluble anti-CTLA4 monoclonal antibody resulted in less augmentation in T cells from individuals with susceptible G/G alleles compared with those possessing protective alleles (A/A).³⁷ Using patients with a combination of CTLA4 genotypes (exon 1 A/G and –318 C/T), differences have been reported between genotypes in terms of intracellular and cell-surface CTLA4. Taken together, these studies indicate that CTLA4 exerts less profound inhibitory effects on T-cell proliferation in people with CTLA4 genotype susceptibility and provide a mechanism to explain the link between CTLA4 polymorphisms and different clinical outcomes. Therefore, our finding of association of CTLA4 polymorphisms with MALT lymphoma has biologic plausibility; decreasing vigor of T-cell inhibition in persons with homozygous G/G allele would be expected to increase susceptibility to tissue-destructive inflammatory processes after H pylori infection and to enhance the likelihood of B-cell proliferation.

Although we found that CTLA4 polymorphisms appeared to have a role on genetic susceptibility to gastric MALT lymphoma, none of the genotypes or haplotypes had a significant impact on predicting tumor response after anti-Helicobacter therapy. Because previous reports suggested that H pylori–specific tumor-infiltrating T cells might play only an assistant role in the early phase of tumor development of gastric MALT lymphoma,^38,39 it was no surprise to find a poor correlation between T-cell deregulation and tumor response. We noted that treatment response after eradication of H pylori was related to tumor stage. This result was in agreement with previous reports.

Investigators have reported that the CTLA4 49A allele might confer susceptibility to NHLs.^13,14 However, we detected a higher risk of developing gastric MALT lymphoma with the CTLA4 49G allele. Such discrepancies may arise from different study designs. In contrast to our studies selecting gastric MALT lymphoma only, Monne et al¹³ enrolled heterogeneous patients, including both B- and T-cell lymphoma and MALT lymphoma patients. Genetic heterogeneity in the pathogenesis of different lymphomas may account for the variability in different studies of host susceptibility. Because expression of CTLA4 or its ligands was different in tumor and reactive cells among different subtypes of lymphoma,³⁸ the actual genetic effect might be unraveled after proper categorization of investigated patients.

Previous reports have indicated that ethnic differences in the distribution of CTLA4 genotypes exist.^11-14 In our study, CTLA4 49G allele was present in 88.4% of the control population, which is higher than the reported rate in the white population. A similar high frequency of the CTLA4 49G allele was also noted in Japanese and Korean populations.³¹ According to official cancer registry records in 1998 to 2003, the incidence rate of gastric MALT lymphoma in Taiwan was estimated to be 0.34 per 100,000 per year, which was lower than the incidence rate in northeastern Italy (13.2 per 100,000 per year).³² Therefore, the high CTLA4 49G allele carriage in Taiwan did not directly link to a higher incidence rate of gastric MALT lymphoma. Because MALT lymphomagenesis is a complex disease resulting from inappropriately regulated gastric immune response to H pylori infection, some genes other than the CTLA4 49G allele may also be involved in disease development. Knowledge of other risk-conferring alleles and investigation in other ethnic groups are needed in future studies to provide a better understanding of this special subset of H pylori–related diseases.

There are certain limitations in our study. First, the CTLA4 G alleles per se could be involved in pathogenesis or represent mere genetic markers that are in linkage disequilibrium with other causative variants. Strong linkage disequilibrium has been found between single nucleotide polymorphisms within a linkage disequilibrium block delimited by MH30 and D2S72,⁴⁰ which encompasses all three single nucleotide polymorphisms of CTLA4 in our study. Although 49 A/G is the most frequently reported susceptible locus, Ueda et al¹¹ have demonstrated that the strongest disease association was the CT60 A/G polymorphism, which may be a common denominator for autoimmune disease. Of interest, haplotype with G allele at CT60 and G allele at position 49 can encode an alternatively spiced CTLA4 mRNA and result in lower mRNA levels of the soluble CTLA4 isoforms compared with the haplotype containing A allele at both positions.¹¹ However, we did not find genetic association between CT60 polymorphisms and gastric MALT lymphoma. Further fine mapping of CTLA4 and neighboring genes within the region will be necessary to clarify the susceptible allele of gastric MALT lymphoma. Furthermore, functional analyses of these polymorphisms may add further information on genetic association studies and elucidate the role of different genotypes on the pathogenesis of gastric MALT lymphoma. Second, tumorigenesis in humans is a multistep process, and a specific genetic event may contribute only partially to the acquisition of a single acquired capability of the tumor.⁴¹ Other genetic factors, such as TNF-857 T allele and GST T1 null genotype, and certain microbial and environmental factors that may play in concert to cause tumor formation and genetic heterogeneity in different ethnic population should also be taken into consideration. Third, although patients were enrolled from four different hospitals located in different regions of Taiwan, inherent selection bias cannot be completely excluded in hospital-based case-control studies. More patients are needed for both confirmation of our preliminary findings and further stratification studies. Fourth, ethnic differences and disease heterogeneity may account for variation in host susceptibility. Because of the relative rarity of the gastric MALT lymphoma, we did not have the chance to test the validity in other ethnic population. Further evaluation from different ethnic populations with possible meta-analysis might help clarify the real genetic effect.⁴²

In conclusion, among the six polymorphisms in the CD28-CTLA4-ICOS region, we found that CTLA4 49G itself or a neighboring gene might confer a significant relative risk for gastric MALT lymphoma. CTLA4 –318T carriage for reduced risk of gastric MALT lymphoma is probably related to linkage disequilibrium effect. Larger genetic studies in other ethnic populations will offer additional information about the general contribution of the CTLA4 gene to the development of gastric MALT lymphoma; and studies on the functional significance of the polymorphisms in the CD28-CTLA4-ICOS region will elucidate the mechanisms of the association between the costimulatory molecule gene and MALT lymphoma.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Tsu-Yao Cheng, Jaw-Town Lin Administrative support: Li-Tzong Chen, Chia-Tung Shun, Hsiu-Po Wang, Ming-Tsang Lin, Ann-Lii Cheng, Ming-Shiang Wu Provision of study materials or patients: Jaw-Town Lin, Li-Tzong Chen, Hsiu-Po Wang, Ming-Tsang Lin, Tsang-En Wang, Ann-Lii Cheng, Ming-Shiang Wu Collection and assembly of data: Tsu-Yao Cheng, Li-Tzong Chen Data analysis and interpretation: Tsu-Yao Cheng, Chia-Tung Shun, Ming-Shiang Wu Manuscript writing: Tsu-Yao Cheng, Jaw-Town Lin, Ming-Shiang Wu Final approval of manuscript: Jaw-Town Lin, Ming-Shiang Wu

 

	NOTES

 
Supported by Grant No. NSC-94-2314- B002-234 from the National Science Council, Executive Yuan, Taiwan.

T.-Y.C. and J.-T.L. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Fischbach W, Kestel W, Kirchner T, et al: Malignant lymphomas of the upper gastrointestinal tract: Results of a prospective study in 103 patients. Cancer 70:1075-1080, 1992[CrossRef][Medline]

2. Isaacson PG: Update on MALT lymphomas. Best Pract Res Clin Haematol 18:57-68, 2005[Medline]

3. Sepulveda AR, Coelho LG: Helicobacter pylori and gastric malignancies. Helicobacter 7:S37-S42, 2002 (suppl 1)[CrossRef]

4. Houghton J, Fox JG, Wang TC: Gastric cancer: Laboratory bench to clinic. J Gastroenterol Hepatol 17:495-502, 2002[CrossRef][Medline]

5. Cavalli F, Isaacson PG, Gascoyne RD, et al: MALT lymphomas. Hematology (Am Soc Hematol Educ Program) 1:241-258, 2001

6. Greiner A, Marx A, Heesemann J, et al: Idiotype identity in a MALT-type lymphoma and B cells in Helicobacter pylori associated chronic gastritis. Lab Invest 70:572-578, 1994[Medline]

7. Hussell T, Isaacson PG, Crabtree JE, et al: Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. J Pathol 178:122-127, 1996[CrossRef][Medline]

8. Guindi M: Role of activated host T cells in the promotion of MALT lymphoma growth. Semin Cancer Biol 10:341-344, 2000[CrossRef][Medline]

9. Tivol EA, Borriello F, Schweitzer AN, et al: Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541-547, 1995[CrossRef][Medline]

10. Waterhouse P, Penninger JM, Timms E, et al: Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985-988, 1995[Abstract/Free Full Text]

11. Ueda H, Howson JM, Esposito L, et al: Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506-511, 2003[CrossRef][Medline]

12. Zheng C, Huang D, Liu L, et al: Cytotoxic T-lymphocyte antigen-4 microsatellite polymorphism is associated with multiple myeloma. Br J Haematol 112:216-218, 2001[CrossRef][Medline]

13. Monne M, Piras G, Palmas A, et al: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene polymorphism and susceptibility to non-Hodgkin's lymphoma. Am J Hematol 76:14-18, 2004[CrossRef][Medline]

14. Piras G, Monne M, Uras A, et al: Genetic analysis of the 2q33 region containing CD28-CTLA4-ICOS genes: Association with non-Hodgkin's lymphoma. Br J Haematol 129:784-790, 2005[CrossRef][Medline]

15. Sharpe AH, Freeman GJ: The B7-CD28 superfamily. Nat Rev Immunol 2:116-126, 2002[CrossRef][Medline]

16. Kristiansen OP, Larsen ZM, Pociot F: CTLA-4 in autoimmune diseases: A general susceptibility gene to autoimmunity? Genes Immun 1:170-184, 2000[Medline]

17. Ihara K, Ahmed S, Nakao F, et al: Association studies of CTLA-4, CD28, and ICOS gene polymorphisms with type 1 diabetes in the Japanese population. Immunogenetics 53:447-454, 2001[CrossRef][Medline]

18. Haimila K, Smedberg T, Mustalahti K, et al: Genetic association of coeliac disease susceptibility to polymorphisms in the ICOS gene on chromosome 2q33. Genes Immun 5:85-92, 2004[CrossRef][Medline]

19. Rollinson S, Levene AP, Mensah FK, et al: Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and antioxidative capacity. Blood 102:1007-1011, 2003[Abstract/Free Full Text]

20. Hellmig S, Vollenberg S, Goebeler-Kolve ME, et al: IL-1 gene cluster polymorphisms and development of primary gastric B-cell lymphoma in Helicobacter pylori infection. Blood 104:2994-2995, 2004[Free Full Text]

21. Hellmig S, Fischbach W, Goebeler-Kolve ME, et al: Association study of a functional Toll-like receptor 4 polymorphism with susceptibility to gastric mucosa-associated lymphoid tissue lymphoma. Leuk Lymphoma 46:869-872, 2005[CrossRef][Medline]

22. Hang J, Zhou W, Zhang H, et al: TLR4 Asp299Gly and Thr399Ile polymorphisms are very rare in the Chinese population. J Endotoxin Res 10:238-240, 2004[Medline]

23. Wu MS, Chen LT, Shun CT, et al: Promoter polymorphisms of tumor necrosis factor-alpha are associated with risk of gastric mucosa-associated lymphoid tissue lymphoma. Int J Cancer 110:695-700, 2004[CrossRef][Medline]

24. Wu MS, Shun CT, Huang SP, et al: Effect of interleukin-1beta and glutathione S-transferase genotypes on the development of gastric mucosa-associated lymphoid tissue lymphoma. Haematologica 89:1015-1017, 2004[Abstract/Free Full Text]

25. Chen LT, Lin JT, Shyu RY, et al: Prospective study of Helicobacter pylori eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue lymphoma of the stomach. J Clin Oncol 19:4245-4251, 2001[Abstract/Free Full Text]

26. Lee YJ, Huang FY, Lo FS, et al: Association of CTLA4 gene A-G polymorphism with type 1 diabetes in Chinese children. Clin Endocrinol (Oxf) 52:153-157, 2000[CrossRef][Medline]

27. Gough SC, Walker LS, Sansom DM: CTLA4 gene polymorphism and autoimmunity. Immunol Rev 204:102-115, 2005[CrossRef][Medline]

28. Djilali-Saiah I, Schmitz J, Harfouch-Hammoud E, et al: CTLA-4 gene polymorphism is associated with predisposition to celiac disease. Gut 43:187-189, 1998[Abstract/Free Full Text]

29. Braun J, Donner H, Siegmund T, et al: CTLA-4 promoter variants in patients with Graves' disease and Hashimoto's thyroiditis. Tissue Antigens 51:563-566, 1998[Medline]

30. Holopainen PM, Partanen JA: Technical note: Linkage disequilibrium and disease-associated CTLA4 gene polymorphisms. J Immunol 167:2457-2458, 2001[Abstract/Free Full Text]

31. Marron MP, Raffel LJ, Garchon HJ, et al: Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. Hum Mol Genet 6:1275-1282, 1997[Abstract/Free Full Text]

32. Doglioni C, Wotherspoon AC, Moschini A, et al: High incidence of primary gastric lymphoma in northeastern Italy. Lancet 339:834-835, 1992[CrossRef][Medline]

33. Filipovich AH, Mathur A, Kamat D, et al: Primary immunodeficiencies: Genetic risk factors for lymphoma. Cancer Res 52:S5465-S5467, 1992 (suppl 19)

34. Kouki T, Sawai Y, Gardine C, et al: CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves' disease. J Immunol 165:6606-6611, 2000[Abstract/Free Full Text]

35. Ligers A, Teleshova N, Masterman T, et al: CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms. Genes Immun 2:145-152, 2001[CrossRef][Medline]

36. Maurer M, Loserth S, Kolb-Maurer A, et al: A polymorphism in the human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene (exon 1 +49) alters T-cell activation. Immunogenetics 54:1-8, 2002[CrossRef][Medline]

37. Anjos S, Nguyen A, Ounissi-Benkalha H, et al: A common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J Biol Chem 277:46478-46486, 2002[Abstract/Free Full Text]

38. Xerri L, Devilard E, Hassoun J, et al: In vivo expression of the CTLA4 inhibitory receptor in malignant and reactive cells from human lymphomas. J Pathol 183:182-187, 1997[CrossRef][Medline]

39. Isaacson PG, Du MQ: MALT lymphoma: From morphology to molecules. Nat Rev Cancer 4:644-653, 2004[CrossRef][Medline]

40. Amundsen SS, Naluai AT, Ascher H, et al: Genetic analysis of the CD28/CTLA4/ICOS (CELIAC3) region in coeliac disease. Tissue Antigens 64:593-599, 2004[CrossRef][Medline]

41. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100:57-70, 2000[CrossRef][Medline]

42. Lohmueller KE, Pearce CL, Pike M, et al: Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33:177-182, 2003[CrossRef][Medline]

Submitted December 30, 2005; accepted May 8, 2006.

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