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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

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.

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.

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