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©Ferrata Storti Foundation Malignant Lymphomas original paper haematologica 2001; 86:602-608 No substantial difference in genotype http://www.haematologica.it/2001_06/0602.htm frequencies of interleukin and myeloperoxidase polymorphisms between malignant lymphoma patients and non-cancer controls KEITARO MATSUO,*^ NOBUYUKI HAMAJIMA,* RITSURO SUZUKI,° SHIGEO NAKAMURA,‡ MASAO SETO,° YASUO MORISHIMA,† KAZUO TAJIMA* *Aichi Cancer Center, Division of Epidemiology and Preven- tion; °Aichi Cancer Center, Division of Molecular Medicine; ‡Aichi Cancer Center, Department of Hematology and Correspondence: Keitaro Matsuo M.D., Aichi Cancer Center Research Chemotherapy; †Aichi Cancer Center, Division of Pathology Institute, Division of Epidemiology and Prevention, 1-1 Kanokoden Chikusa-ku Nagoya 464-8681, Japan. Phone: international + 81-52- and Genetics; ^Nagoya University Graduate School of Medi- 7642988 - Fax: international +81-52-7635233 cine, Department of Epidemiology; Nagoya, Japan E--mail: [email protected] Background and Objectives. The functional polymor- ytokines play important roles in the hema- phisms regulating immunologic responses may influence topoietic and immune systems. Their functions the proliferation or suppression of malignant lymphoma. Cinclude control of cellular and humoral We examined the association between malignant lym- immune responses, with an impact on inflammation, phoma risk and the polymorphisms of the IL-1 gene fam- chemotaxis, tumor regression, hematopoiesis, and ily [IL-1B –31 C/T, IL-1A –889 C/T, and IL-1RN 86-bp acute-phase responses.1 Interleukin-1 (IL-1), which variable number of terminal repeat (VNTR)] and myeloperoxidase (MPO –463 G/A). is a prototypic multifunctional cytokine synthesized by a variety of cell types, including activated macro- Design and Methods. The hospital-based case-control phages and stimulated B-lymphocytes, is an essen- study was conducted in Japan. Genotypes were exam- ined in a total of 372 lymphoma cases and 241 non-can- tial mediator of inflammation and immunity. It can cer control subjects. The relative risks were estimated by exert either inhibitory or promoting effects on neo- unconditional logistic regression analysis. plasms including hematologic malignancies.2 Accu- Results. The overall allele distribution of these polymor- mulated evidence indicates that the production and phisms did not differ substantially between patients and activity of IL-1, particularly IL-1β, one prominent controls; the odds ratios were 0.73 (95% confidence member of the IL-1 family, may regulate the effects interval, 0.48-1.11) for the T allele carriers of IL-1B rel- of IL-1. The allelic state of IL-1 genes has been sug- ative to the non-carriers, 1.01 (0.56-1.82) for the 2- gested to determine basal production and inducible repeat allele (allele 2) carriers of IL-1RN, 0.96 (0.62- responses of IL-1. 1.48) for the T allele carriers of IL-1A, and 1.04 (0.70- The IL-1 gene cluster, comprising the IL-1A, IL1-B 1.57) for the A allele carriers of MPO. Subgroup analy- ses according to histology [diffuse large B-cell lymphoma and IL-1 receptor antagonist (IL-1RN), is located on (DLBL), follicular lymphoma, low-grade lymphoma of human chromosome 2q.3 These genes code for three mucosa associated lymphoid tissue, and others] failed to ligands of the IL-1 family: the first two (IL-1α and IL- illustrate differences except for DLBL which showed a 1β) with agonist properties towards membrane IL-1 possible association with IL-1A and IL-1B polymorphisms. receptors, also located on 2q and the third (IL-IRa) a Interpretation and Conclusions. Our data show a limit- competitive antagonist. IL-1B has three polymor- ed association between these polymorphisms and malig- phisms at -511, -31, and +3954, the former two nant lymphoma risk in total. The possible association of being tightly linked.4 The T allele at -31 makes a TATA the IL-1A and IL-1B polymorphisms with DLB-needs fur- box, which may enhance gene expression. An asso- ther clarification. ©2001, Ferrata Storti Foundation ciation between IL-1B polymorphism and risk of gas- tric cancer was reported,4 and several other studies showed that this polymorphism is associated with Key words: malignant lymphoma, genetic predisposition 5,6 of disease, IL-1, myeloperoxidase, gene polymorphism various diseases. The 2-repeat type (allele 2) of IL- 1RN variable number of terminal repeat (VNTR) enhances the production of IL-1β,7 and is associat- ed with several diseases.4,8,9 IL-1β is a primarily haematologica vol. 86(6):june 2001 Inflammation-related polymorphisms and malignant lymphoma 603 cytosolic cytokine. Approximately 10% to 15% of IL- information such as age, sex, and histologic subtype 1α is myristaylated and transported to the cell sur- were made anonymous after checking for overlap- face (membrane IL-1), but IL-1α is not detected in the ping cases. Matched case sampling was not con- serum under normal conditions.2 IL-1A is reported to ducted to avoid the reduction of power.18 have three polymorphisms; C-899T, 46bp VNTR at Genotyping intron 6, and G4845T. One study showed that the The gene polymorphisms evaluated in this study combination of T/T of IL-1A –889 and T/- of IL-1B were IL-1B -31C/T, IL-1RN VNTR at intron 2, IL-1A –511 was related to high plasma levels of IL-1β.10 –899 C/T and MPO -463 G/A. Typing was accom- Myeloperoxidase (MPO) is another enzyme which plished according to previously described methods has an impact on inflammation. Its gene has a poly- for IL-1RN VNTR at intron 2,1,19 and MPO -463.20 For morphism –463 G/A. The A allele of this polymor- IL-1B –31 C/T and IL-1A –889 C/T, a novel method phism reduces mRNA expression,11 and subsequently named polymerase chain reaction with confronting reduces tissue damage accompanying local inflam- two-pair primers (PCR-CTPP) was used, which does mation.12 Several studies with chronic granulomatous not require restriction enzyme digestion for genotyp- disease,12 malignancies such as lung13 and pharyn- ing.21 Briefly, confronting two-pair primers (F1 and geal cancer14 and Alzheimer’s disease,15 showed that this MPO gene polymorphism had a pathogenic R1 for T allele, F2 and R2 for C allele, R1 including effect. adenine at the end and F2 including cytosine at the The present hospital-based, case-control study was end) contained in one tube produces allele-specific conducted in Aichi Cancer Center to evaluate the PCR products for the C allele and T allele, as well as effects of polymorphisms in the IL-1 family (IL-1A - a product between F1 and R2. Descriptions of typing 889 C/T, IL-1B –31 C/T, and IL-1RN 86-bp VNTR at of each polymorphism are shown in Table1. intron 2) and MPO –463 G/A on the susceptibility to Statistical analysis various histologic subtypes of malignant lymphoma. All odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for sex as well as age as a con- Design and Methods tinuous variable, instead of age-sex matching, using The study population an unconditional logistic regression model. Accor- The cases were recruited from patients who were dance with the Hardy-Weinberg equilibrium, which diagnosed histologically as having malignant lym- indicates an absence of discrepancies between geno- phomas in Aichi Cancer Center. The 383 cases com- type and allele frequencies, was checked for in the prised two groups: 109 prevalent cases who visited control-subjects by using the χ2 test. The genotype outpatient clinics and provided a venous blood sam- frequencies among cases and controls were also com- ple; and 274 incident cases diagnosed between 1993 pared with the χ2 test. Subgroup analyses according and 2000 whose lymphoma tissue DNAs were avail- to histologic subtype were conducted for diffuse large able. Because eleven cases overlapped between the B-cell lymphoma (DLBL), low-grade lymphoma of two groups, 372 cases were eligible for analysis. Con- mucosa-associated lymphoid tissue type (MALT), fol- trols (n=241) were outpatients without any history of licular lymphoma, and the others. The statistical pow- cancer who visited ACC during March to December er for 241 controls and 341 cases was more than 95% 1999 for gastroscopy.16,17 Of the 241 controls, 97 for OR=2 or 0.5 under a two-side significance level of (40.2%) stated they were receiving medication for a 0.05, with a genotype frequency among the controls total of 107 diseases (not confirmed by their medical being between 30% and 70%. All statistical analyses records); 23 with gastric/duodenal ulcer, another 23 were performed using STATA version 6 software (STA- with so-called gastritis, 16 with hypertension, 8 for TA Corporation Inc., College Station, TX, USA). pain including arthritis and lumbago, 7 with diabetes mellitus, 7 with hyperlipidemia, and the other 23 with Results miscellaneous diseases. Patients with autoimmune The characteristics of the 372 cases and 241 con- diseases were not included in the control group. All trols are shown in Table 2. The cases included 123 dif- cases and controls were Japanese. Written informed fuse large B-cell lymphomas, 71 low-grade lym- consent for analyzing DNA polymorphisms was phomas of mucosa associated lymphoid tissue (MALT) obtained from all the prevalent cases and controls. type and 74 follicular lymphomas (FL), and 104 oth- The samples from prevalent cases and controls were er lymphomas (22 Hodgkin’s diseases, 16 marginal obtained from peripheral blood. The use of all sam- zone B-cell lymphomas, 15 diffuse lymphomas other ples was approved by Ethical Committee of Aichi Can- than DLBL, 11 peripheral T-cell lymphomas, 9 mantle cer Center. The stocked tissue DNA samples with cell lymphomas, 5 lymphoblastic lymphomas, 5 haematologica vol.
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