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Rheumatology Advance Access published online on June 26, 2009
Rheumatology, doi:10.1093/rheumatology/kep166
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Combination of TNF-RII, CYP1A1 and GSTM1 polymorphisms and the risk of Japanese SLE: findings from the KYSS study

Takahiko Horiuchi1, Masakazu Washio2, Chikako Kiyohara3, Hiroshi Tsukamoto1, Yoshifumi Tada4, Toyoko Asami5, Saburo Ide2, Gen Kobashi6, Hiroki Takahashi7 and and the Kyushu Sapporo SLE Study Group*

1Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 2Department of Community Health and Clinical Epidemiology, St Mary's College, Kurume, 3Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 4Department of Internal Medicine, Faculty of Medicine, Saga University, 5Rehabilitation Center, Saga University Hospital, Saga, 6Molecular Biostatistics Research Team, Research Center for Charged Particle Therapy, National Institute of Radiological Science, Chiba and 7First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.

Correspondence to: Takahiko Horiuchi, Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: horiuchi{at}intmed1.med.kyushu-u.ac.jp


  Abstract

Objectives. Association of the polymorphisms of the genes, TNF receptor type II gene (TNF-RII), cytochrome P4501A1 gene (CYP1A1) and glutathione S-transferase M1 gene (GSTM1), with SLE was investigated. TNF-RII mediates inflammatory and immune response, whereas CYP1A1 and GSTM1 are involved in the metabolism of xenobiotics. These three genes are involved in the generation of reactive oxygen species (ROS), which play a critical role for autoimmune diseases.

Methods. A total of 152 SLE patients and 427 healthy individuals in a female Japanese population were enrolled in the study. Case–control studies were performed for the polymorphisms of these three genes.

Results. The carriers of TNF-RII 196R were at a significantly increased risk for SLE with odds ratio (OR) of 1.59 (95% CI = 1.01, 2.52). CYP1A1 3801C homozygotes had a significantly increased risk of SLE (OR = 2.47, 95% CI = 1.28, 4.78). On the other hand, GSTM1 null genotype was not associated with SLE risk. As for combination action of two loci, CYP1A1 3801C/GSTM1 null combination was more strongly associated with an increased risk of SLE (OR = 4.35; 95% CI = 1.76, 10.73). Moreover, TNF-RII 196M/CYP1A1 3801C/GSTM1 null genotype combination was most significantly associated with SLE (OR = 5.83; 95% CI = 2, 17.04).

Conclusions. The individuals carrying two or more ‘at-risk’ genotypes of TNF-RII, CYP1A1 and GSTM1 had a significantly more increased risk for SLE compared with those having each ‘at-risk’ genotype. Combination of the risk genotypes will be important to more clearly identify the population at risk for SLE.

KEY WORDS: Polymorphism, Combination, Reactive oxygen species, TNF-RII, CYP1A1, GSTM1

*Members of the Kyushu Sapporo SLE (KYSS) Study Group are listed in alphabetical order for each affiliation: Saburo Ide, Hiroko Kodama, Masakazu Washio (principal investigator) (St Mary's College); Koichi Akashi, Mine Harada, Takahiko Horiuchi (co-principal investigator), Chikako Kiyohara (co-principal investigator), Hiroshi Tsukamoto (Graduate School of Medical Sciences, Kyushu University); Toyoko Asami, Takao Hotokebuchi, Kohei Nagasawa, Yoshifumi Tada, Osamu Ushiyama (Faculty of Medicine, Saga University); Mitsuru Mori, Asae Oura, Yasuhisa Sinomura, Hiromu Suzuki, Hiroki Takahashi, Motohisa Yamamoto (Sapporo Medical University School of Medicine), Gen Kobashi (Research Center for Charged Particle Therapy, National Institute of Radiological Science); Takashi Abe (Kushiro City General Hospital); Hisato Tanaka (Tanaka Hospital); Norihiko Nogami (Wakakusuryouikuen Hospital); Kazushi Okamoto (Aichi Prefectural College of Nursing and Health); Naomasa Sakamoto (Hyogo College of Medicine); Satoshi Sasaki (National Institute of Health and Nutrition); Yoshihiro Miyake (Faculty of Medicine, Fukuoka University), Tetsuji Yokoyama (National Institute of Public Health); Yutaka Inaba (Juntendo University School of Medicine); Masaki Nagai (Saitama Medical School).

Submitted 23 January 2009; revised version accepted 20 May 2009.
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