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Association of polymorphic alleles of CTLA4 with inflammatory bowel disease in the Japanese

World Journal of Gastroenterology 2005年第27期11卷 4188-4193页

作者： Haruhisa Machida Kazuhiro Tsukamoto Chun-Yang Wen Yukiko Narumi Saburou Shikuwa Hajime Isomoto Fuminao Takeshima Yohei Mizuta norio niikawa Ikuo Murata Shigeru Kohno Second Department of Internal Medicine Nagasaki University School of Medicine 1-7-1 SakamotoNagasaki 852-8501 Japan Department of Pharmacotherapeutics Nagasaki University Graduate School of Biomedical Sciences 1-14 Bunkyo-machi Nagasaki 852-8521Japan Department of Molecular Pathology Atomic Bomb Disease Institute Nagasaki University Graduate School of Biomedical Sciences 1-12-4 Sakamoto Nagasaki 852-8523Japan Department of Human Genetics Nagasaki University Graduate School of Biomedical Sciences 1-12-4 Sakamoto Nagasaki 852-8523 Japan

AIM： To examine an association between the cytotoxic Tlymphocyte antigen 4 （CTLA4） gene that plays a role in downregulation of T-cell activation and inflammatory bowel disease consisting of ulcerative colitis （UC） and Crohn＇s disease （CD） in the ***： We studied 108 patients with UC, 79 patients with CD, and 200 sex-matched healthy controls, with respect to three single nucleotide polymorphisms （SNPs） in CTLA4, such as C-318T in the promoter region, A＋49 Gin exon 1 and G＋6230A in the 3＇ untranslated region （3＇-UTR） by a PCR-restriction fragment length polymorphism method, and to an （AT）, repeat polymorphism in 3＇-UTR by fragment analysis with fluorescence-labeling on denaturing sequence gels. Frequency of alleles and genotypes and their distribution were compared statistically between patients and controls and among subgroups of patients, using X^2 and Fisher exact ***： The frequency of ＂A/A＂ genotype at the G＋6230A SNP site was statistically lower in UC patients than in controls （3.7% vs 11.0%, P = 0.047, odds ratio （OR） = 0.311）. Moreover, the frequency of ＂G/G＂ genotype at the A＋49G SNP site was significantly higher in CD patients with fistula （48.6%） than those without it （26.2%）（P = 0.0388, OR=2.67）.CONCLUSION： The results suggest that CTLA4 located at 2q33 is a determinant of UC and responsible for fistula formation in CD in the Japanese.

关键词： Ulcerative colitis CTLA4 gene Diseasesusceptible gene Crohn's disease Fistula formation

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NAT2＊6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis

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World Journal of Gastroenterology 2007年第45期13卷 6003-6008页

作者： Norihide Higuchi Naoko Tahara Katsunori Yanagihara Kiyoyasu Fukushima Naofumi Suyama Yuichi Inoue Yoshitsugu Miyazaki Tsutomu Kobayashi Koh-ichiro Yoshiura norio niikawa, Chun-Yang Wen, Hajime Isomoto,Saburou Shikuwa, Katsuhisa Omagari, Yohei Mizuta, Shigeru Kohno, Kazuhiro Tsukamoto norio niikawa Chun-Yang Wen Hajime Isomoto Saburou Shikuwa Katsuhisa Omagari Yohei Mizuta Shigeru Kohno Kazuhiro Tsukamoto Department of Pharmacotherapeutics Nagasaki University Graduate School of Biomedical Sciences 1-14 Bunkyo-machi Nagasaki 852-8521 Japan Department of Internal Medicine Nagasaki University Graduate School of Biomedical Sciences Sakamoto 1-7-1 Nagasaki 852-8501 Japan Division of Internal Medicine Japanese Red Cross Nagasaki Genbaku Isahaya Hospital Isahaya 859-0497 Japan Department of Internal Medicine Nagasaki Municipal Medical Center Nagasaki 852-8012 Japan Y Department of Internal Medicine Isahaya Health Insurance General Hospital Isahaya 854-8501 Japan Department of Human Genetics Nagasaki University Graduate School of Biomedical Sciences Sakamoto 1-12-4 Nagasaki 852-8523 Japan SORST JST Kawaguchi Japan Department of Digestive Disease Center Beihua University Jilin 132013 Jilin Province China

AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression ***: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A , was signifi cantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was signif icantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti- TB drug-induced hepatotoxicity.

关键词： Tuberculosis Anti-tuberculosis drugs Drug-induced hepatotoxicity NAT2-haplotype DNA-baseddiagnosis

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