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American Journal of Epidemiology Advance Access originally published online on August 20, 2009
American Journal of Epidemiology 2009 170(6):747-756; doi:10.1093/aje/kwp196
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American Journal of Epidemiology © The Author 2009. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Association Between Heme Oxygenase-1 Gene Promoter Polymorphisms and Type 2 Diabetes in a Chinese Population

Fangfang Song, Xiangyang Li, Muxun Zhang, Ping Yao, Nianhong Yang, Xiufa Sun, Frank B. Hu and Liegang Liu

Correspondence to Prof. Liegang Liu, Department of Nutrition and Food Hygiene and MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, People's Republic of China (e-mail: lgliu{at}mails.tjmu.edu.cn).

Received for publication December 1, 2008. Accepted for publication June 9, 2009.

The authors aimed to determine whether 2 functional polymorphisms in the heme oxygenase-1 (HO-1) gene promoter are associated with type 2 diabetes mellitus (T2DM). A Chinese case-control study involving 1,103 newly diagnosed T2DM patients, 371 patients with impaired glucose regulation (IGR), and 1,615 controls was performed (December 2004–December 2007). A (GT)n microsatellite polymorphism and a single nucleotide polymorphism, T(-413)A, were genotyped, and their functional relevance was evaluated by examining the level of HO-1 protein expression. For the (GT)n microsatellite polymorphism, genotypes with the L (GT)n allele (≥25 GT repeats) were associated with increased odds of IGR or T2DM compared with the S/S genotype (<25 GT repeats) (S/L genotype: odds ratio (OR) = 1.35, P = 0.048; L/L genotype: OR = 1.65, P = 0.006). Subsequent haplotype analysis showed that haplotype TL contributed to increased odds of IGR or T2DM compared with haplotype TS (OR = 1.56, P = 0.003). In functional analyses, HO-1 expression level was significantly reduced in persons with IGR and T2DM carrying the L/L (GT)n genotype compared with persons with the S/S genotype. Further haplotype combination assay confirmed the functional dominance of the (GT)n microsatellite polymorphism over the T(-413)A single nucleotide polymorphism. These results support an association between the HO-1 (GT)n microsatellite polymorphism, HO-1 expression levels, and the odds of T2DM.

diabetes mellitus, type 2; heme oxygenase-1; polymorphism, genetic


Abbreviations: CI, confidence interval; FAM, 5'-carboxyl-fluorescein amidite; HO-1, heme oxygenase-1; IGR, impaired glucose regulation; SD, standard deviation; SNP, single nucleotide polymorphism


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