Molecular and Cellular Endocrinology 325 (2010) 128–134 Contents lists available at ScienceDirect Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce Functional polymorphism of hOGG1 gene is associated with type 2 diabetes mellitus in Chinese population Caixia Sun a,b , Xiufang Liu a,b , Huan Zhang a,b , Wenwen Guo a,b , Zhenming Cai a,b , Huimei Chen a,b , Kui Zhang c , Dalong Zhu d , Yaping Wang a,b,∗ a Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China b Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China c Laboratory of Clinic Biochemistry, Medical School Affiliated Drum Tower Hospital, Nanjing University, Nanjing, China d Department of Endocrinology, Medical School Affiliated Drum Tower Hospital, Nanjing University, Nanjing, China article info Article history: Received 19 March 2010 Received in revised form 7 May 2010 Accepted 11 May 2010 Keywords: Type 2 diabetes mellitus hOGG1 gene Polymorphism 8-OHdG Promoter activity abstract hOGG1 protein excises the 8-hydroxy-2 ′ -deoxyguanine (8-OHdG) which is associated with type 2 dia- betes mellitus (T2DM). Our aim of this work is to explore whether the polymorphisms of hOGG1 gene are associated with T2DM. We screened the polymorphisms in the 5 ′ -UTR (c.-18G>T, c.-23A>G, c.-45G>A and c.-53G>C) and c.977C>G (Ser326Cys) in exon 7 of hOGG1 gene. A case–control study indicated that c.-23A/G heterozygote was markedly associated with diabetes (P = 0.004, OR = 2.648, 95%CI = 1.355–5.176) and with an increased level of C-peptide (705.00 versus 545.91 pmol/L, P = 0.044). Furthermore, a significantly increased risk of T2DM was observed in the subjects carrying heterozygous variant of c.-23A>G and homozygous mutation of Ser326Cys (OR = 3.684, 95%CI = 1.400–9.697). The pro- moter activity of the variant allele c.-23G decreased 30–40% in Hela and HEK293 cell lines. In conclusion, the variant c.-23A>G of hOGG1 gene could decrease the gene promoter activity and was a risk factor for T2DM. © 2010 Elsevier Ireland Ltd. All rights reserved. 1. Introduction When exposure to the radiation and chemicals, as well as dur- ing normal cellular metabolism, reactive oxygen species (ROS) are generated and cause base modifications in DNA, including the oxidation of guanine residues to 8-hydroxy-2 ′ -deoxyguanine (8-OHdG). During DNA replication, 8-OHdG pairs with adenine (A) more actively than with cytosine (C), leading to the G:C to A:T mutation and creating a scenario for a mutator phenotype (Nakabeppu, 2001). This ROS-induced mutagenesis might alter function of various genes and play an important role in the etiol- ogy of several diseases, such as degenerative diseases, cancers and diabetes (Helbock et al., 1999; Hoeijmakers, 2001; Niedernhofer et al., 2006). In human, base excision repair (BER) system specifically removes 8-OHdG to repair the oxidative DNA damage, and hOGG1 (human 8-oxoguanine glycosylase 1) is one of the key glycosylases involved in BER system (Frosina, 2004). hOGG1 protein can excise the oxidized base from 8-OHdG:A base pairs during DNA replica- tion, and initiate the BER system to repair 8-OHdG damage (Arai ∗ Corresponding author at: Department of Medical Genetics, Nanjing University School of Medicine, Nanjing 210093, China. Tel.: +86 25 83686495; fax: +86 25 83686559. E-mail address: wangyap@nju.edu.cn (Y. Wang). et al., 1997; Radicella et al., 1997). If BER system cannot eliminate 8-OHdG in genomic DNA efficiently, the G:C to A:T mutation would occur. Increasing evidences illustrate that the deficiency of the BER pathway is involved in several diseases. Genetic variation in BER genes may alter repair function and contribute to diseases such as cancer and some age-related diseases (Goode et al., 2002; Garcia- Closas et al., 2006; Zhang et al., 2006). Our laboratory reported that AluYb8MYH polymorphism was associated with increased oxida- tive damage and age-related diseases (Sun et al., 2010). Paz-Elizur et al. (2003) demonstrated that reduced hOGG1 activity is a major risk factor in the formation of sporadic lung cancer. So far, the variant of c.977C>G (Ser326Cys) in hOGG1 gene has been inves- tigated as a candidate polymorphism susceptible for many types of diseases (Weiss et al., 2005). However, hOGG1 gene is highly polymorphic and most of the other variants have not been well studied. Type 2 diabetes mellitus (T2DM), is an insulin-resistant state characterized by hyperglycemia. It has been shown that hyper- glycemia could augment free-radical production (Singh et al., 2001), and the occurrence of T2DM is associated with an elevated level of oxidative damage to DNA (Seghrouchni et al., 2002). Hence, oxidative stress is the common pathogenic factor contributing to T2DM (Evans et al., 2002). In detail, the 8-OHdG is the most often reported DNA damage in diabetes (Dandona et al., 1996). The asso- ciation between the BER gene which specifically excises 8-OHdG 0303-7207/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2010.05.005