Role of genetic variant A-204C of cholesterol 7a-hydroxylase (CYP7A1) in susceptibility to gallbladder cancer q Anvesha Srivastava a , Sachchida Nand Pandey a , Gourdas Choudhuri b , Balraj Mittal a, * a Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, India b Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, India Received 19 September 2007; received in revised form 27 November 2007; accepted 27 November 2007 Available online 21 February 2008 Abstract Gallbladder carcinoma (GBC) usually arises in the background of gallstone disease. Cholesterol 7a-hydroxylase (CYP7A1) is a rate-limiting enzyme for cholesterol catabolism and bile acid synthesis. A-204C genetic polymorphism in CYP7A1 may influence gene expression and thus affect the risk of gallstone disease and GBC. We aimed to study the association of A-204C variation of CYP7A1 gene promoter polymorphism in GBC patients, gallstone patients and healthy subjects. The study included 141 histopathologically pro- ven GBC patients, ultrasonographically proven 185 symptomatic gallstone patients and 200 gallstone-free healthy subjects. Genotyping was done by PCR-RFLP method. CYP7A1 A-204C genotypes in control population were in Hardy–Weinberg equilibrium. The CC genotype conferred marginally significant risk for gallstone disease (p = 0.051; OR = 1.54; 95% CI = 0.9–3.4). In GBC patients, the CYP7A1 A-204C polymorphism conferred high risk for GBC at genotype (p = 0.005; OR = 2.78; 95% CI: 1.3–5.6) as well as allele levels (p = 0.008; OR = 1.58 and 95% CI: 1.1–2.2). After stratification of GBC patients on the basis of presence or absence of gallstones, CC genotype imparted higher risk for GBC without stones (p = 0.002; OR = 4.44: 95% CI = 1.7–11.3). The association of the polymorphism with GBC was more pronounced in female GBC patients, and also in cancer patients who developed GBC at advanced age. The CC genotype of CYP7A1 is an independent genetic risk factor for GBC but plays a modest role in susceptibility to gallstone disease. The GBC pathogenesis by CYP7A1 polymorphism appears to be independent of gallstone pathway and probably involves genotoxicity due to lipid peroxidation mechanisms. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Gallbladder cancer; Gallstone; Polymorphism; CYP7A1; Lipid peroxidation Carcinoma of gallbladder (GBC) still continues to be a diagnostic and therapeutic challenge, characterized by late presentation and dismal outcome. It is the most common malignant lesion of the biliary tract particularly in women of North India [1–3]. Etiology of GBC is still obscure and associated risk factors recognized so far include cholelithi- osis, obesity, reproductive factors, chronic infection and environmental exposure to specific chemicals [4–6]. GBC incidence shows marked regional specificity, for instance, in India its incidence is very high in north (4.5/100,000 for males and 10.1/100,000 for females) as compared to southern part of the country [2,7]. Geographic discrepancy may be attributed to different genetic and environmental factors together with dietary patterns [8]. Worldwide geo- graphic variability of GBC incidence has been correlated with prevalence of cholelithiosis [2,4,9,10]. Gallstones, par- ticularly of cholesterol type, are also quite common in north India with prevalence of around 6% in adult popula- tion [11]. Family clustering, twin studies, animal models and epidemiological evidences have implicated important role of both genetic and environmental factors in confer- ring individual’s susceptibility for gallstone disease and gallbladder cancer [12]. 1096-7192/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2007.11.014 q CYP7A1 in gallbladder cancer susceptibility. * Corresponding author. Fax: +91 522 2668017/2668973. E-mail addresses: balraj@sgpgi.ac.in, bml_pgi@yahoo.com (B. Mittal). www.elsevier.com/locate/ymgme Available online at www.sciencedirect.com Molecular Genetics and Metabolism 94 (2008) 83–89