Genetic polymorphisms in alcohol metabolism, alcohol intake and the risk of stomach cancer in Warsaw, Poland Fang Fang Zhang 1 * , Lifang Hou 2 , Mary Beth Terry 3 , Jolanta Lissowska 4 , Alfredo Morabia 5 , Jinbo Chen 6 , Meredith Yeager 7 , Witold Zatonski 4 , Stephen Chanock 7 and Wong-Ho Chow 8 1 Department of Epidemiology, School of Public Health, University of North Texas Health Science Center, Fort Worth, TX 2 Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 3 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 4 Division of Cancer Epidemiology and Prevention, Cancer Center and M. Sklosowska-Curie Institute of Oncology, Warsaw, Poland 5 Center for the Biology of Natural Systems, Queens College-CUNY, Flushing, NY 6 Department of Epidemiology and Biostatistics, School of Medicine, University of Pennsylvania, Philadelphia, PA 7 Core Genotyping Facility, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD 8 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD Genetic variations increasing blood levels of acetaldehyde, the first metabolite of alcohol, refrain their carriers from drinking alcohol but may also put them at increased risk of cancer because of the mutagenic and carcinogenic effect of acetaldehyde. In a popula- tion-based study of 305 cases and 428 controls in Warsaw, Poland, we evaluated the effect of polymorphisms in alcohol metabolizing genes, including ADH1B (Ex915C>T, Ex3123A>G, Ex3158A>T and Ex9177A>G), ADH1C (Ex8-56A>G and Ex6-14G>A) and ALDH2 (Ex1182A>G), on levels of alcohol drinking and suscepti- bility of stomach cancer. We found that among control subjects frequency of alcohol drinking varied by alcohol metabolizing genotype. In particular, the weekly consumption of individuals carrying the AA, GA and GG genotypes of ALDH2 Ex1182A >G polymorphism were 3.75, 2.26 and 1.53 drinks, respectively (p 5 0.04). However, none of the assessed polymorphisms in these 3 genes had a measurable effect on stomach cancer risk. When stratified by ALDH2 Ex1182A>G polymorphism, alcohol-related increases in stomach cancer risk were restricted to individuals with the AG/GG genotypes, with a more than 2-fold risk among daily drinkers (OR 5 2.63, 95% CI 5 1.00–6.88) and 3-fold risk (OR 5 3.66, 95% CI 5 1.19–11.24) among those with 40 or more drink-years. In summary, our results suggested that the ALDH2 Ex1182 G allele may be functionally deficient in eliminating acet- aldehyde and discourage alcohol drinking. Furthermore, heavy drinkers of alcohol who were genetically prone to accumulate acetaldehyde may face an increased risk of stomach cancer. ' 2007 Wiley-Liss, Inc. Key words: stomach cancer; alcohol metabolism; genetic polymorphism Alcohol consumption has been linked to an increased risk of stomach cancer in some but not all studies. 1–3 In addition to the di- versity in exposures such as drinking patterns and type of alcohols consumed, genetic variations in alcohol metabolism may also have contributed to the inconsistencies in the observed associations. Alcohol itself is not proved to be a carcinogen, whereas the first oxidative metabolite of ethanol, acetaldehyde, can interfere with DNA synthesis and repair and has direct mutagenic and carcino- genic effect. 4 It may also induce the production of cytochrome P-4502E1 (CYP2E1), leading to the generation of reactive oxygen species and enhancement of procarcinogen activation. 4 The con- version from alcohol to acetaldehyde is catalyzed by the enzyme alcohol dehydrogenase (ADH), and the subsequent oxidation from acetaldehyde to acetate is catalyzed by the enzyme aldehyde dehy- drogenase (ALDH). Identifying a carcinogenic effect of alcohol is complicated by the fact that the potentially deleterious polymor- phisms, which increase acetaldehyde formation or decrease its elimination, also tend to discourage their carriers from drinking alcohol because of facial flushing and other unpleasant responses at excessive acetaldehyde accumulation. We have previously evaluated the association between alcohol intake and stomach cancer risk in Poland, a country that has one of the highest stomach cancer incidence in the world and a high per capita alcohol consumption. 5 In the present study, we further examine whether polymorphisms in alcohol metabolizing genes (ADH1B, ADH1C and ALDH2) are related to stomach cancer risk, and explore whether alcohol-related stomach cancer risk is modi- fied by genetic polymorphisms. Five different classes and 7 differ- ent isoenzymes exist for ADH, among which only ADH1B and ADH1C are polymorphic. 6–8 Several variants in ADH1B and ADH1C genes have been shown to result in a ‘‘fast’’ metabolism from ethanol to acetaldehyde. 6 ALDH is grouped into 3 classes. 6–8 A well-known polymorphism in class II ALDH, ALDH2 Ex12- 12G>A, has been identified in East Asian populations that is re- sponsible for the deficient elimination of acetaldehyde from the body. However, this functional polymorphism has not been seen in other populations. 6 The ALDH2 gene is located on the long arm of chromosome 12 (12q24.2) and spans 44 kb. We investigated a polymorphism in the 5 0 untranslated region of the ALDH2 gene that has been found to present in all populations studied, the ALDH2 Ex1182 A>G polymorphism. 9–11 Material and methods Study design The study design has been described elsewhere. 12,13 Briefly, a population-based case–control study was conducted in which patients newly diagnosed with stomach cancer between March 1, 1994 and April 30, 1996 were identified by collaborating physi- cians in each of the 22 hospitals serving the study area. Cases had to be Warsaw residents aged 21–79 years at that time. A total of 72 clinics and endoscopic departments within the hospitals and 8 private endoscopic units were covered. Diagnostic information was abstracted in a standardized manner from hospital records and endoscopy, surgical and pathology reports by a collaborating phy- sician or by the study physician. All pathological slides were reviewed for confirmation of the diagnosis by 2 study pathologists. Controls were randomly selected among Warsaw residents from a computerized registry of all legal residents in Poland, the Polish Electronic System of Residence Evidence, and frequency-matched to cases by gender and age in 5-year strata. This study was approved by the Institutional Review Board of both participating institutes. Grant sponsor: Intramural Research Program, NIH. *Correspondence to: University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA. Fax: 1817-735-0443. E-mail: fazhang@hsc.unt.edu Received 15 March 2007; Accepted after revision 10 May 2007 DOI 10.1002/ijc.22973 Published online 13 July 2007 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 121, 2060–2064 (2007) ' 2007 Wiley-Liss, Inc. Publication of the International Union Against Cancer