Impact of alcohol consumption with polymorphisms in alcohol‐metabolizing enzymes on pancreatic cancer risk in Japanese

Abstract

The putative impact of alcohol on pancreatic cancer (PC) risk remains controversial. Here, we conducted a case-control study in Japanese to assess the impact of alcohol in conjunction with polymorphisms in alcohol-metabolizing enzymes. Cases were 160 patients with pancreatic cancer at Aichi Cancer Center, Nagoya, Japan. Two control groups of 800 age-and sex-matched non-cancer subjects each were independently selected. The impact of alcohol and polymorphisms in aldehyde dehydrogenase 2 (ALDH2) Glu504Lys, alcohol dehydrogenase (ADH) 1B His48Arg, and ADH1C Arg272Gln on PC risk was examined with multivariate analysis adjusted for potential confounders to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results showed no independent impact of alcohol or genotype on PC risk except former drinking. To avoid reverse causation, former drinkers were excluded in further analyses. In the analysis of the combined effects of alcohol consumption and genotype, significant impact of alcohol was seen for those subjects with ALDH2 Lys+ allele, ADH1B His/His, or ADH1C Arg/Arg (trend P = 0.077, 0.003, or 0.020, respectively), each of which is associated with a high concentration or rapid production of acetaldehyde. Analysis of genotype combinations showed that 'ever drinking' with both ADH1B His/His and ALDH2 Lys + was the most potent risk factor for PC relative to 'never drinkers' with both ADH1B T he mortality of pancreatic cancer (PC) in Japan is increasing, and is now the sixth leading cause of cancer death. The ageadjusted incidence rates and mortality of PC are 9.1 and 8.4 for men and 5.3 and 4.9 for women, respectively.(1) Because of the difficulty in detecting this cancer in the early operable stage and lack of any curative treatment apart from complete surgical removal, 5-year relative survival rate is only 5.5%. (2) Epidemiological research of PC risk should therefore play an important role in both prevention and decreasing the number of PC deaths.Lifestyle and other risk factors known to affect the incidence of PC include age, smoking, obesity, diabetes mellitus, chronic pancreatitis, and family history of PC.(3-7) The effect of alcohol consumption on risk has also been investigated in many casecontrol or cohort studies, but results have been inconsistent. (7)(8)(9)(10)(11)(12)(13)(14) In many studies, the impact of alcohol disappeared after adjustment for potential confounders, particularly smoking habits, (12)(13)(14) while several groups found a significant impact of alcohol even after adjustment for confounders.(10,11) In our previous report, an impact of alcohol was seen only among former drinkers, and not among current drinkers. Alcohol is first oxidized to acetaldehyde by the alcohol dehydrogenase (ADH) enzymes, particularly ADH1B and ADH1C. Acetaldehyde is further oxidized to acetate by aldehyde dehydrogenase (ALDH) enzymes, to which ALDH2 is the major contributor. Encoding genes display polymorphisms that modulate individual differences in alcohol-oxidizing capability.(15,16) Regarding ADH1B His48A...

Acetaldehyde and Retinaldehyde-Metabolizing Enzymes in Colon and Pancreatic Cancers

“…1) [14]. The ability of these ALDHs to repress cellular acetaldehyde levels is consistent with a role for ALDHs in colon and pancreatic cancers and is supported strongly by the association of ALDH2 deficiency with high incidence of CRC and pancreatic cancer in heavy ethanol drinkers [15, 16]. In addition to metabolizing acetaldehyde, ALDH1 isozymes are the primary enzymes involved in the metabolism of retinaldehyde to retinoic acid (RA), a signaling molecule that plays a crucial role in cellular proliferation and differentiation [11].…”

Association of Alcohol Intake and Smoking with Malignant Lymphoma Risk in Japanese: A Hospital-Based Case-Control Study at Aichi Cancer Center

“…Daily alcohol consumption (in grams) was determined by totaling the amount of pure alcohol in the average daily consumption of Japanese sake (rice wine), shochu (distilled spirit), beer, wine, and whiskey. The amount of ethanol in each beverage has been described elsewhere (22). The subjects were categorized based on drinking status into the three groups of never, former, and current drinkers.…”

Cigarette Smoking and Pancreatic Cancer Risk: A Revisit with an Assessment of the Nicotine Dependence Phenotype

“…Nonetheless, the medical background of the controls would remain the potential souse of bias. In this regard, our previous study in women demonstrated that this matter had only limited impact: more than 66% of non-cancer outpatients at ACCH have no specific medical condition, while the remaining 34% have specific diseases such as benign tumors, non-neoplastic polyps or both (13.1%), mastitis (7.5%), gastrointestinal disease (4.1%), or benign gynecologic disease (4.1%) (Kanda et al, 2009;Kawase et al, 2009). The situation for men is thought to be comparable.…”