POPULATION DISTRIBUTION OF ALCOHOL DEHYDROGENASE CLASS I IN FRANCE: COMPARISON WITH OTHER POPULATIONS, AND DISTRIBUTION WITH RESPECT TO GENDER AND AGE

Alcohol & Alcoholism Vol. 33, No. 2, pp. 173-183, 1998 POPULATION DISTRIBUTION OF ALCOHOL DEHYDROGENASE CLASS I IN FRANCE: COMPARISON WITH OTHER POPULATIONS, AND DISTRIBUTION WITH RESPECT TO GENDER AND AGE C. COUTELLE*, P. J. WARD, P. QUATTROCCHI, B. FLEURY and THE FRENCH GROUP FOR RESEARCH ON ALCOHOL AND LIVERf Universite Victor Segalen Bordeaux 2, Bordeaux cedex, France (Received 24 July 1997; in revised form 6 October 1997; accepted 11 November 1997) Abstract — In Caucasians, a genetic polymorphism is known for some alcohol dehydrogenase (ADH) systems (/J and y). Knowledge of population frequencies of the ft and y hepatic isozyme variants in France is a prerequisite to understanding any role this genetic variation might play in determining the risk of alcohol-related diseases. For the present study, the ADH phenotypes of 115 French Caucasian control subjects, consisting of 64 men and 51 women, were studied. The )32 subunit was found to have a very low frequency. The relative frequencies of ADH y subunits observed in French Caucasians were found to be in good agreement with those already observed in other Caucasian populations. When gender and age were taken into account, a particular group corresponding to young men (age <50 years) was characterized by a manifest discordance with the comparable female population. INTRODUCTION The consequences of alcohol abuse vary from one individual to another. The numerous physiological and environmental factors implicated in alcoholrelated diseases are insufficient to explain why some subjects develop alcoholic pathology while others continue to drink without any apparent serious damage. For example, among excessive drinkers, only 12 to 13% develop alcoholic cirrhosis (Fleury et al., 1988). Certain factors are required for the development of alcohol-related pathology, including a possible genetic susceptibility (von Wartburg, 1980ft). *Author to whom correspondence should be addressed at: University Victor Segalen Bordeaux 2, B.P. 10, 146, rue Leo Saignat, 33076 Bordeaux cedex, France. fFrench Group for Research on Alcohol and Liver — biochemical analysts: A. Cassaigne, C. Coutelle, D. Higueret, A. Iron (Victor Segalen Bordeaux 2 University, Bordeaux); hormonal biochemists: J. Giboudeau, J. Gu6chot, M. Vaubourdolle (St Antoine Hospital, Paris); clinical investigators: M. Amouretti, C. B£raud, P. Berthelot, O. Chazouilleres, P. Couzigou, B. Fleury, B. Nalpas, R. Poupon (St Antoine Hospital and Laennec Hospital, Paris and HautLeVeque Hospital, Bordeaux); epidemiologist: R. E. Poupon (INSERM U21, Villejuif). There are several existing potential biological markers for susceptibility to alcoholism, particularly the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzyme systems. Ingested alcohol is metabolized principally in the liver, where it is oxidized to acetaldehyde by several enzymatic systems, the main one being ADH. Most of the acetaldehyde is further metabolized to acetate by ALDH. These two enzymes are present in multiple isozymic forms. The present study concerns the enzyme ADH, which is coded for by at least five different gene loci. The isozymes which play the largest role are coded for by loci 1, 2, and 3, and together make up the so-called Class I ADH enzymes. Genetic polymorphisms exist at the ADH2 and ADH3 loci. The product of ADH2 gene, denoted /?, consists of three subtypes /?1, /?2, and j93. The so-called 'atypical' j82 subunit has a His for Arg47 substitution relative to fi\ (Buhler et al., 1984b). The pip\ protein, known as the 'usual' ADH, is the most common. According to Bosron et al. (1983) it is present in all Caucasian populations and prevalent also in Blacks. In Asiatic populations, it is less frequent than the /?2/?2 form (Harada et al, 1980; Hittle and Crabb, 1988; Thomasson et al., 1991). For example, the /?2 173 © 1998 Medical Council on Alcoholism 174 C. COUTELLE et al. subunit is present in 85% of Japanese, (Harada et MATERIALS AND METHODS al., 1980) and constitutes a genetic risk factor for alcoholism among Orientals (Agarwal and Subjects Goedde, 1990). It has been established that the Control subjects were all French Caucasians incidence of alcoholism in Asian groups is and were all moderate alcohol consumers. They influenced by genetic polymorphisms at ADH were recruited from patients presenting at the gene loci which, in addition to the ALDH2 Bordeaux Regional Hospital who were to undergo polymorphism, partly account for the aversion to laparotomy for an abdominal infection. Their alcohol of some members of that population average alcohol consumption was <40g/day. (Agarwal and Goedde, 1987; Chao et al., 1994). None had any history of liver disease (i.e. no The 'atypical' ADH possesses a strong activity at clinical or biological symptoms). Their liver physiological pH (von Wartburg and Schurch, histology revealed no abnormalities and they all 1968) and migrates more cathodally in starch gel tested negative for the presence of HBs antigen. electrophoresis (Smith et al., 1971). The total number of control subjects recruited was Two alleles are known at the ADH3 locus, the 115, comprising 54 men and 61 women aged ADH'3 &r\&ADH23 alleles, which code for the y\ and between 19 and 81 years. Drug addicts or ex-drug y2 subunits respectively. The y2 subunit has a Gin addicts and regular consumers or ex-consumers of for Arg27i substitution relative to y 1 (Buhler et al., corticosteroids and other medications known to be 1984a). This substitution may affect the coenzyme hepatotoxic were excluded from the study. The dissociation rate and may explain the elevated study was approved by the Ethics Committees of V max for ethanol oxidation in yl relative to y2 the Institutions involved. (Bosron et al., 1988). Dimeric association among these subunits leads to the formation of the Tissue samples homozygous ylyl and y2y2 isozymes and to the Tissue samples were taken surgically from heterozygous yly2 isozyme. living subjects and obtained during laparotomy The results of electrophoresis or electrophore- for an abdominal malfunction (chiefly bile duct grams (or zymograms) present a variety of bands infection) or by biopsy. Each liver specimen was which characterize the ADH phenotype of the placed immediately in a polypropylene tube and individual. The known polymorphisms of the immersed in liquid nitrogen for transportation and ADH2 and ADH3 loci correspond to codominant storage at —80°C until analysis which was alleles; each of the two alleles being therefore performed at the Victor Segalen Bordeaux 2 expressed in a heterozygous individual. This allows Biochemical Laboratory. the precise allocation of genotypes to phenotypes via reference to a genetic model, and the results Sample preparation: the liver homogenates expressed in terms of a phenotype distribution can The homogenate was prepared and placed in a thus be translated into allelic frequencies. polypropylene conical micropotter. The su (...truncated)