Elsevier

Drug and Alcohol Dependence

Volume 144, 1 November 2014, Pages 239-244
Drug and Alcohol Dependence

Genetic variation in alcohol metabolizing enzymes among Inuit and its relation to drinking patterns

https://doi.org/10.1016/j.drugalcdep.2014.09.774Get rights and content

Highlights

  • We genotyped seven SNPs related to alcohol metabolism in 4162 Inuit.

  • We compared the SNPs with self-reported alcohol drinking patterns.

  • The SNP pattern differed from the general population of Denmark.

  • The SNP pattern differed a lot from Han Chinese.

  • The Inuit may be at increased genetic risk for developing alcohol problems.

Abstract

Background

Variation in genes involved in alcohol metabolism is associated with drinking patterns worldwide. We compared variation in these genes among the Inuit with published results from the general population of Denmark and, due to the Asian ancestry of the Inuit, with Han Chinese. We analyzed the association between gene variations and drinking patterns among the Inuit.

Methods

We genotyped 4162 Inuit participants from two population health surveys. Information on drinking patterns was available for 3560. Seven single nucleotide polymorphisms (SNPs) were examined: ADH1B arg48his, ADH1C ile350val, ADH1C arg272gln, ALDH2 glu504lys, ALDH2 5′-UTR A-357G, ALDH1B1 ala86val and ALDH1B1 arg107leu.

Results

The allele distribution differed significantly between Inuit and the general population of Denmark. A protective effect on heavy drinking was found for the TT genotype of the ALDH1B1 arg107leu SNP (OR = 0.59; 95% CI 0.37–0.92), present in 3% of pure Inuit and 37% of Danes. The ADH1C GG genotype was associated with heavy drinking and a positive CAGE test (OR 1.34; 95% CI 1.05–1.72). It was present in 27% of Inuit and 18% of Danes. The Asian genotype pattern with a high frequency of the ADH1B A allele and an ALDH2 gene coding for an inactive enzyme was not present in Greenland.

Conclusions

ADH1C and ALDH1B1 arg107leu SNPs play a role in the shaping of drinking patterns among the Inuit in Greenland. A low frequency of the ALDH1B1 arg107leu TT genotype compared with the general population in Denmark deserves further study. This genotype was protective of heavy drinking among the Inuit.

Introduction

Alcohol related somatic, psychiatric and social consequences are major public health problems in many indigenous populations, including the Inuit in Greenland. In Greenland, the average yearly consumption of alcohol has for the last 20 years been equivalent to 12 l of pure alcohol per person aged 15 and above (Statistics Greenland, 2013) but binge drinking is prevalent (Jeppesen and Larsen, 2008).

Alcohol is metabolized by two isoenzymes, i.e., alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), coded from different gene loci (Hempel et al., 1984, Yoshida et al., 1984, Bosron and Li, 1986, Eriksson et al., 2001). Variations in alcohol metabolizing enzymes have been associated with a higher frequency of alcohol problems (Tolstrup et al., 2008), higher prevalence of binge drinking (drinking five drinks or more per occasion (Husemoen et al., 2008)) and alcohol-induced hypersensitivity (Linneberg et al., 2010). In East Asians, an allele of ALDH encoding inactive acetaldehyde dehydrogenase is prevalent. Carriers of this allele experience malaise and flushing when drinking, and it has consistently been shown that such individuals binge-drink less often and have lower risk of alcoholism compared with individuals with functional ALDH (Harada et al., 1982, Higuchi et al., 1994, Higuchi et al., 1996, Muramatsu et al., 1995, Luczak et al., 2006, Zintzaras et al., 2006). This allele has not been observed in a general white population (Tolstrup et al., 2008), but it is unknown if it exists in Inuit. However, neither typical nor atypical flushing has been reported from Greenland.

The ancestors of the Inuit migrated from Siberia to Alaska as late as 2000 years ago and arrived in Greenland from arctic Canada within the last millennium (Gulløv, 2004, Reich et al., 2012). The distribution of the genetic variations in ADH and ALDH among Inuit and related indigenous populations of Alaska and Siberia is largely unknown. Among Alaska Natives entering treatment for alcoholism the allele distributions of ADH and ALDH were similar to those of a general sample of Yupik Eskimos, and not significantly different among seven indigenous populations in the study. The distribution of alleles did not resemble the typical Asian distribution (Segal, 1999). Other studies showed that the inactive ALDH2 allele was absent among Alaska Natives, Siberian Eskimos and Chuckchi (Thomasson et al., 1992, Avksentyuk et al., 1994).

The purpose of the present study was to compare the variation in genes that are involved in alcohol metabolism among the Greenland Inuit with published results from the general population of Denmark and Han Chinese. Specifically, we wanted to test the hypothesis that the Inuit carried the allele of ALDH encoding inactive acetaldehyde dehydrogenase which has been found among East Asians. Secondly, we wanted to analyze if the association between such genes and drinking patterns among the Inuit were similar to those reported in the literature and thus to determine the role of genetics in drinking behaviour in this indigenous population.

Section snippets

Methods

The data were collected as part of two population surveys in Greenland. Only participants categorized at enrolment as indigenous Greenlanders (synonym: Inuit) based on the primary language of the participant and self-identification were included in the analyses. In 1999–2001, data (N = 1299) were collected by interview and clinical examination in six towns and villages on the west coast of Greenland as part of a general population health survey with a participation rate of 67% (Bjerregaard et

Results

The study base consisted of 4162 Inuit with information about at least one of the SNPs. Among these, 531 were born in East or North Greenland and reported having four Inuit grandparents. These were considered the least admixed Inuit. Information about alcohol consumption was available for 3560 participants. Table 1 shows the characteristics of the study populations. Non-drinkers made up 17% among men and 23% among women, heavy drinkers 14% among men and 11% among women; 35% and 22%,

Discussion

The study is the largest study of SNPs related to alcohol metabolism among the Inuit. Alcohol problems have been a major public health problem in this population since the 1950s and both among lay persons and health professionals the role of genetics has been debated. The present study clearly shows that the protective Asian genotype is not present among the Inuit but that the prevalence of other alcohol related SNPs may be important. Drinking patterns were self-reported which may introduce a

Role of funding sources

None of the funding sources had any role in study design, collection, analysis or interpretation of data.

Contributors

PB made data collection and analyzed the data with assistance from SSM. PB and JST had designed the study. UB designed the questionnaire for drinking patterns. TH managed the genetic analyses. Later, PB wrote the first draft of the manuscript. Finally, all authors made a fair amount of contribution and approved the final manuscript.

Conflict of interest

No conflict declared.

Acknowledgements

The study was supported by Karen Elise Jensen's Foundation, NunaFonden, Medical Research Council of Denmark, Medical Research Council of Greenland and the Commission for Scientific Research in Greenland.

References (41)

  • E. Bosch et al.

    High level of male-biased Scandinavian admixture in Greenlandic Inuit shown by Y-chromosomal analysis

    Hum. Genet.

    (2003)
  • W.F. Bosron et al.

    Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism

    Hepatology

    (1986)
  • Y.C. Chao et al.

    Investigation of alcohol metabolizing enzyme genes in Chinese alcoholics with avascular necrosis of hip joint, pancreatitis and cirrhosis of the liver

    Alcohol Alcohol.

    (2003)
  • W.Y. Chou et al.

    An A/G polymorphism in the promoter of mitochondrial aldehyde dehydrogenase (ALDH2): effects of the sequence variant on transcription factor binding and promoter strength

    Alcohol. Clin. Exp. Res.

    (1999)
  • C.J. Eriksson et al.

    Functional relevance of human ADH polymorphism

    Alcohol. Clin. Exp. Res.

    (2001)
  • M. Fischer et al.

    Association of the aldehyde dehydrogenase 2 promoter polymorphism with alcohol consumption and reactions in an American Jewish population

    Alcohol. Clin. Exp. Res.

    (2007)
  • H.W. Goedde et al.

    Distribution of ADH2 and ALDH2 genotypes in different populations

    Hum. Genet.

    (1992)
  • S. Harada et al.

    A novel polymorphism, −357 G/A. of the ALDH2 gene: linkage disequilibrium and an association with alcoholism

    Alcohol. Clin. Exp. Res.

    (1999)
  • S. Higuchi et al.

    Alcohol and aldehyde dehydrogenase genotypes and drinking behavior in Japanese

    Alcohol. Clin. Exp. Res.

    (1996)
  • Cited by (0)

    View full text