Gastroenterology
Volume 137, Issue 5 , Pages 1768-1775, November 2009

Functional Variants in ADH1B and ALDH2 Coupled With Alcohol and Smoking Synergistically Enhance Esophageal Cancer Risk

  • Ri Cui

      Affiliations

    • Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
    • ,
  • Yoichiro Kamatani

      Affiliations

    • Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
    • ,
  • Atsushi Takahashi

      Affiliations

    • Laboratory for Statistical Analysis, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan
    • ,
  • Masayuki Usami

      Affiliations

    • Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
    • ,
  • Naoya Hosono

      Affiliations

    • Laboratory for Genotyping Development, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan
    • ,
  • Takahisa Kawaguchi

      Affiliations

    • Laboratory for Medical Informatics, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan
    • ,
  • Tatsuhiko Tsunoda

      Affiliations

    • Laboratory for Medical Informatics, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan
    • ,
  • Naoyuki Kamatani

      Affiliations

    • Laboratory for Statistical Analysis, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan
    • ,
  • Michiaki Kubo

      Affiliations

    • Laboratory for Genotyping Development, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan
    • ,
  • Yusuke Nakamura

      Affiliations

    • Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
    • Laboratory for International Alliance, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan
    • ,
  • Koichi Matsuda

      Affiliations

    • Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
    • Corresponding Author InformationReprint requests Address requests for reprints to: Koichi Matsuda, MD, PhD, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. fax: (81) 3-5449-5123

Received 30 January 2009; accepted 31 July 2009. published online 20 August 2009.

Background & Aims

Esophageal squamous cell carcinoma (ESCC) is prevalent among Asian populations, with marked regional variations in incidence and mortality. Patients with ESCC have a very poor prognosis, but detection of ESCC at earlier stages could improve clinical outcome. Therefore, identification of epidemiologic factors that influence the development of ESCC would facilitate prevention and/or early detection of the disease.

Methods

We performed a 2-step genome-wide association study with subsequent replication analysis using a total of 1070 Japanese ESCC cases and 2836 controls. We also used logistic regression analysis to estimate the effect of gene-gene and gene-environmental interactions.

Results

We identified the significant associations of ESCC with 4q21-23 and 12q24 regions, which include nonsynonymous single nucleotide polymorphisms (SNP) in ADH1B (rs1229984, P = 6.76 × 10−35) and ALDH2 (rs671, P = 3.68 × 10−68) that were previously shown to be associated with ESCC susceptibility. Multiple logistic regression analysis revealed SNP rs671, rs1229984, alcohol drinking, and smoking as the independent risk factors for ESCC (odds ratios of 1.66, 1.85, 1.92, and 1.79, respectively). Moreover, individuals who had both genetic and lifestyle-related risk factors had a nearly 190 times higher risk of ESCC than those who had neither of these.

Conclusions

We found 2 known functional variants involved in the metabolism of alcohol and tobacco by-products as the most significant risk factors for the development of ESCC in a Japanese population. The individuals carrying both risk genotypes have a higher baseline risk of ESCC that is substantially increased by 2 lifestyle risk factors.

Abbreviations used in this paper: CI, confidence interval, ESCC, esophageal squamous cell cancer, OR, odds ratio, SNP, single nucleotide polymorphism

To access this article, please choose from the options below

Login to an existing account or Register a new account.

  • Purchase this article for 30.00 USD (You must login/register to purchase this article)

    Online access for 24 hours. The PDF version can be downloaded as your permanent record.

  • Subscribe to this title

    Get unlimited online access to this article and all other articles in this title 24/7 for one year.

  • Claim access now

    For current subscribers with Society Membership or Account Number.

  • Visit SciVerse ScienceDirect to see if you have access via your institution.
 

 Conflicts of interest The authors disclose no conflicts.

 Funding This study was conducted as a part of Biobank Japan, funded by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government.

PII: S0016-5085(09)01425-5

doi:10.1053/j.gastro.2009.07.070

Refers to article:

  • Genome-Wide Association Study in Esophageal Squamous Cell Carcinoma , 28 September 2009

    Adam J. Bass, Matthew Meyerson
    Gastroenterology November 2009 (Vol. 137, Issue 5, Pages 1573-1576)

Gastroenterology
Volume 137, Issue 5 , Pages 1768-1775, November 2009

Article Tools

* Image Usage & Resolution