Heterozygosity for the alpha1-antitrypsin Z allele may confer genetic risk of cholangiocarcinoma

Aliment Pharmacol Ther. 2011 Feb;33(3):389-94. doi: 10.1111/j.1365-2036.2010.04534.x. Epub 2010 Dec 8.

Abstract

Background: Alpha1-antitrypsin (α1AT) deficiency caused by Z allele homozygosity represents a well-established risk factor for hepatocellular carcinoma. Previous studies have also implicated α1AT Z heterozygosity in cholangiocarcinogenesis.

Aim: To assess the 'common' Z and S alleles as well as the promoter variant rs8004738 for association with cholangiocarcinoma.

Methods: We genotyped 182 Caucasian patients and 350 controls for rs28929474 (Z), rs17580 (S) and the variant rs8004738. Exploratory analyses were performed in relation to gender and cholangiocarcinoma localisation.

Results: rs28929474 was significantly enriched in the cholangiocarcinoma group (4.1 vs. 1.7%; OR 2.46, 95% CI 1.14-5.32; Bonferroni corrected p(c) = 0.036), reinforced by Armitage trend testing (OR 2.53; p(c) = 0.032). The rs8004738 (promoter) minor allele tended to be overrepresented in Z heterozygotes (30.0 vs. 16.7%: P = 0.13). Exploratory data analyses suggested a high genetic risk for extrahepatic tumour localisation (OR 3.0; p(c) = 0.016) and potentially female Z allele carriers (OR 3.37; unadjusted P = 0.022, p(c) = 0.088).

Conclusions: These data point to a novel role of α1AT Z heterozygosity as a potential genetic susceptibility factor for cholangiocarcinoma formation and suggest a contribution of aberrant α1AT function in biliary carcinogenesis. However, given the overall low rs28929474 minor allele frequency, larger studies are warranted to confirm and extend our findings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Bile Duct Neoplasms / genetics*
  • Bile Ducts, Intrahepatic*
  • Cholangiocarcinoma / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Risk Factors
  • White People / genetics
  • alpha 1-Antitrypsin / genetics*

Substances

  • alpha 1-Antitrypsin