Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels

Nat Commun. 2015 Jul 15;6:7754. doi: 10.1038/ncomms8754.

Abstract

Alpha-1 antitrypsin (AAT) encoded by SERPINA1 is an acute-phase inflammation marker, and AAT deficiency (AATD) is known as one of the common genetic disorders in European populations. However, no genetic determinants to AAT levels apart from the SERPINA gene clusters have been identified to date. Here we perform a genome-wide association study of serum AAT levels followed by a two-staged replication study recruiting a total of 9,359 Japanese community-dwelling population. Three missense variants of metabolic syndrome-related genes, namely, rs671 in ALDH2, rs1169288 in HNF1A and rs1260326 in GCKR, significantly associate with AAT levels (P≤1.5 × 10(-12)). Previous reports have shown the functional relevance of ALDH2 and HNF1A to AAT. We observe a significant interaction of rs671 and alcohol consumption on AAT levels. We confirm the association between AAT and rs2896268 in SERPINA1, which is independent of known causative variants of AATD. These findings would support various AAT functions including metabolic processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adult
  • Aged
  • Alcohol Drinking / metabolism
  • Aldehyde Dehydrogenase / genetics*
  • Aldehyde Dehydrogenase, Mitochondrial
  • Asian Continental Ancestry Group
  • Female
  • Gene Expression Profiling
  • Genome-Wide Association Study
  • Genotype
  • Hepatocyte Nuclear Factor 1-alpha / genetics*
  • Humans
  • Japan
  • Male
  • Metabolic Syndrome / genetics*
  • Middle Aged
  • Mutation, Missense
  • alpha 1-Antitrypsin / blood
  • alpha 1-Antitrypsin / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • GCKR protein, human
  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • SERPINA1 protein, human
  • alpha 1-Antitrypsin
  • ALDH2 protein, human
  • Aldehyde Dehydrogenase
  • Aldehyde Dehydrogenase, Mitochondrial