Clozapine-induced Agranulocytosis Is Associated With Rare HLA-DQB1 and HLA-B Alleles

Nat Commun. 2014 Sep 4;5:4757. doi: 10.1038/ncomms5757.

Abstract

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

Publication types

  • Multicenter Study
  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Agranulocytosis / chemically induced
  • Agranulocytosis / genetics*
  • Agranulocytosis / immunology
  • Alleles
  • Amino Acid Substitution
  • Antipsychotic Agents / adverse effects*
  • Case-Control Studies
  • Clozapine / adverse effects*
  • Exome*
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • HLA-B Antigens / genetics*
  • HLA-B Antigens / immunology
  • HLA-DQ beta-Chains / genetics*
  • HLA-DQ beta-Chains / immunology
  • Heterozygote
  • Humans
  • Odds Ratio
  • Psychotic Disorders / drug therapy
  • Psychotic Disorders / genetics
  • Psychotic Disorders / immunology
  • Severity of Illness Index

Substances

  • Antipsychotic Agents
  • HLA-B Antigens
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • Clozapine