Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles

Nat Genet. 2012 Mar 25;44(5):502-10. doi: 10.1038/ng.2205.

Abstract

Trans-acting genetic variants have a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B cells, we identify new predominantly cell type-specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 in monocytes and B cells, respectively. Additionally, we observe a B cell-specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 × 10(-15)), PRIC285 (P = 3.0 × 10(-10)) and an upstream region of CDKN1A (P = 2 × 10(-52)), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor γ (PPARγ) signaling in autoimmune pathogenesis. We also find that specific human leukocyte antigen (HLA) alleles form trans associations with the expression of AOAH and ARHGAP24 in monocytes but not in B cells. In summary, we show that mapping gene expression in defined primary cell populations identifies new cell type-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Autoimmune Diseases / etiology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genetic Markers / genetics*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • HLA Antigens / genetics*
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Monocytes / immunology
  • Monocytes / metabolism*
  • PPAR gamma / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Quantitative Trait Loci / genetics*

Substances

  • GKLF protein
  • Genetic Markers
  • HLA Antigens
  • Kruppel-Like Transcription Factors
  • PPAR gamma