Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus

PLoS Genet. 2010 Feb 12;6(2):e1000841. doi: 10.1371/journal.pgen.1000841.

Abstract

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adult
  • Alleles
  • Asian Continental Ancestry Group / genetics*
  • Cohort Studies
  • DNA-Binding Proteins
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Haplotypes / genetics
  • Humans
  • Interferon Regulatory Factors / genetics
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Leukocytes, Mononuclear / metabolism
  • Linkage Disequilibrium / genetics
  • Lupus Erythematosus, Systemic / enzymology
  • Lupus Erythematosus, Systemic / genetics*
  • Male
  • Membrane Proteins / genetics
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Principal Component Analysis
  • Proto-Oncogene Protein c-ets-1 / genetics*
  • Reproducibility of Results
  • STAT4 Transcription Factor / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • src-Family Kinases / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • BANK1 protein, human
  • DNA-Binding Proteins
  • ETS1 protein, human
  • IRF5 protein, human
  • Interferon Regulatory Factors
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nuclear Proteins
  • Proto-Oncogene Protein c-ets-1
  • STAT4 Transcription Factor
  • WDFY4 protein, human
  • protein-tyrosine kinase p55(blk)
  • src-Family Kinases
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3