Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated With Systemic Lupus Erythematosus

Am J Hum Genet. 2005 Mar;76(3):528-37. doi: 10.1086/428480. Epub 2005 Jan 18.

Abstract

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes--the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes--we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P<10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Case-Control Studies
  • DNA-Binding Proteins / genetics*
  • Female
  • Finland
  • Gene Frequency
  • Genetic Linkage
  • Humans
  • Iceland
  • Interferon Regulatory Factors
  • Lupus Erythematosus, Systemic / genetics*
  • Male
  • Polymorphism, Single Nucleotide*
  • Protein-Tyrosine Kinases / genetics*
  • Sweden
  • TYK2 Kinase
  • Transcription Factors / genetics*

Substances

  • DNA-Binding Proteins
  • IRF5 protein, human
  • Interferon Regulatory Factors
  • Transcription Factors
  • Protein-Tyrosine Kinases
  • TYK2 Kinase
  • TYK2 protein, human

Associated data

  • OMIM/152700