Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study

Am J Hum Genet. 2012 Apr 6;90(4):648-60. doi: 10.1016/j.ajhg.2012.02.023. Epub 2012 Mar 29.

Abstract

Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 × 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) = 8.62 × 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 × 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10(-8) < p(meta-Euro) < 9.99 × 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Asian People / genetics
  • Black People / genetics
  • Black or African American
  • Chromosome Mapping
  • Egg Proteins / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Haplotypes / genetics
  • Hispanic or Latino / genetics
  • Humans
  • Ikaros Transcription Factor / genetics*
  • Indians, North American / genetics
  • Interferon Regulatory Factors / genetics*
  • Lupus Erythematosus, Systemic / ethnology
  • Lupus Erythematosus, Systemic / genetics*
  • Male
  • Membrane Proteins / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Sequence Analysis, DNA
  • White People / genetics

Substances

  • Egg Proteins
  • IKZF3 protein, human
  • Interferon Regulatory Factors
  • Membrane Proteins
  • TMEM39A protein, human
  • ZPBP2 protein, human
  • interferon regulatory factor-8
  • Ikaros Transcription Factor

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