Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

Nat Genet. 2008 Feb;40(2):204-10. doi: 10.1038/ng.81. Epub 2008 Jan 20.

Abstract

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) < P(overall) < 1.6 x 10(-23); odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 x 10(-5)) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at > or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.

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

  • Alleles
  • Area Under Curve
  • CD11b Antigen / genetics*
  • Case-Control Studies
  • Chromosomes, Human, Pair 1
  • Chromosomes, Human, Pair 11
  • Chromosomes, Human, Pair 16
  • Chromosomes, Human, Pair 3
  • Chromosomes, Human, Pair 6
  • Cohort Studies
  • Confidence Intervals
  • European Continental Ancestry Group
  • Female
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genome, Human*
  • HLA Antigens / genetics
  • Haplotypes
  • Humans
  • Interferon Regulatory Factors / genetics
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Linkage Disequilibrium
  • Logistic Models
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / immunology
  • Nerve Tissue Proteins / genetics*
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics
  • Protein-Serine-Threonine Kinases / genetics*
  • ROC Curve
  • Risk Factors
  • STAT4 Transcription Factor / genetics

Substances

  • CD11b Antigen
  • Genetic Markers
  • HLA Antigens
  • IRF5 protein, human
  • ITGAM protein, human
  • Interferon Regulatory Factors
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • STAT4 Transcription Factor
  • STAT4 protein, human
  • PXK protein, human
  • Protein-Serine-Threonine Kinases
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22