title: Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.
abstract: BACKGROUND
  Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci.
  
  
  METHODS
  We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.
  
  
  RESULTS
  Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case-control series (rs13277113; odds ratio, 1.39; P=1x10(-10)) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10(-11)).
  
  
  CONCLUSIONS
  We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Hom
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Barmak
authors.initials: B
authors.lastname: Modrek
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Taylor
authors.forename: Ward
authors.initials: W
authors.lastname: Ortmann
authors.forename: Sophie
authors.initials: S
authors.lastname: Garnier
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Chung
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Ferreira
authors.forename: P V Krishna
authors.initials: PV
authors.lastname: Pant
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Ballinger
authors.forename: Roman
authors.initials: R
authors.lastname: Kosoy
authors.forename: F Yesim
authors.initials: FY
authors.lastname: Demirci
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.forename: Amy H
authors.initials: AH
authors.lastname: Kao
authors.forename: Chao
authors.initials: C
authors.lastname: Tian
authors.forename: Iva
authors.initials: I
authors.lastname: Gunnarsson
authors.forename: Anders A
authors.initials: AA
authors.lastname: Bengtsson
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: Susan
authors.initials: S
authors.lastname: Manzi
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D009656:North America; D020641:Polymorphism, Single Nucleotide; D013548:Sweden; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; C509295:ITGAM protein, human; D019061:src-Family Kinases