title: A polymorphism in TLR2 is associated with arterial thrombosis in a multiethnic population of patients with systemic lupus erythematosus.
abstract: OBJECTIVE
  Thrombosis is a serious complication of systemic lupus erythematosus (SLE). Studies that have investigated the genetics of thrombosis in SLE are limited. We undertook this study to assess the association of previously implicated candidate genes, particularly Toll-like receptor (TLR) genes, with pathogenesis of thrombosis.
  
  
  METHODS
  We genotyped 3,587 SLE patients from 3 multiethnic populations for 77 single-nucleotide polymorphisms (SNPs) in 10 genes, primarily in TLRs 2, 4, 7, and 9, and we also genotyped 64 ancestry-informative markers (AIMs). We first analyzed association with arterial and venous thrombosis in the combined population via logistic regression, adjusting for top principal components of the AIMs and other covariates. We also subjected an associated SNP, rs893629, to meta-analysis (after stratification by ethnicity and study population) to confirm the association and to test for study population or ethnicity effects.
  
  
  RESULTS
  In the combined analysis, the SNP rs893629 in the KIAA0922/TLR2 region was significantly associated with arterial thrombosis (logistic P = 6.4 × 10(-5) , false discovery rate P = 0.0044). Two additional SNPs in TLR2 were also suggestive: rs1816702 (logistic P = 0.002) and rs4235232 (logistic P = 0.009). In the meta-analysis by study population, the odds ratio (OR) for arterial thrombosis with rs893629 was 2.44 (95% confidence interval 1.58-3.76), without evidence for heterogeneity (P = 0.78). By ethnicity, the effect was most significant among African Americans (OR 2.42, P = 3.5 × 10(-4) ) and European Americans (OR 3.47, P = 0.024).
  
  
  CONCLUSIONS
  TLR2 gene variation is associated with thrombosis in SLE, particularly among African Americans and European Americans. There was no evidence of association among Hispanics, and results in Asian Americans were limited due to insufficient sample size. These results may help elucidate the pathogenesis of this important clinical manifestation.
authors.affiliation: University of California, San Francisco.
authors.forename: Rachel
authors.initials: R
authors.lastname: Kaiser
authors.forename: Ling Fung
authors.initials: LF
authors.lastname: Tang
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Taylor
authors.forename: Kirsten
authors.initials: K
authors.lastname: Sterba
authors.forename: Joanne
authors.initials: J
authors.lastname: Nititham
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Brown
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Gerald
authors.initials: G
authors.lastname: McGwin
authors.forename: Graciela S
authors.initials: GS
authors.lastname: Alarcón
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: Luis M
authors.initials: LM
authors.lastname: Vilá
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: Joyce
authors.initials: J
authors.lastname: Rauch
authors.forename: Emily
authors.initials: E
authors.lastname: Miller
authors.forename: Kara
authors.initials: K
authors.lastname: Mesznik
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics / Q000706:statistics & numerical data; D001158:Arteries; D001213:Asian / Q000235:genetics / Q000706:statistics & numerical data; D005006:Ethnicity / Q000235:genetics* / Q000706:statistics & numerical data; D005260:Female; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics / Q000706:statistics & numerical data; D006801:Humans; D016015:Logistic Models; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013927:Thrombosis / Q000208:ethnology* / Q000235:genetics*; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics; D020246:Venous Thrombosis / Q000208:ethnology / Q000235:genetics; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data; D055815:Young Adult
chemical_list: C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9