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.
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.
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).
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.