Brief Report: A Polymorphism in TLR2 Is Associated With Arterial Thrombosis in a Multiethnic Population of Patients With Systemic Lupus Erythematosus

Abstract

ObjectiveThrombosis 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.MethodsWe 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.ResultsIn 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).ConclusionTLR2 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.

Caveolin-1 regulates chemokine receptor 5-mediated contribution of bone marrow-derived cells to dermal fibrosis

“…While the available tissue sections were not full-thickness and thus did not allow us to quantify the thickness of the dermis,images of SSc skin (particularly at higher magnification) revealed that collagen fibrils were packed more densely than in control skin (Figure 2). Interestingly, as in SSc patients (Marangoni et al, 2012), lipodystrophy (a loss of the subcutaneous adipose cell layer) was also observed in bleomycin-treated mice (Figure 1). …”

“…Skin fibrosis in SSc is associated with loss of subcutaneous adipose tissue (lipodystrophy) (Marangoni et al, 2012). Similarly, we observed a loss of subcutaneous adipose tissue concomitant with dermal fibrosis in the Pump Model, both of which were blocked by CSD.…”

The Commensal Microbiota Enhances ADP-Triggered Integrin αIIbβ3 Activation and von Willebrand Factor-Mediated Platelet Deposition to Type I Collagen

“…As expected, we found platelet deposition to type I collagen to be related to VWF plasma levels. The relevance of TLR2 in arterial thrombosis is complemented by a clinical study in systemic lupus erythematosus patients, which has identified single nucleotide polymorphisms in the Tlr2 gene that were linked to arterial thrombosis [ 39 ].…”

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“…The magnitude of the association of polymorphisms with autoimmune disease varies depending on genetics, demographics and environmental factors. Many association studies reported that TLR-2 polymorphisms predisposed to autoimmune disease 19,20,21 . However, some polymorphisms of TLR2 might not be associated with autoimmune disease like rheumatoid arthritis (RA) 29 .…”

“…Another polymorphism in TLR2 at position 677 (Arg677Trp) was associated with susceptibility to lepromatous leprosy 18 . Several studies reported that TLR2 polymorphisms predisposed to autoimmune diseases 19,20,21 . So far, only one study had shown association of TLR4 polymorphism with GBS 22 .…”