#COBLYN V.KENNEDY TRIAL#

Recent studies have also indicated a role for platelets in inflammation and immunity ( 4, 5), which may imply potential for repurposing GPIbО± as a target for prevention/treatment of immune-related disease.

#COBLYN V.KENNEDY TRIAL#

Given the potential of GPIbО± as an antithrombotic target, its efficacy for the treatment of thrombotic thrombocytopenic purpura is currently being investigated in a phase II trial ( 3).

Genetic evidence supports the assertion that GPIbО± influences atherothrombosis via increased platelet counts ( 3). It functions as a receptor for von Willebrand factor (vWF) and is implicated in atherothrombosis ( 2). Platelet glycoprotein Ib О±-chain (GPIbО±) is a platelet surface membrane protein ( 1). The role of platelets in thrombosis is well-established however, our findings provide some novel genetic evidence that platelets may be causally implicated in the development of oligoarticular and RF-negative polyarticular JIA, and indicate that GPIbО± may serve as a putative therapeutic target for these JIA subtypes. GPIbО± instrumented by cis-pQTL did not appear to affect cardiovascular risk, although the GPIbО± trans-pQTL was associated with an increased risk of cardiovascular diseases and autoimmune diseases but a decreased risk of autoinflammatory diseases, suggesting that this trans-acting instrument operates through other pathways.

These effects of GPIbО± appeared to be mediated by platelet count and were supported by strong evidence of colocalization (probability of all 3 traits sharing a common causal variant в‰Ґ0.80). ResultsДЄfter correction for multiple testing (Bonferroni-corrected threshold P в‰¤ 2 Г— 10 в€’3), GPIbО±, instrumented by either cis-pQTL or trans-pQTL, was causally implicated with an increased risk of oligoarticular and rheumatoid factor (RF)вЂ“negative polyarticular juvenile idiopathic arthritis (JIA). Putative associations (GPIbО±/platelet count/disease) detected by MR analyses were subsequently assessed using multiple-trait colocalization analyses. To assess if platelet count mediated the effect, we then performed a two-step MR study. We performed a two-sample Mendelian randomization (MR) study, using both a cis-acting protein quantitative trait locus ( cis-pQTL) and trans-pQTL near the GP1BA and BRAP genes as instruments. To ascertain the role of platelet glycoprotein Ib О±-chain (GPIbО±) plasma protein levels in cardiovascular, autoimmune, and autoinflammatory diseases and whether its effects are mediated by platelet count.

Coblyn v.kennedy