Platelet glycoprotein Ib alpha chain as a putative therapeutic target for juvenile idiopathic arthritis: a Mendelian randomization study.

Luo, Shan; Clarke, Sarah; Ramanan, Athimalaipet; Thompson, Susan D; Langefeld, Carl D; Marion, Miranda C; Grom, Alexei A; Schooling, C Mary; Gaunt, Tom R; Au Yeung, Shiu Lun; Zheng, Jie

OBJECTIVE To ascertain the role of platelet glycoprotein Ib alpha chain (GPIbα) plasma protein levels in cardiovascular, autoimmune and autoinflammatory diseases and whether its effects are mediated by platelet count. METHODS We performed a two-sample Mendelian randomization (MR) study, using both cis and trans-acting protein expression quantitative trait loci (pQTL) near GP1BA and BRAP genes as instruments. To assess if platelet count mediated the effect, we then performed a two-step MR study. Putative associations (GPIbα/ platelet count/ disease) detected by MR analyses were subsequently assessed using multiple-trait-colocalization analyses. RESULTS After correcting for multiple testing (P ≤ 2×10-3 ), GPIbα, instrumented by either cis-pQTL or trans-pQTL, was causally implicated with increased risk of juvenile idiopathic arthritis (JIA - oligoarticular and rheumatoid factor negative subtypes). These effects of GPIbα appear to be mediated by platelet count and are supported by strong evidence of colocalization (probability of all three traits sharing a common causal variant ≥ 0.80). GPIbα instrumented by cis-pQTL did not appear to affect cardiovascular risk, although the GPIbα trans-pQTL associates with increased risk of cardiovascular diseases and autoimmune diseases but decreased risk of autoinflammatory diseases, suggesting this trans- instrument acts through other pathways. CONCLUSION The role of platelets in thrombosis is well-established, however our findings provided some novel genetic evidence that platelets may be causally implicated in the development of JIA, and GPIba as a putative therapeutic target for these JIA subtypes.