The University of Hong Kong, Hong Kong, China, and University of Bristol, Bristol, UK.
University of Bristol and University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
Arthritis Rheumatol. 2021 Apr;73(4):693-701. doi: 10.1002/art.41561. Epub 2021 Feb 21.
To ascertain the role of platelet glycoprotein Ib α-chain (GPIbα) plasma protein levels in cardiovascular, autoimmune, and autoinflammatory diseases and whether its effects are mediated by platelet count.
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 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.
After correction for multiple testing (Bonferroni-corrected threshold P ≤ 2 × 10 ), GPIbα, instrumented by either cis-pQTL or trans-pQTL, was causally implicated with an increased risk of oligoarticular and rheumatoid factor (RF)-negative polyarticular juvenile idiopathic arthritis (JIA). These effects of GPIbα 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 ≥0.80). GPIbα instrumented by cis-pQTL did not appear to affect cardiovascular risk, although the GPIbα 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.
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 GPIbα may serve as a putative therapeutic target for these JIA subtypes.
确定血小板糖蛋白 Ib α 链（GPIbα）血浆蛋白水平在心血管、自身免疫和自身炎症性疾病中的作用，以及其作用是否通过血小板计数介导。
我们进行了一项两样本孟德尔随机化（MR）研究，使用位于 GP1BA 和 BRAP 基因附近的顺式作用蛋白数量性状基因座（cis-pQTL）和反式-pQTL 作为工具。为了评估血小板计数是否介导了这种效应，我们随后进行了两步 MR 研究。通过 MR 分析检测到的假定关联（GPIbα/血小板计数/疾病）随后使用多性状共定位分析进行评估。
经过多次测试校正（Bonferroni 校正阈值 P≤2×10），GPIbα 由 cis-pQTL 或 trans-pQTL 仪器化，与少关节炎和类风湿因子（RF）阴性多关节炎青少年特发性关节炎（JIA）的风险增加有关。GPIbα 的这些作用似乎通过血小板计数介导，并且强烈支持共定位的证据（3 个特征共享共同因果变异的概率≥0.80）。由 cis-pQTL 仪器化的 GPIbα 似乎不会影响心血管风险，尽管 GPIbα trans-pQTL 与心血管疾病和自身免疫性疾病的风险增加有关，但与自身炎症性疾病的风险降低有关，表明这种反式作用工具通过其他途径起作用。
血小板在血栓形成中的作用是明确的；然而，我们的研究结果提供了一些新的遗传证据，表明血小板可能与少关节炎和 RF 阴性多关节炎 JIA 的发展有因果关系，并表明 GPIbα 可能是这些 JIA 亚型的潜在治疗靶点。
