Platelet Glycoprotein Ib α‐Chain as a Putative Therapeutic Target for Juvenile Idiopathic Arthritis: A Mendelian Randomization Study

Objective 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. Methods We performed a two‐sample Mendelian randomization (MR) study, using both a ci...

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Published in:Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2021-04, Vol.73 (4), p.693-701
Main Authors: Luo, Shan, Clarke, Sarah L. N., Ramanan, Athimalaipet V., Thompson, Susan D., Langefeld, Carl D., Marion, Miranda C., Grom, Alexei A., Schooling, C. Mary, Gaunt, Tom R., Yeung, Shiu Lun Au, Zheng, Jie
Format: Article
Language:English
Subjects:
Arthritis
Arthritis, Juvenile - genetics
Arthritis, Juvenile - immunology
Autoimmune diseases
Cardiovascular diseases
Chains
Female
Full Length
Gene mapping
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Glycoproteins
Health risks
Humans
Inflammatory diseases
Male
Mendelian Randomization Analysis
Pediatric Rheumatology
Phenotype
Platelet Glycoprotein GPIb-IX Complex - genetics
Platelets
Proteins
Quantitative Trait Loci
Randomization
Rheumatoid factor
Risk
Therapeutic applications
Therapeutic targets
Thromboembolism
Thrombosis
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Summary:Objective 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. Methods 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. Results After correction for multiple testing (Bonferroni‐corrected threshold P ≤ 2 × 10−3), 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. Conclusion 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.
ISSN:2326-5191
2326-5205
DOI:10.1002/art.41561