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Article: Platelet glycoprotein Ib α-chain as a putative therapeutic target for juvenile idiopathic arthritis: a Mendelian randomization study

TitlePlatelet glycoprotein Ib α-chain as a putative therapeutic target for juvenile idiopathic arthritis: a Mendelian randomization study
Authors
Issue Date2021
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2326-5205
Citation
Arthritis & Rheumatology, 2021, v. 73 n. 4, p. 693-701 How to Cite?
AbstractObjective: 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.
Persistent Identifierhttp://hdl.handle.net/10722/290483
ISSN
2023 Impact Factor: 11.4
2023 SCImago Journal Rankings: 3.708
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLuo, S-
dc.contributor.authorClarke, SLN-
dc.contributor.authorRamanan, AV-
dc.contributor.authorThompson, SD-
dc.contributor.authorLangefeld, CD-
dc.contributor.authorMarion, MC-
dc.contributor.authorGrom, AA-
dc.contributor.authorSchooling, CM-
dc.contributor.authorGaunt, TR-
dc.contributor.authorAu Yeung, SL-
dc.contributor.authorZheng, J-
dc.date.accessioned2020-11-02T05:42:52Z-
dc.date.available2020-11-02T05:42:52Z-
dc.date.issued2021-
dc.identifier.citationArthritis & Rheumatology, 2021, v. 73 n. 4, p. 693-701-
dc.identifier.issn2326-5191-
dc.identifier.urihttp://hdl.handle.net/10722/290483-
dc.description.abstractObjective: 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.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2326-5205-
dc.relation.ispartofArthritis & Rheumatology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titlePlatelet glycoprotein Ib α-chain as a putative therapeutic target for juvenile idiopathic arthritis: a Mendelian randomization study-
dc.typeArticle-
dc.identifier.emailSchooling, CM: cms1@hkucc.hku.hk-
dc.identifier.emailAu Yeung, SL: ayslryan@hku.hk-
dc.identifier.authoritySchooling, CM=rp00504-
dc.identifier.authorityAu Yeung, SL=rp02224-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1002/art.41561-
dc.identifier.pmid33079445-
dc.identifier.pmcidPMC8048917-
dc.identifier.scopuseid_2-s2.0-85101207844-
dc.identifier.hkuros318430-
dc.identifier.volume73-
dc.identifier.issue4-
dc.identifier.spage693-
dc.identifier.epage701-
dc.identifier.isiWOS:000620192100001-
dc.publisher.placeUnited States-
dc.identifier.issnl2326-5191-

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