Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Luo S

PROVIDER: S-EPMC8048917 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Luo Shan S Clarke Sarah L N SLN Ramanan Athimalaipet V AV Thompson Susan D SD Langefeld Carl D CD Marion Miranda C MC Grom Alexei A AA Schooling C Mary CM Gaunt Tom R TR Yeung Shiu Lun Au SLA Zheng Jie J

Arthritis & rheumatology (Hoboken, N.J.) 20210221 4

<h4>Objective</h4>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.<h4>Methods</h4>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 tw ...[more]

PMID: 33079445

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Project description:BackgroundSeveral observational studies have suggested an association between low serum bilirubin levels and Behçet's disease uveitis. However, the causal inference between bilirubin level and juvenile idiopathic arthritis-associated uveitis (JIAU) remains ambiguous. We investigated the potential causal relationship between serum bilirubin levels and JIAU using a bidirectional two-sample Mendelian randomization (MR) framework.MethodsWe systemically integrated summary-level data from published large-scale genome-wide association studies on bilirubin level and JIAU in a Caucasian British population. To determine the causal effect of bilirubin level on JIAU, we constructed strong instrumental variables using 47 and 80 single-nucleotide polymorphisms (SNPs) specific to direct bilirubin and total bilirubin levels, respectively. For reverse causal inference, seven SNPs associated with JIAU were included in our study. Multiple complementary methods were further performed to evaluate the robustness of MR estimates.ResultsThe inverse-variance weighted estimate did not show any significant causal associations of genetically predicted serum direct or total bilirubin level with the risk of JIAU (odds ratio [OR]: 1.010, 95% confidence interval [CI]: 0.750-1.359, p = 0.947; OR: 0.867, 95% CI: 0.688-1.093; p = 0.227, respectively). MR-Egger and weighted median methods also obtained similar associations. Additionally, the results of reverse MR analyses using JIAU as exposure showed no associations of genetically predicted risk of JIAU with serum bilirubin levels (p > 0.05). In sensitivity analysis, the causal estimate between serum bilirubin levels and JIAU did not differ when SNPs associated with possible confounders were omitted.ConclusionGenetic evidence from our bidirectional analysis did not support a causal association between serum bilirubin levels and JIAU risk in the Caucasian British population. Future large-scale studies should be conducted to validate these findings and explore any causal effects on the disease process.

Project description:BackgroundHaptoglobin (Hp), a liver derived acute phase inflammatory protein (APP), has scarcely been studied in juvenile idiopathic arthritis (JIA). Hp can occur in blood as two isoforms (Hp1 and Hp2) in precursor and mature forms. Routine clinical chemistry immunoturbidimetry does not discern these forms. It is unknown how different forms relate to disease activity in JIA. Our aims were to determine allele frequency and plasma concentrations of different Hp forms at higher versus lower JIA disease activity and compare to other APPs.MethodsPlasma from JIA (n = 77) and healthy (n = 42) children were analyzed for apparent Hp allelic frequency and densitometric concentrations of alpha forms by Western blot (WB). Polymerase chain reaction (PCR) (buffy coat) was performed in a subset to estimate conformity with genetics. At higher versus lower juvenile arthritis disease activity score (JADAS27) (which includes erythrocyte sedimentation rate (ESR)), total mature Hp concentration from WB was compared and correlated against immunoturbidimetry and total protein, albumin, serum amyloid A (SAA) and C-reactive protein (CRP).ResultsAt 300-fold dilution needed to study mature forms in Western blot, precursors were undetectable. Hp2 contributed most signal in most samples. Hp allele frequency was similar in JIA and controls. Both mature forms, taken separately or by sum, declined following treatment, but remained above concentrations of healthy controls, even in a remission subset that achieved JADAS27 < 1. Densitometry correlated with immunoturbidimetry. Hp concentrations correlated with JADAS27, albumin (negatively), CRP and SAA with immunoturbidimetric method correlating strongest to JADAS27 (Spearman R ~ 0.6, p < 0.0001).ConclusionHp allele frequency in JIA is similar to the general population, indicating that children with JIA should have the same possibility as in healthy children to produce preHp2 (zonulin), thought to increase intestinal permeability. Circulating Hp concentrations largely parallel other APPs and ESR; none of these measures correlate very strongly to JADAS27 score but Hp can be measured from capillary sampling which is impossible with ESR.

Dataset Information

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

Objective

Methods

Results

Conclusion

Publications

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

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