PLCL1 regulates fibroblast-like synoviocytes inflammation via NLRP3 inflammasomes in rheumatoid arthritis

ObjectivesPrimary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS.MethodsWe performed a genome-wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta-analysis of approximately 7 million variants were evaluated for functional and biological process enrichment. The genetic risk variability for PAPS in different populations was also assessed. Hierarchical clustering, Mahalanobis distance, and Dirichlet Process Mixtures with uncertainty clustering methods were used to assess genetic similarities between PAPS and other immune-mediated diseases.ResultsWe revealed genetic associations with PAPS in a regulatory locus within the HLA class II region nearHLA-DRAand inSTAT4with a genome-wide level of significance. 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele in the HLA class II locus is associated with overexpression ofHLA-DRB6,HLA-DRB9,HLA-DPB2,HLA-DQA2andHLA-DQB2, and is independent of the association between PAPS andHLA-DRB1*1302. Functional analyses highlighted immune and nervous system related pathways in PAPS-associated loci. The comparison with other immune-mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sjögren’s syndrome, suggesting colocalized causal variations close toSTAT4,TNPO3, andBLK.ConclusionsThis study represents a comprehensive large-scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease.

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multi-GPA-Tree: Statistical approach for pleiotropy informed and functional annotation tree guided prioritization of GWAS results

Khatiwada,

Yilmaz,

Wolf

et al. 2023

PLoS Comput Biol

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Genome-wide association studies (GWAS) have successfully identified over two hundred thousand genotype-trait associations. Yet some challenges remain. First, complex traits are often associated with many single nucleotide polymorphisms (SNPs), most with small or moderate effect sizes, making them difficult to detect. Second, many complex traits share a common genetic basis due to ‘pleiotropy’ and and though few methods consider it, leveraging pleiotropy can improve statistical power to detect genotype-trait associations with weaker effect sizes. Third, currently available statistical methods are limited in explaining the functional mechanisms through which genetic variants are associated with specific or multiple traits. We propose multi-GPA-Tree to address these challenges. The multi-GPA-Tree approach can identify risk SNPs associated with single as well as multiple traits while also identifying the combinations of functional annotations that can explain the mechanisms through which risk-associated SNPs are linked with the traits. First, we implemented simulation studies to evaluate the proposed multi-GPA-Tree method and compared its performance with existing statistical approaches. The results indicate that multi-GPA-Tree outperforms existing statistical approaches in detecting risk-associated SNPs for multiple traits. Second, we applied multi-GPA-Tree to a systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and to a Crohn’s disease (CD) and ulcertive colitis (UC) GWAS, and functional annotation data including GenoSkyline and GenoSkylinePlus. Our results demonstrate that multi-GPA-Tree can be a powerful tool that improves association mapping while facilitating understanding of the underlying genetic architecture of complex traits and potential mechanisms linking risk-associated SNPs with complex traits.

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PLCL1 regulates fibroblast-like synoviocytes inflammation via NLRP3 inflammasomes in rheumatoid arthritis

Cited by 4 publications

References 31 publications

Mechanisms of NLRP3 inflammasome in rheumatoid arthritis and osteoarthritis and the effects of traditional Chinese medicine

Mechanisms of NLRP3 inflammasome in rheumatoid arthritis and osteoarthritis and the effects of traditional Chinese medicine

A genome-wide association study suggests new susceptibility loci for primary antiphospholipid syndrome

multi-GPA-Tree: Statistical approach for pleiotropy informed and functional annotation tree guided prioritization of GWAS results

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