CLEC4A – Rheumatoid Arthritis

This summary outlines the association between the dendritic cell immunoreceptor gene (CLEC4A) and rheumatoid arthritis. Multiple independent studies in Asian populations have demonstrated that specific polymorphisms in CLEC4A contribute significantly to disease susceptibility, particularly in patients with ACPA-negative rheumatoid arthritis (PMID:22829930). The studies employed case–control designs with large sample sizes and robust meta-analyses, which together strengthen the clinical validity of this association. The gene’s involvement in immune regulation further supports its relevance in the pathogenesis of rheumatoid arthritis. These findings underscore the gene’s potential as a marker for diagnostic decision‑making and as a target for therapeutic intervention. The evidence, derived from independent cohorts, suggests a replicable and meaningful association between CLEC4A variants and rheumatoid arthritis risk.

Genetic evidence from the replication study demonstrated that the single nucleotide polymorphism (SNP) rs2377422 is significantly associated with rheumatoid arthritis in a Han Chinese population, with an odds ratio of 1.92 (PMID:22829930). Further validation via meta‑analysis across multiple Asian ethnic groups confirmed this association, with an overall odds ratio of 1.17. Although family‐based segregation data are limited, the strength of the association in case series involving over one thousand probands and replication in independent cohorts underscores the robustness of the genetic association with rheumatoid arthritis. The genetic evidence is further enhanced by the consistency of the direction and magnitude of the effect across studies.

In addition to the association studies, secondary investigations have provided corroborative evidence by demonstrating alterations in CLEC4A mRNA expression. One study reported that individuals harboring the risk genotype for rs2377422 exhibited increased mRNA expression levels of CLEC4A, linking genotype to a measurable functional consequence (PMID:22829930). This genotype–phenotype correlation provides an important functional link that reinforces the pathogenic role of the gene in rheumatoid arthritis. Moreover, the replication of these association findings in distinct ethnic cohorts and the consistency with prior evidence from Caucasian populations further argue for the gene’s role in disease development.

Functional assessments have also been critical in establishing the mechanistic basis for the association. Expression studies in porcine tissues have identified multiple mRNA splice variants of CLEC4A, including a canonical isoform that is most abundantly expressed (PMID:33592571). These functional data imply that the diversity of CLEC4A transcripts may affect receptor function and immune cell signaling, which is crucial in the context of autoimmune disorders like rheumatoid arthritis. The presence of different isoforms, some with transmembrane segments and others truncated, supports a complex regulation of CLEC4A function that might be perturbed in disease states.

Integration of the genetic and functional evidence suggests that CLEC4A influences rheumatoid arthritis risk through both its variable expression and its role in immune cell activation. Although the precise molecular mechanism remains to be fully elucidated, the convergence of data from large-scale genetic association studies and biologically relevant functional assays strengthens the support for a pathogenic role of CLEC4A variants. The observed increase in gene expression associated with the risk allele is consistent with a model of dysregulated immune response. This multifaceted evidence underscores the clinical utility of screening for CLEC4A variants in patients with rheumatoid arthritis.

Key take‑home: The robust association between CLEC4A variants and rheumatoid arthritis, reinforced by both genetic and functional data, positions CLEC4A as a promising biomarker for risk stratification and personalized management of rheumatoid arthritis.

References

• PloS One • 2012 • A replication study confirms the association of dendritic cell immunoreceptor (DCIR) polymorphisms with ACPA‑negative RA in a large Asian cohort PMID:22829930
• Human Immunology • 2015 • Contribution of dendritic cell immunoreceptor (DCIR) polymorphisms in susceptibility of systemic lupus erythematosus and primary Sjogren's syndrome PMID:26429306
• Molecular Immunology • 2021 • Expression of CLEC4A in porcine tissues and leukocyte populations and characterization of mRNA splice variants PMID:33592571

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