|(G;G)||1.4||Normal risk for rheumatoid arthritis|
|(G;T)||1.8||0.87 reduced risk for rheumatoid athritis|
|(T;T)||1.8||0.87 reduced risk for rheumatoid athritis|
rs4810485 is a SNP associated with rheumatoid arthritis (RA), a chronic autoimmune disease characterized by joint inflammation. At this locus, the minor allele, T, protects against RA. The SNP is located on chromosome 20q13 in the second intron of the CD40 gene, which encodes a receptor that is expressed on the surface of multiple immune cells. CD40 binds the ligand CD154 which is expressed by activated T cells, and this interaction plays a critical role in T cell helper activity in the immune system. rs4810495 is closely linked with another SNP, rs1883832, that appears to lesson translation of the CD40 gene, affecting this critical signaling pathway that leads to B cell proliferation [PMID 17344890]. Mouse model knockouts of CD40 have been shown to alleviate arthritis [PMID 9379064].
The association between rs4810485 and RA was first identified through a genome-wide association study (GWAS) meta-analysis and two subsequent replication studies in patients with European ancestry [PMID 18794853]. This study looked at the major allele G versus the minor allele T in a meta-analysis of previous GWAS followed by two replication studies. In the GWAS meta-analysis, which had 3,393 cases and 12,460 controls, they found rs4810485 to be associated with RA with a p-value of 2.4x10-7 and an odds ratio of 0.83. Two replication studies looking at 31 loci in combined 3,929 cases and 5,807 controls found the position to be associated with the disease with a p-value of 0.0032 and an odds ratio of 0.91. Jointly, the meta-analysis and replication studies showed an association with a p-value of 8.2x10-9 surpassing a conservative level of significance for joint analysis and an odds ratio of 0.87, suggesting that the minor allele T gives a modest protective effect against RA.
The association with RA was confirmed in a targeted validation study in the United Kingdom with 3,962 cases and 3,531 control patients [PMID 19435719]. This study found rs4810485 to be associated with RA with a p-value of 2x10-4 and an odds ratio of 0.86. Since this was a targeted study looking at 4 specific loci, the p-value is significant. Again, the odds ratio suggests a modest protective affect for the minor allele T.
An additional study looked at this SNP and its association with RA in individuals of Korean ancestry [PMID 19180477]. This study found no association between rs4810485 and RA in patients with Korean ancestry. The targeted validation study looked at 5 SNPs associated with RA in Europeans in 1,113 Korean cases and 988 controls, and found a p-value of 0.39 and an odds ratio of 1.06, suggesting no association between the SNP and RA in Koreans. This case highlights the importance of accounting for ancestry when testing genome-wide associations.
[PMID 19644859] Association of a single-nucleotide polymorphism in CD40 with the rate of joint destruction in rheumatoid arthritis
|Title||Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk lock|
|Odds Ratio||1.18 [1.11-1.25]|
[PMID 20498205] Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers
[PMID 21645569] A CD40 and an NCOA5 gene polymorphism confer susceptibility to psoriasis in a Southern European population: A case-control study
[PMID 21914625] A common SNP in the CD40 region is associated with systemic lupus erythematosus and correlates with altered CD40 expression: implications for the pathogenesis
[PMID 22087016] CD40 gene polymorphisms confer risk of Behcet's disease but not of Vogt-Koyanagi-Harada syndrome in a Han Chinese population
[PMID 22645426] CD40 Gene Polymorphisms Associated with Susceptibility and Coronary Artery Lesions of Kawasaki Disease in the Taiwanese Population
[PMID 19159017] STAT2*C related genotypes and allele but not TLR4 and CD40 gene polymorphisms are associated with higher susceptibility for asthma.
[PMID 19180477] Genetic risk factors for rheumatoid arthritis differ in Caucasian and Korean populations.
[PMID 19435719] Association of CD40 with rheumatoid arthritis confirmed in a large UK case-control study.
[PMID 19674979] Overlap of disease susceptibility loci for rheumatoid arthritis and juvenile idiopathic arthritis.
[PMID 20018027] Conditional analysis of the major histocompatibility complex in rheumatoid arthritis.
[PMID 20426808] AntEpiSeeker: detecting epistatic interactions for case-control studies using a two-stage ant colony optimization algorithm.
[PMID 20439292] Genetic variants in the prediction of rheumatoid arthritis.
[PMID 20444755] Investigation of rheumatoid arthritis susceptibility genes identifies association of AFF3 and CD226 variants with response to anti-tumour necrosis factor treatment.
[PMID 23166616] Study of Association of CD40-CD154 Gene Polymorphisms with Disease Susceptibility and Cardiovascular Risk in Spanish Rheumatoid Arthritis Patients
[PMID 23256180] Association of genetic polymorphisms in CD40 with susceptibility to SLE in the Korean population
[PMID 23257401] Single nucleotide polymorphism of CD40 region and the risk of systemic lupus erythematosus
[PMID 23696745] Human Genetics in Rheumatoid Arthritis Guides a High-Throughput Drug Screen of the CD40 Signaling Pathway
[PMID 22328738] Comprehensive assessment of rheumatoid arthritis susceptibility loci in a large psoriatic arthritis cohort.
[PMID 23678157] Integrative analyses for functional mechanisms underlying associations for rheumatoid arthritis.
[PMID 25305459] Lack of association between CD40 polymorphisms and acute rejection in German liver transplant recipients
[PMID 25373542] Associations of rs4810485 and rs1883832 polymorphisms of CD40 gene with susceptibility and clinical findings of Behçet's disease
[PMID 25908480] Associations between the functional CD40 rs4810485 G/T polymorphism and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis
[PMID 26474561] The association of CD40 polymorphisms with CD40 serum levels and risk of systemic lupus erythematosus
[PMID 27722794] Gene-gene interaction between CD40 and CD226 gene on systemic lupus erythematosus in the Chinese Han population.
[PMID 29214033] Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma.
[PMID 31183392] Analysis of Genetic Variation in CD40 and CD40L: Relationship with mRNA Relative Expression and Soluble Proteins in Acute Coronary Syndrome.
[PMID 32018016] Impact of CD40 gene polymorphisms on the risk of immune thrombocytopenic purpura.