ABSTRACT
OBJECTIVES: C1858T single nucleotide polymorphism in PTPN22 encoding the R620W allele variant of Lyp-PTPN22 (a protein phosphatase negatively regulating T-cell activation) has been associated with autoimmunity. This work has investigated the possible association between PTPN22 C1858T (rs2476601) polymorphism and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) in a Colombian population. METHODS: A case-control study included 1,042 samples from 413 RA, 94 SLE and 101 SSc patients and 434 healthy controls. The TaqMan allele discrimination assay was used for genotyping. RESULTS: The case-control study provided robust evidence of association between allele 1858T and RA (p=5E-05), as well as between 1858T and SLE (p=0.004). These observations were confirmed for both diseases by meta-analysis (p=2E-04, pooled OR 1.9; 1.3-2.7 95% CI for RA; p<0.0001, pooled OR 2.8, 1.8-4.5 95% CI for SLE). No significant association was observed between 1858T and SSc (p=0.98, OR 1.11, 0.46-2.65 95% CI). CONCLUSIONS: The study suggested that the PTPN22 1858T variant influences RA and SLE genetic background but not that of SSc in the Colombian population.
Subject(s)
Arthritis, Rheumatoid/genetics , Genetic Predisposition to Disease/genetics , Lupus Erythematosus, Systemic/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Scleroderma, Systemic/genetics , Adult , Arthritis, Rheumatoid/epidemiology , Case-Control Studies , Colombia/epidemiology , Female , Gene Frequency , Genetic Predisposition to Disease/epidemiology , Genetic Variation/genetics , Genotype , Humans , Lupus Erythematosus, Systemic/epidemiology , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Risk Factors , Scleroderma, Systemic/epidemiologyABSTRACT
BACKGROUND: A functional polymorphism located at -1 from the start codon of the CD40 gene, rs1883832, was previously reported to disrupt a Kozak sequence essential for translation. It has been consistently associated with Graves' disease risk in populations of different ethnicity and genetic proxies of this variant evaluated in genome-wide association studies have shown evidence of an effect in rheumatoid arthritis and multiple sclerosis (MS) susceptibility. However, the protective allele associated with Graves' disease or rheumatoid arthritis has shown a risk role in MS, an effect that we aimed to replicate in the present work. We hypothesized that this functional polymorphism might also show an association with other complex autoimmune condition such as inflammatory bowel disease, given the CD40 overexpression previously observed in Crohn's disease (CD) lesions. METHODOLOGY: Genotyping of rs1883832C>T was performed in 1564 MS, 1102 CD and 969 ulcerative colitis (UC) Spanish patients and in 2948 ethnically matched controls by TaqMan chemistry. PRINCIPAL FINDINGS: The observed effect of the minor allele rs1883832T was replicated in our independent Spanish MS cohort [p = 0.025; OR (95% CI) = 1.12 (1.01-1.23)]. The frequency of the minor allele was also significantly higher in CD patients than in controls [p = 0.002; OR (95% CI) = 1.19 (1.06-1.33)]. This increased predisposition was not detected in UC patients [p = 0.5; OR (95% CI) = 1.04 (0.93-1.17)]. CONCLUSION: The impact of CD40 rs1883832 on MS and CD risk points to a common signaling shared by these autoimmune conditions.
