Abstract
The functional single-nucleotide polymorphism (SNP) of the gene PTPN22 is a susceptibility locus for rheumatoid arthritis (RA). The study presented here describes the association of the PTPN22 1858T allele with RA in a German patient cohort; 390 patients with RA and 349 controls were enrolled in the study. For 123 patients, clinical and radiographic documentation over 6 years was available from the onset of disease. Genotyping of the PTPN22 1858 SNP was performed using an restriction fragment length polymorphism PCR-based genotyping assay. The odds ratio to develop RA was 2.57 for carriers of the PTPN22 1858T allele (95% confidence interval (CI) 1.85–3.58, p < 0.001), and 5.58 for homozygotes (95% CI 1.85–16.79). The PTPN22 1858T allele was significantly associated not only with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) positive RA, but also with RF and anti-CCP negative disease. The frequency of the PTPN22 1858T allele was increased disproportionately in male patients (53.8% compared to 33.0% in female patients, p < 0.001), and the resulting odds ratio for male carriers was increased to 4.47 (95% CI 2.5–8.0, p < 0.001). Moreover, within the male patient population, the rare allele was significantly associated with the HLA-DRB1 shared epitope (p = 0.01). No significant differences in disease activity or Larsen scores were detected. The results provide further evidence that the PTPN22 1858T allele is associated with RA irrespective of autoantibody production. The increased frequency of the risk allele in male patients and its association with the shared epitope indicate that the genetic contribution to disease pathogenesis might be more prominent in men.
Highlights
Rheumatoid arthritis (RA) is a complex autoimmune disease with a strong genetic contribution to its pathogenesis
Individuals with values ≥40 IU/ml on at least one occasion were regarded as rheumatoid factor (RF) positive since this cutoff has been established by the central laboratory facility and is recommended for routine clinical use
The CT and TT genotype was present in 37.9% of patients and 19.2% of healthy controls, resulting in an Odds ratios (OR) of 2.57
Summary
Rheumatoid arthritis (RA) is a complex autoimmune disease with a strong genetic contribution to its pathogenesis. Studies on twins have shown concordance rates between 12% and 15% in monozygotic twins compared to 4% in dizygotic twins [1] Calculations based on these data have estimated an overall heritability of about 60% [2,3], indicating that genetic factors account for the majority of population susceptibility to RA. An association between the minor allele (T) of a missense single-nucleotide polymorphism (SNP; R620W (rs2476601, 1858C/T)) in the protein tyrosine phosphatase non-receptor type 22 gene (PTPN22) and susceptibility to RA has been described [5]; this has been confirmed in several large cohorts of patients and controls [6,7,8,9,10,11,12,13,14,15,16,17,18]. The PTPN22 1858T variant has recently been described to result in a gain-of-function form of the enzyme [23], leading to stronger suppression of the early
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