Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus

Abstract

Objective. The expression of autoimmunity in mice deficient in programmed death 1 (PD-1) suggests that PD-1 is a candidate gene involved in the development of human autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We therefore tested the potential association between PD-1 and the development of SLE and RA by conducting case-control genetic-association studies.Methods. Ninety-eight SLE patients, 84 RA patients, and sex-matched control subjects for each disease group were recruited and genotyped for a singlenucleotide polymorphism, C؉872T, in the human PD-1 gene. The significance of the association of the PD-1 gene with SLE or with RA was analyzed by statistical tests for the difference in genotype distribution between disease and control groups.Results. The human PD-1 gene was found to be significantly associated with disease development in RA patients, but not SLE patients. The risk of RA development appeared to be significantly increased by carriage of the T allele (odds ratio 3.32, P < 0.0001) or the C/T genotype (odds ratio 3.52, P < 0.00005).Conclusion. The PD-1 gene is significantly associated with RA susceptibility, suggesting the possibility that PD-1 may contribute to the pathogenesis of RA.Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are two human autoimmune diseases that are mediated by damaging immune overreactivity to self antigens. Although the pathogenesis of SLE and RA remains unclear, it is possible that dysregulated lymphocyte activation initiates the breakdown of tolerance and predisposes the patient to the development of these autoimmune diseases, because lymphocyte activation appears to be governed by immunostimulatory and immunoinhibitory signals that are delivered through lymphocyte surface receptors. More solid evidence to support this hypothesis comes from the fact that autoimmune diseases can develop in mice that have either an overexpression of a stimulatory receptor or a deficiency of an inhibitory receptor. However, further efforts toward establishing a correlation between each immunoregulatory receptor and human autoimmune diseases are still needed in order to gain more insight into the disease pathogenesis and to develop better therapeutic strategies.Programmed death 1 (PD-1), which was originally identified in a T cell line undergoing activationinduced cell death, is a CD28 family member that contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif and is expressed on the surface of activated T cells and B cells (1-5). As an immunoinhibitory receptor, PD-1 has been shown to inhibit lymphocyte activation and cytokine production after interacting with its ligands PDL-1 (B7-H1) and PDL-2 (B7-DC) (6-10). The immunoinhibitory function of PD-1 was further supported by the observation that mice deficient in PD-1 expression developed autoimmune diseases, despite having distinct phenotypes on different genetic backgrounds. C57BL/6 mice with PD-1 deficiency had an increased incidence of progressive glomerulonephrit...

PDCD1: a tissue-specific susceptibility locus for inherited inflammatory disorders

“…40 We have shown here that two of the PDCD1 SNPs influencing IgE responses also confer susceptibility to RA. Prokunina et al 41 and Lin et al 42 have also very recently reported associations of distinct single PDCD1 SNPs with RA in studies of relatively small cohorts (PD-1 þ 7078 and PD-1 þ 7717, respectively). The significance of these observations is questionable, however, given that, for the Taiwanese cases studied by Lin et al, the locus did not exhibit Hardy-Weinberg equilibrium, and that the association reported by Prokunina et al was relatively weak (P ¼ 0.053).…”

Association of a CD24 gene polymorphism with susceptibility to systemic lupus erythematosus

“…The observation that an inherited variation in CD24 predisposes to both MS and SLE is intriguing, and supports current hypotheses that common cellular and molecular pathogenetic mechanisms might be involved in multiple inflammatory diseases. The general observation that other inflammatory and autoimmune diseases are associated with the same genes (e.g., CTLA4 [27], PTPN22 [28][29][30], and PDCD1 [31][32][33][34]) suggests it may be useful to evaluate the role of CD24 in other diseases.…”

Association between a PD-1 gene polymorphism and antisperm antibody-related infertility in Iranian men

“…Moreover PD 1.3 SNP has been reported in different autoimmune settings, including rheumatoid arthritis [14], Type I diabetes [11], Multiple sclerosis [15], Ankylosing spondylitis [16] and Allergy [17].…”

“…To date, more than 30 SNPs have been identified in human PD-1 gene [10,11]. Prokunina et al reported that the allele A of a SNP named PD1.3 (PD1.3A) in intron 4 is associated with the development of SLE in Europeans (relative risk=2.6) and Mexicans (relative risk=3.5) [12] To date, Single Nucleotide Polymorphism association with PD 1.3 has been reported in several auto-antibody associated autoimmune diseases; including psoriasis [13], rheumatoid arthritis [14], Type I diabetes [11], Multiple sclerosis [15], Ankylosing spondylitis [16] and Allergy [17].…”