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

Abstract

Variation in genes encoding costimulatory molecules expressed on lymphocytes has been expected to contribute to the genetic component of inflammatory disease, but only the gene encoding the inhibitory protein, CTLA-4, seems consistently to confer disease susceptibility. Studies in murine models implicate the inhibitory product of the pd1 gene, programmed death-1, in the maintenance of peripheral tolerance to self-antigens. We identify 22 single-nucleotide polymorphisms (SNPs) in the equivalent human gene, PDCD1, a number of which show significant associations with the specific immunoglobulin E response to grass allergens in atopic individuals. Stepwise analyses indicate that four of the disease-associated SNPs have independent effects. The two most common haplotypes show positive and negative associations but rarer haplotypes are also likely to be of influence. In a case-control study, multiple regression analysis of genotypic data implies that PDCD1 also confers susceptibility to rheumatoid arthritis. Along with work linking PDCD1 with susceptibility to another autoimmune condition, systemic lupus erythematosus, our data identify PDCD1 as a second immunomodulatory gene with pleiotropic effects in human disease. Genes encoding negative regulators may generally confer a significant fraction of the genetic risk associated with inherited inflammatory disorders.

Bias in association studies of systemic lupus erythematosus susceptibility due to geographical variation in the frequency of a programmed cell death 1 polymorphism across Europe

“…8 There were also reports of association of PDCD1 with SLE phenotypes or other immune-mediated diseases that were independent of the PD1.3 SNP. 11,12,16,17 Often polymorphisms show a gradient of frequencies across Europe. These patterns of variation have been called allele frequency clines.…”

“…In other study, SNPs different from PD1.3 were associated with RA susceptibility in British patients and with the atopic phenotype of Australian subjects. 17 Further research will be necessary to clarify the role of PDCD1 variation given the important involvement of this immunoreceptor in autoimmunity and chronic viral infections. 6,7 It can be questioned whether differences in PDCD1 variants between different populations could be related with changes in SLE prevalence.…”

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

“…Previous studies have shown that PD-1 gene polymorphisms are correlated with autoimmune diseases such as ankylosing spondylitis [17], rheumatoid arthritis [10], and systemic lupus erythematous [20]. 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].…”

“…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].…”