ClinVar

Prokunina et al. (2002) identified a 7146G-A regulatory polymorphism (see AF363458), which they called PD-1.3, in an intronic enhancer in the PDCD1 gene. They found an association between susceptibility to SLE (605218) and the G allele. The presence of adenine (A) disrupted the predicted DNA-binding site for RUNX1 (151385) in the first repeat; specific binding occurred when guanine (G) was present at this site. The enhancer-like structure in intron 4 of PDCD1 containing the G/A SNP includes 4 imperfect tandem repeats containing binding sites for transcription factors exclusively involved in hematopoietic differentiation and inflammation, including RUNX1. Prokunina et al. (2002) proposed that RUNX1 binds to the wildtype PDCD1 enhancer to modulate transcription of PDCD1. On cellular activation with self-antigen, the wildtype enhancer may provide a rapid increase in PDCD1 expression, and PDCD1, containing an immunoreceptor tyrosine-based inhibitory motif, inhibits autoreactive cells and preserves self-tolerance. Disruption of the RUNX1 binding site by the presence of adenine could lead to aberrant regulation of PDCD1, contributing to the dysregulated self-tolerance and to the chronic lymphocyte hyperactivity characteristic of SLE. Alternatively, the defect in PDCD1 expression may take place during early lymphocyte development.

Among 939 German patients with multiple sclerosis (MS; 126200), Kroner et al. (2005) reported an association between the A allele of the PD-1.3 polymorphism and disease progression. Of 94 patients with primary progressive MS, 44% had the G/G genotype, and 53% had the A/G genotype. Of 5 MS patients who were homozygous for the A allele, 3 had primary progressive MS, and 1 had secondary progressive MS. In vitro studies showed that PDCD1-mediated inhibition of T-cell activation and cytokine secretion was impaired in cells from patients with the A allele compared to cells from patients with only the G allele. Presence of the A allele did not confer susceptibility to disease development.