Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus

Abstract

This study aimed to test the functional effects of the PD1.3 single nucleotide polymorphism (SNP) (rs11568821), which were proposed based on its association to systemic lupus erythematosus (SLE) susceptibility and in electrophoretic mobility shift assays (EMSA) results. We analysed transcriptional effects of the PD1.3 locus by enhancer reporter assays. Results were against the hypothesis that the PD1.3 locus acts as enhancer in transcriptional regulation of PDCD1. In addition, they excluded a differential effect of the PD1.3 alleles. EMSA results confirmed that oligonucleotides with the PD1.3 G allele bind RUNX1 but not those with the A allele. However, binding to PD1.3 G oligonucleotides was much lower than binding to positive control oligonucleotides. Criss-cross experiments showed that this was due to flanking nucleotides in the PD1.3 sequence that negatively affect RUNX1 binding. These results cast doubts on the functional relevance of the PD1.3 SNP and, together with the lack of association in several studies, put into question its role as an SLE susceptibility factor. Investigation of other PDCD1 polymorphisms is needed to uncover the possible effect of this gene on SLE susceptibility.

Abnormality of RUNX1 signal transduction in psoriatic CD34+ bone marrow cells

“…PDCD1 binds to its ligands, including PD‐L1 and PD‐L2, then recruits protein tyrosine kinases, which produces a coactivated effect that is necessary for inhibition of the dysimmunity reaction. A recent study reported that the anomalous connection of RUNX1 and the PDCD1 single nucleotide polymorphism PD1.3 is essential to the pathogenesis of systemic lupus erythematosus (SLE) 21 . We did not find significant difference in mRNA expression of PDCD1 between the psoriasis and control groups.…”

“…A recent study reported that the anomalous connection of RUNX1 and the PDCD1 single nucleotide polymorphism PD1.3 is essential to the pathogenesis of systemic lupus erythematosus (SLE). 21 We did not find significant difference in mRNA expression of PDCD1 between the psoriasis and control groups.…”

A predictive model of treatment outcome in patients with chronic HCV infection using IL28B and PD-1 genotyping

“…Based on their model, patients who carry this allele may have a lower expression of PD-1 molecule in activated lymphocytes, and could have a better response to IFN-a stimulation. However other authors, using a luciferase reporter assays, showed that the two alleles of PD-1.3 have similar effects on reporter gene transcription [39]. In spite of the possible implication of this polymorphism in the regulation of protein expression, this study clearly showed that PD-1.3 modulated the outcome to treatment for HCV infection treatment.…”

TNF-α and TGF-β Counter-Regulate PD-L1 Expression on Monocytes in Systemic Lupus Erythematosus

“…The mechanistic link between PD-1 or PD-L1 expression and the pathogenesis of human SLE is not well understood. Polymorphisms in the PD-1 gene are associated with SLE susceptibility in some populations of adults and children1112131415. However, PD-L1 gene polymorphisms were not associated with SLE1617.…”