PDCD1 – Systemic Lupus Erythematosus

Programmed cell death 1 (PDCD1) encodes the inhibitory receptor PD-1, which regulates peripheral tolerance by attenuating T-cell activation. Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by multisystem inflammation and autoantibody production. PDCD1 was prioritized as a candidate within the SLEB2 linkage locus in Nordic multiplex families and later investigated in large case–control and family-based cohorts.

A landmark study genotyped 2,510 individuals for single-nucleotide polymorphisms (SNPs) in PDCD1 and identified an intronic SNP, c.627+189G>C, that was enriched in European SLE cases (12% of alleles) compared to controls (5%) (relative risk=2.6) and in Mexican cases (7% vs. 2%) ([PMID:12402038]). This variant resides within an intronic enhancer and was shown to alter a RUNX1 transcription factor‐binding site.

Subsequent case–control analyses in a Spanish population (518 patients, 800 controls) revealed no association of the PD1.3 A allele with SLE (9.0% in cases vs. 13.0% in controls) and demonstrated marked population‐specific differences in haplotype structure across PDCD1 ([PMID:15334473]).

A study of childhood‐onset SLE in 250 Mexican patients and 355 controls replicated association of the PD1.3A allele (P=0.0019; OR=2.73) but found no correlation with lupus nephritis; the ACG haplotype containing PD1.3A was also enriched in patients (5.5% vs. 2.1%) ([PMID:17228327]).

Family-based transmission disequilibrium testing in 844 US simplex families across four ethnic groups identified a haplotype with PD1.3A associated with SLE in Caucasians (P=0.01) and distinct risk SNPs in Hispanics, with further haplotype correlations to clinical subphenotypes such as nephritis and antiphospholipid positivity ([PMID:17344889]).

Functional assays have probed the mechanistic impact of PD1.3: electrophoretic mobility shift assays confirm differential binding of RUNX1 to the G allele, but enhancer reporter assays failed to demonstrate allele-specific transcriptional activity, suggesting context-dependent effects of this intronic SNP ([PMID:18401354]).

Despite replicated association in multiple cohorts and mechanistic evidence for altered transcription factor binding, the lack of monogenic segregation, population heterogeneity, and incomplete functional concordance support a moderate level of clinical validity. PDCD1 regulatory variants contribute to SLE susceptibility, informing risk stratification and highlighting PD-1 pathway modulation as a potential therapeutic avenue in SLE.

References

• Nature Genetics • 2002 • A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. PMID:12402038
• Arthritis and Rheumatism • 2004 • Association of PDCD1 with susceptibility to systemic lupus erythematosus: evidence of population-specific effects. PMID:15334473
• European Journal of Human Genetics • 2007 • Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus. PMID:17228327
• Genes and Immunity • 2007 • Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort. PMID:17344889
• Genes and Immunity • 2008 • Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus. PMID:18401354

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