PXK – Systemic Lupus Erythematosus

PXK was first implicated in systemic lupus erythematosus (SLE) through a genome-wide association scan in 720 European cases and 2 337 controls, with replication in 1 846 cases and 1 825 controls demonstrating association at 3p14.3 (P_overall = 1.1 × 10⁻⁷ to 1.6 × 10⁻²³; odds ratio = 0.82–1.62) ([PMID:18204446]). Subsequent European replication cohorts (1 579 cases, 1 726 controls; OR = 1.19, P = 0.0038) ([PMID:19442287]) and a pan-meta-GWAS (6 835 SSc/SLE cases, 14 274 controls; P = 3.27 × 10⁻¹¹, OR = 1.20) ([PMID:23740937]) reinforced this finding. However, multiple Asian studies failed to replicate PXK rs6445975 association in 527 Korean cases/517 controls (OR = 1.06, P = 0.57) ([PMID:21243490]) and in 910 Hong Kong Chinese/1 440 controls (P = 0.36) ([PMID:19225526]), and a conditional fine-mapping analysis attributed the SLE signal at this locus to DNASE1L3 (rs35677470 causing c.616C>T (p.Arg206Cys)), which impairs DNASE1L3 secretion without abolishing enzymatic function ([PMID:33455918]).

No Mendelian segregation or coding variants in PXK have been reported in familial SLE. Functional studies of PXK isoforms demonstrate roles in channel modulation and Na⁺/K⁺-ATPase regulation but do not link PXK directly to SLE pathophysiology. Given the lack of consistent replication across populations, absence of variant-level pathogenic data, and locus reassignment to DNASE1L3, the PXK–SLE association is best classified as disputed. Clinicians should not prioritize PXK genotyping for SLE risk assessment in the absence of further confirmatory evidence.

References

• Nature Genetics • 2008 • Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci PMID:18204446
• Rheumatology International • 2012 • Different genetic effect of PXK on systemic lupus erythematosus in the Korean population PMID:21243490
• Genes and Immunity • 2009 • Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese PMID:19225526
• Arthritis Research & Therapy • 2009 • Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study PMID:19442287
• Human Molecular Genetics • 2013 • A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci PMID:23740937
• Annals of the Rheumatic Diseases • 2021 • Arg206Cys substitution in DNASE1L3 causes a defect in DNASE1L3 protein secretion that confers risk of systemic lupus erythematosus PMID:33455918

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