Purpose Peptidylarginine deiminase (PAD) 1–4 and PAD6 are responsible for protein citrullination. PAD4 is highly expressed in neutrophils and is essential for NETosis, which has been implicated in the pathogenesis of SLE, especially lupus nephritis (LN). Single nucleotide polymorphisms (SNPs) in PADI4 are responsible for altered stability of PAD4 transcripts, altered functionality of the enzyme and differential expression in neutrophils. We aimed to investigate the risk of SLE and LN conferred by SNPs in PADI4.

Methods 236 SLE patients and 484 healthy controls were genotyped for 9 SNPs in PADI4, to investigate potential associations with occurrence of SLE and LN. Selected SNPs are known to alter functionality and/or expression of the enzyme and/or have previously been associated with other autoimmune diseases, including rheumatoid arthritis. Genotypes were analysed using an in-house multiplex bead-based Luminex assay. All analyses were corrected for age and gender.

Results Compared to homozygous carriage of the major alleles, heterozygous carriage of the minor allele of rs1748033 as well as both heterozygous and homozygous carriage of the minor allele of rs1635564 were associated with increased occurrence of SLE (p=0.02, OR 1.54, 95% CI: 1.07 to 2.22, and p=0.02, OR 1.55, 95% CI: 1.08 to 2.23 and p=0.03, OR 2.06, 95% CI: 1.07 to 3.94, respectively). Additionally, homozygous minor allele carriage of rs1635564 was associated with an increased occurrence of LN (p=0.03, OR 3.35, 95% CI: 1.2 to 10.97) showing a possible additive effect of the number of minor alleles present (table 1).

Carriages of the minor alleles of five other SNPs (rs11203366, rs11203367, rs874881, rs2240340 and rs11203368) were associated with increased occurrence of LN (table 1).

Conclusions Polymorphisms in PADI4 may alter the functionality and/or expression of the enzyme and lead to altered production of NETs, possibly affecting the altered clearance of NETs observed in lupus nephritis, thereby contributing to the pathogenesis of this severe clinical manifestation of SLE. PADI4_rs1635564 could be a potential marker for both SLE and LN.