Caspase recruitment domain containing protein 14 (CARD14) is an adaptor protein which mediates NF-kB signalling in keratinocytes. Gain-of-function CARD14 variants have been associated with various inflammatory skin diseases, including psoriasis vulgaris and generalised pustular psoriasis (GPP). Here, we sought to investigate the involvement of CARD14 in palmar plantar pustulosis (PPP), a localised form of pustular psoriasis.

CARD14 changes were analysed in 160 PPP cases (125 females, 35 males; mean age of onset: 41 years) ascertained by trained dermatologists as part of the APRICOT clinical trial or the PLUM research study. Sequence variants were identified by interrogating whole-exome profiles (103 affected individuals) or Sanger sequencing the CARD14 coding region (57 cases). This revealed eleven rare variants predicted to have a deleterious effect on protein function. A burden test demonstrated a statistically significant association between these changes and PPP (odds ratio: 2.5; 95 % CI: 1.39 to 4.65; p = 0.0023). Single-marker analysis also uncovered a low-frequency allele with deleterious potential (E422K) that occurred more frequently in cases compared to controls (OR 1.7; 95% CI: 1.07 to 2.69; p= 0.025).

Of note, the associated variants were distributed across the entire gene length and mapped outside of the mutation hotspot affected by known gain-of-function changes.

Taken together these findings support an involvement of CARD14 in the pathogenesis of PPP and suggest that risk alleles may act through loss-of-function mechanisms.

CARD14 variants are associated with palmar plantar pustulosis