Abstract
Palmoplantar pustulosis (PPP) is a debilitating inflammatory skin disorder that presents with painful pustules on the palms and soles. While PPP has a negative impact on quality of life, treatment efficacy is often limited as disease pathways are poorly understood. Most PPP patients are former or current smokers, but a causal role of cigarette smoking has not been established. Meanwhile, the genetic underpinnings of the disease have been the subject of limited investigation, as the rarity of PPP has hindered the ascertainment of substantial patient cohorts.The aim of this study was to address this research gap and identify genetic determinants of PPP through the analysis of multiple, well-characterised datasets.
In the first phase of the research, a candidate gene analysis was undertaken in a UK cohort. Whole-exome sequencing data generated in 236 unrelated cases was mined to investigate variants in 4 candidate genes (IL36RN, MPO, AP1S3 and CARD14) and the HLA region. This demonstrated that rare CARD14 variants were more frequent among PPP cases compared to gnomAD population controls (P=1.5x10-3).
Next, the study cohort was expanded to include cases originating from Finland and Norway.
The resulting dataset, which included a total of 1,456 cases and 402,050 controls, was examined in a genome-wide association study (GWAS) meta-analysis. This revealed two genome-wide significant associations, in proximity of CCHCR1/PSORS1C3 (rs887467, P=2.9 x 10-11) and FCGR3B/FCGR3A (rs61802325, P=1.6 x 10-8). Thirteen suggestive association signals (P<5x10-6) were also observed. Interestingly, one genome-wide significant (CCHCR1) and one suggestive (IL4) locus had been previously associated with eczema susceptibility.
Downstream analyses showed that the PPP association signals colocalised with skin expression quantitative loci (eQTL) for CCHCR1 and FCGR3B, suggesting a causal role for these genes. Meanwhile, the integration of GWAS and single-cell RNA sequencing data showed that disease associated genes were over-represented in dendritic cells transcriptional modules. Finally, a Mendelian Randomization analysis established a causal relationship between smoking initiation and PPP.
These findings shed new light on the determinants of PPP, pointing to a disruption of innate and adaptive immune responses, that is likely exacerbated by cigarette smoking.
| Date of Award | 1 Dec 2024 |
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| Original language | English |
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| Supervisor | Francesca Capon (Supervisor) & Catherine Smith (Supervisor) |