The identification of robust endotypes – disease subgroups of clinical relevance – is fundamental to stratified medicine. We hypothesised that HLA-C*06:02 status, the major genetic determinant of psoriasis, defines a psoriasis endotype of clinical relevance. Using two UK-based cross-sectional datasets – an observational severe psoriasis study (Biomarkers of Systemic Treatment Outcomes in Psoriasis, BSTOP; n=3,767) and a large population-based bioresource (UK Biobank, including n=5,519 individuals with psoriasis) – we compared demographic, environmental and clinical variables of interest in HLA-C*06:02-positive (one or two copies of the HLA-C*06:02 allele) compared to HLA-C*06:02-negative (no copies) individuals of European ancestry. We used multivariable regression analyses to account for mediation effects established a priori. We confirm previous observations that HLA-C*06:02-positive status is associated with earlier age of psoriasis onset and extend findings to reveal an association with disease expressivity in females (BSTOP: p=2.7×10-14, UK Biobank: p=1.0×10-8). We also show HLA-C*06:02-negative status to be associated with characteristic clinical features (large plaque disease, odds ratio [OR] for HLA-C*06:02 = 0.73, p=7.4×10-4; nail involvement, OR=0.70, p=2.4×10-6); higher central adiposity (BSTOP: waist circumference difference 2.0 cm, p=8.4×10-4; UK Biobank: 1.4 cm, p=1.5×10-4), especially in women; and a higher prevalence of other cardiometabolic comorbidities. These findings extend the clinical phenotype delineated by HLA-C*06:02 and highlight its potential as an important biomarker to consider in future multi-marker stratified medicine approaches.
- HLA-C Antigens/genetics
- Stratified medicine