Differences in Clinical Features and Comorbid Burden between HLA-C∗06:02 Carrier Groups in >9,000 People with Psoriasis

The identification of robust endotypes???disease subgroups of clinical relevance???is fundamental to stratified medicine. We hypothesized that HLA-C*06:02 status, the major genetic determinant of psoriasis, defines a psoriasis endotype of clinical relevance. Using two United Kingdom-based cross-sectional datasets???an observational severe-psoriasis study (Biomarkers of Systemic Treatment Outcomes in Psoriasis; 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) with those in 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 (Biomarkers of Systemic Treatment Outcomes in Psoriasis: P = 2.7 x 10-14, UK Biobank: P = 1.0 x 10-8). We also show HLA-C*06:02-negative status to be associated with characteristic clinical features (large plaque disease, OR for HLA-C*06:02 = 0.73, P = 7.4 x 10-4; nail involvement, OR = 0.70, P = 2.4 x 10-6); higher central adiposity (Biomarkers of Systemic Treatment Outcomes in Psoriasis: waist circumference difference of 2.0 cm, P = 8.4 x 10-4; UK Biobank: waist circumference difference of 1.4 cm, P = 1.5 x 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 multimarker stratified medicine approaches.