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

Abstract

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× 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, 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 (Biomarkers of Systemic Treatment Outcomes in Psoriasis: waist circumference difference of 2.0 cm, P= 8.4× 10-4; UK Biobank: waist circumference difference of 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 multimarker stratified medicine approaches.