Genome-Wide Association Study of Ustekinumab Response in Psoriasis

Abstract

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Heterogeneous genetic and environmental factors contribute to the psoriasis phenotype, resulting in a wide range of patient response to targeted therapies. Here, we investigate genetic factors associated with response to the IL-12/23 inhibitor ustekinumab in psoriasis. To date, only HLA-C*06:02 has been consistently reported to associate with ustekinumab response in psoriasis. Genome-wide association testing was performed on the continuous outcome of percent change in Psoriasis Area Severity Index (PASI) at 12 weeks of ustekinumab therapy relative to baseline. A total of 439 European ancestry individuals with psoriasis were included [mean age, 46.6 years; 277 men (63.1%)]. 310 (70.6%) of the participants comprised the discovery cohort and the remaining 129 (29.4%) individuals comprised the validation cohort. Chromosome 4 variant rs35569429 was significantly associated with ustekinumab response at 12 weeks at a genome-wide significant level in the discovery cohort and replicated in the validation cohort. Of psoriasis subjects with at least one copy of the deletion allele of rs35569429, 44% achieved PASI75 (75% improvement in PASI from baseline) at week 12 of ustekinumab treatment, while for subjects without the deletion allele, 75% achieved PASI75 at week 12. We found that differences in treatment response increased when rs35569429 was considered alongside HLA-C*06:02. Psoriasis patients with the deletion allele of rs35569429 who were HLA-C*06:02 negative had a PASI75 response rate of 35% at week 12, while those without the deletion allele who were HLA-C*06:02 positive had a PASI75 response rate of 82% at week 12. Through GWAS, we identified a novel SNP that is potentially associated with response to ustekinumab in psoriasis.

Keywords

• GWAS
• psoriasis
• ustekinumab
• pharmacogenetics
• precision medicine
• pharmacogenomics