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Abstract
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.
Highlights
Psoriasis is a common, chronic immune-mediated skin disease that affects at least 2% of the population worldwide [1]
There was no correlation between age, BMI, and duration of the disease with the primary outcome of percent Psoriasis Area Severity Index (PASI) improvement, and so these clinical variables were not included as covariates in the linear regression model (Supplementary Figure 1)
The association of rs35569429 with ustekinumab response was validated in an independent cohort of psoriasis patients
Summary
Chronic immune-mediated skin disease that affects at least 2% of the population worldwide [1]. Moderate-to-severe psoriasis is treated with phototherapy and systemic agents, including targeted biologic inhibitors of TNF-a, IL-12/23, IL-17, and IL-23. Patient responses to biologic therapy can vary widely, from poor overall response to gradual loss of therapeutic sensitivity [2]. Response differences are largely influenced by patient weight and adherence, drug dose and GWAS of Psoriasis Ustekinumab Response bioavailability, and pharmacokinetic covariates, such as drug immunogenicity [3]. The molecular heterogeneity of psoriasis may contribute to differential therapeutic responses. There are no molecular biomarkers routinely used in clinical practice to facilitate selection of the therapies tailored to individual patients
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