Genome-wide association analysis of anti-TNF-alpha treatment response in Chinese patients with psoriasis

Background: TNF-alpha inhibitors are effective biological agents for treating psoriasis, but the treatment responses differ across patients. This study aimed to identify genetic biomarkers of anti-TNF-alpha response in Chinese psoriasis patients using a genome-wide association approach. Methods: We recruited two independent cohorts of Chinese psoriasis patients administered etanercept biosimilar (with or without methotrexate). We identified 61 and 87 good responders (PASI improvement & GE;75%), 19 and 10 poor responders (PASI improvement < 50%) after 24 weeks treatment in the two cohorts, respectively. Then we performed genome-wide association studies (GWAS) on anti-TNF-alpha response in each cohort independently, followed by a fixed-effects inverse-variance meta-analysis in the 148 good and 29 poor responders. Results: We tested genetic associations with > 3 million genetic variants in either cohort. Meta-analysis identified significant associations within seven loci at p < 10(-5), which also showed consistent association evidence in the two cohorts. These seven loci include rs2431355 (OR = 6.65, p = 4.46 x 10(-7), IQGAP2-F2RL2 on 5q13.3), rs11801616 (OR = 0.11, p = 1.75 x 10(-6), SDC3 on 1p35.2), rs3754679 (OR = 0.17, p = 7.71 x 10(-6), CNOT11 on 2q11.2), rs13166823 (OR = 0.09, p = 3.71 x 10(-6), IRF1-AS1 on 5q31.1), rs10220768 (OR = 5.49, p = 1.48 x 10(-6), NPAP1 on 15q11.2), rs4796752 (OR = 5.56, p = 1.49 x 10(-6), KRT31 on 17q21.2), and rs13045590 (OR = 0.08, p = 9.67 x 10(-7), CTSZ on 20q13.3). Of the seven SNPs, six SNPs showed significant eQTL effect (p < 1 x 10(-6)) for several genes in multiple tissues. Conclusion: These results suggest novel biological mechanisms and potential biomarkers for the response to anti-TNF therapies. These findings warrant further validation.