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. 2022 Aug 19:13:968935.
doi: 10.3389/fphar.2022.968935. eCollection 2022.

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

Yunqing Ren  1   2 , Ling Wang  3 , Huatuo Dai  1   2 , Guiying Qiu  1   2 , Jipeng Liu  1 , Dianhe Yu  1   2 , Jianjun Liu  3   4 , Cheng-Zhi Lyu  5 , Lunfei Liu  2   6 , Min Zheng  2
Affiliations

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

Yunqing Ren et al. Front Pharmacol. .

Abstract

Background: TNF-α 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-α 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 ≥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-α 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 × 10-7, IQGAP2-F2RL2 on 5q13.3), rs11801616 (OR = 0.11, p = 1.75 × 10-6, SDC3 on 1p35.2), rs3754679 (OR = 0.17, p = 7.71 × 10-6, CNOT11 on 2q11.2), rs13166823 (OR = 0.09, p = 3.71 × 10-6, IRF1-AS1 on 5q31.1), rs10220768 (OR = 5.49, p = 1.48 × 10-6, NPAP1 on 15q11.2), rs4796752 (OR = 5.56, p = 1.49 × 10-6, KRT31 on 17q21.2), and rs13045590 (OR = 0.08, p = 9.67 × 10-7, CTSZ on 20q13.3). Of the seven SNPs, six SNPs showed significant eQTL effect (p < 1 × 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.

Keywords: SNP; anti-TNF-α agents; genome-wide association analysis (GWAS); psoriasis; treatment response.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Results of meta-GWAS of the two cohorts. (A) The −log10 genome-wide p values using a fixed-effects inverse-variance meta-analysis calculated on the basis of data from overlapped 3478293 SNPs in the 148 good responders and 29 poor responders. The blue horizontal line presents a liberal threshold of 10−5 for suggestive significance. The red horizontal line indicates genome-wide significance (p < 5 × 10−8). (B) Quantile-quantile plots of the observed p values versus the expected values form p value of association. λgc = 1.065.
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