Genetic Variant of TNIP1 (rs10036748) Predicts Better Response to Methotrexate in Chinese Psoriasis Patients

1. TT genotype of rs10036748 in TNIP1 shows better response to methotrexate in a Chinese population: A prospective cohort study KX Yan*1, YJ Zhang*2, L Han1, Q Huang1, ZH Zhang1, X Fang1, ZZ Zheng1, N Yawalkar3, YL Chang2, Q Zhang2, L Jin2, DF Qian2, XY Li2, MS Wu2, QH Xu2, XJ Zhang1, and JH Xu*1 1Shanghai Institute of Dermatology and Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, China 2Institute of Dermatology and Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230032, China 3Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern 3012, Switzerland British Journal of Dermatology. DOI: 10.111/bjd.xxxxx

2. Xuejun Zhang, MD, PhD The director of Institute of Dermatology Huashan Hospital, Fudan University Jinhua Xu, MD, PhD The director of Dermatology Department Huashan Hospital, Fudan University

3. Introduction What’s already known? • Methotrexate is the first-line treatment for moderate to severe psoriasis. However, there exists significant heterogeneity in individual responses to methotrexate. • HLA-Cw6-positive patients with psoriasis show improved response to methotrexate treatment

4. Objective • To investigate the association of clinical factors and variants of psoriasis susceptibility genes with clinical responses to methotrexate in a prospective cohort.

5. Methods • A total of 221 psoriatic patients were recruited. • Patients who achieved Psoriasis Area and Severity Index (PASI) improvement of at least 75% at week 12 were defined as responders, whereas those with PASI improvement <50% were defined as non-responders.

6. Methods • Genetic variants for 18 single-nucleotide polymorphisms in 14 susceptibility genes and HLA-Cw6 status in 90 screening patients were initially compared between responders and non-responders. • Statistically significant associations in genetic variants were verified in all 221 patients.

7. Results • Of psoriatic patients, 49% and 45% achieved PASI75 improvement during screening and verification stages, respectively. • Concomitant arthritis with psoriasis and high body mass index (BMI) negatively affect the efficacy of methotrexate. • The TT genotype of rs10036748 in TNIP1 was significantly associated with PASI75 response at week 12 (54% and 37%, p<0.05).

8. Results • A significantly higher PASI90 response was observed in patients with TT genotype of rs10036748 (27% vs. 12%, p<0.01) and TC/TT genotype of rs4112788 in LCE3D (25% vs. 13%, p<0.05) at week 12 compared with those with other genotypes. • After adjustment for all confounding factors, only BMI (p<0.05), arthritis (p<0.05), and genotype of rs10036748 (p<0.05) were significantly associated with clinical responses to methotrexate.

9. Discussion • At week 12, 49% and 45% of patients achieved PASI75 or more during the screening and verification stages, respectively. • which is similar to the results of a previous report that indicated that 45.2% of patients achieved PASI-75 between weeks 12 and 16.

10. Discussion • Only BMI and concomitant arthritis were significantly associated with clinical responses to methotrexate after adjustment for all confounding factors. • A previous study showed that patients with BMI ≥25 had a significantly lower percentage reduction in PASI than those with BMI <25 at week- 16.

11. Discussion • HLA-Cw6 status was not correlated with clinical response to methotrexate • Indhumathi et al. showed that HLA-Cw6 status acts as an independent genetic predictor of clinical responses to methotrexate in a South Indian Tamil population. • This can be ascribed to the time difference in the definition of responders and non-responders.

12. Discussion • TC/TT genotype of rs4112788 in LCE3D was significantly associated with better response than CC genotype during the screening stage. But this association was not observed during the verification stage. • The mean age and disease duration during the screening stage were much elder and longer than those during the verification stage among patients.

13. Discussion • TT genotype of rs10036748 in TNIP1 was significantly associated with better responses to methotrexate treatment in univariate and multivariate analyses. • Rs10036748 is an intron variant of TNIP1 which is located on chromosome 5q33.1, that can affect the expression of TNIP1. • TNIP1 interacts with TNFAIP3 and inhibits the TNF-α–induced– NF-κB inflammation pathway. • Methotrexate suppresses NF-κB activation via adenosine release, which may contribute to the role of MTX in anti-inflammatory, immunomodulatory, and antiproliferative effects. • TNIP1 is not only a susceptibility gene for psoriasis; but also a genetic marker for predicting methotrexate efficacy.

14. ConclusionsWhat does this study add? • Concomitant psoriasis and high body mass index negatively affect the efficacy of methotrexate. • TT genotype of rs10036748 in TNIP1 was significantly associated with better responses to methotrexate.

15. Photographs of the research team Qiong Huang Zhizhong Zheng Yawalkar Nikhil Xu Fang Kexiang Yan Yuanjing Zhang Ling Han Zhenghua Zhang Yuling Chang Qun Zhang Ling Jin Danfeng Qian Xuejun Zhang Xueying Li Mingshun Wu Qiaohu Xu Jinhua Xu

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