Contribution of a European‐Prevalent Variant near CD83 and an East Asian–Prevalent Variant near IL17RB to Herpes Zoster Risk in Tofacitinib Treatment: Results of Genome‐Wide Association Study Meta‐Analyses

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 73; no. 7; pp. 1155 - 1166
• Main Authors: Bing, Nan, Zhou, Huanyu, Chen, Xing, Hirose, Tomohiro, Kochi, Yuta, Tsuchida, Yumi, Ishigaki, Kazuyoshi, Sumitomo, Shuji, Fujio, Keishi, Zhang, Baohong, Valdez, Hernan, Vincent, Michael S., Martin, David, Clark, James D.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.07.2021; John Wiley and Sons Inc
• Subjects: Alleles; Antigens, CD - genetics; Arthritis; Arthritis, Rheumatoid - drug therapy; Asian People - genetics; CD83 Antigen; Cell number; Confidence intervals; Ethnicity; Full Length; Gene frequency; Genetic analysis; Genetic diversity; Genetic factors; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Herpes zoster; Herpes Zoster - chemically induced; Herpes Zoster - epidemiology; Herpes Zoster - genetics; Humans; Immunoglobulins - genetics; Interleukin 1; Janus Kinase Inhibitors - adverse effects; Loci; Logistic Models; Lymphocytes; Membrane Glycoproteins - genetics; Methotrexate; Minority & ethnic groups; Nucleotides; Piperidines - adverse effects; Polymorphism; Polymorphism, Single Nucleotide; Proportional Hazards Models; Psoriasis; Psoriasis - drug therapy; Psoriatic arthritis; Pyrimidines - adverse effects; Receptors, Interleukin-17 - genetics; Rheumatoid Arthritis; Risk; Single-nucleotide polymorphism; Statistical analysis; Ulcerative colitis; White People - genetics
• ISSN: 2326-5191; 2326-5205; 2326-5205
• DOI: 10.1002/art.41655

Objective Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis, and has been previously investigated for psoriasis (PsO). This meta‐analysis of genome‐wide association studies (GWAS) was performed to identify genetic factors associated with increased risk/faster onset of herpes zoster (HZ) in subjects with RA or PsO receiving tofacitinib treatment, and to determine potential mechanisms that could be attributed to the varying rates of HZ across ethnicities. Methods In an ethnicity/indication‐specific, trans‐ethnic, trans‐population meta‐analysis of GWAS in subjects with RA or PsO from phase II, phase III, and long‐term extension studies of tofacitinib, 8 million genetic variants were evaluated for their potential association with time to an HZ event and incidence of an HZ event (case versus control) with tofacitinib treatment, using Cox proportional hazard and logistic regression analyses, respectively. Results In total, 5,246 subjects were included (3,168 with RA and 2,078 with PsO). After adjustment for age, baseline absolute lymphocyte count, genetically defined ethnicity, and concomitant methotrexate use (in RA subjects only), 4 loci were significantly associated with faster onset of HZ in European subjects (P < 5 × 10−8), including a single‐nucleotide polymorphism (SNP) near CD83 (frequency of risk allele ~2% in European subjects versus ~0.1% in East Asian subjects). In the trans‐ethnic, trans‐population meta‐analysis, the CD83 SNP remained significant. Four additional significant loci were identified in the meta‐analysis, among which a SNP near IL17RB was associated with faster onset of HZ (meta‐analysis hazard ratio 3.6 [95% confidence interval 2.40–5.44], P = 7.6 × 10−10; frequency of risk allele ~12% in East Asian subjects versus <0.2% in European subjects). Conclusion Genetic analysis of tofacitinib‐treated subjects with RA or PsO identified multiple loci associated with increased HZ risk. Prevalent variants near the immune‐relevant genes CD83 and IL17RB in European and East Asian populations, respectively, may contribute to risk of HZ in tofacitinib‐treated subjects.