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

Abstract

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.

Figure 1

Overall design of the trans‐ancestry and trans‐population genome‐wide association study (GWAS) meta‐analysis in subjects with rheumatoid arthritis (RA) or psoriasis (PsO). *Black and South Asian subgroups were excluded from the GWAS meta‐analysis due to small sample sizes.

Figure 2

Regional association plots assessing the association of time to herpes zoster event with 4 genetic loci, at CD83 (A), GPR141 (B), TOX3 (C), and ACSF3 (D), in subjects with rheumatoid arthritis or psoriasis.

Figure 3

Regional association plots assessing the association of IL17RB with time to herpes zoster (HZ) event (A) and incidence of HZ (case versus control) (B) in subjects with rheumatoid arthritis or psoriasis. Each point represents a single‐nucleotide polymorphism (SNP) passing quality control in the trans‐ancestry meta‐analysis, plotted with its P value (on a −log₁₀ scale) as a function of genomic position. The purple diamond indicates the lead SNP. Color coding of all other SNPs indicates linkage disequilibrium with the lead SNP (estimated using r² values from East Asian populations in the 1000 Genomes Project database): red = r² ≥ 0.8; gold = 0.6 ≤ r² < 0.8; green = 0.4 ≤ r² < 0.6; cyan = 0.2 ≤ r² < 0.4; blue = r² < 0.2; gray = r² unknown.

Figure 4

Correlation between genotype and cell fraction in peripheral blood CD4+ T cells from 82 healthy Japanese individuals. The test for significance of the data from the regression analyses of correlations between proportions of Th1 (A), Th2 (B), Th17 (C), and Treg cells (D) and genotype was performed using t‐statistics. The horizontal axis indicates the rs58861611 genotype groups. Data are shown as box plots, where each box represents the 25th to 75th percentiles, lines inside the boxes represent the median, the X indicates the mean, and lines outside the boxes represent the 10th and 90th percentiles. Circles indicate outliers.