Identifying such genetic factors could help reveal the mechanisms of, and hence the risk of, varicella zoster virus (VZV) reactivation related to tofacitinib. (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 (< 5 10?8), including a single\nucleotide polymorphism (SNP) near (frequency of risk allele ~2% in European subjects versus ~0.1% in East Asian subjects). In the trans\ethnic, trans\population meta\analysis, the SNP remained significant. Four additional significant loci were identified in the meta\analysis, among which a SNP near was associated with faster onset of HZ (meta\analysis hazard ratio 3.6 [95%?confidence interval 2.40C5.44], = 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 and Marbofloxacin in European and East Asian populations, respectively, may contribute to risk of HZ in tofacitinib\treated subjects. INTRODUCTION Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ulcerative colitis (UC), and has been previously investigated for psoriasis (PsO). Tofacitinib is an orally bioavailable small molecule whose inhibitory activity involves blockade of the ATP binding Marbofloxacin site (1). In cellular settings where the various JAKs signal in combination, tofacitinib preferentially inhibits H3/h signaling by heterodimeric receptors associated with JAK1 and/or JAK3, and has functional selectivity over JAK2 (1). The efficacy and safety of tofacitinib have been studied across multiple immune\mediated inflammatory diseases, including RA (2, 3, 4, 5, 6, 7) and PsO (8, 9, 10, 11). The safety profile of tofacitinib in subjects with RA or PsO is generally similar to that of tumor necrosis factor inhibitors and other biologic disease\modifying antirheumatic drugs (bDMARDs), with the exception of herpes zoster (HZ) rates (12, 13, 14, 15). HZ risk is elevated in subjects with RA in comparison to the general Marbofloxacin population (16), and the risk is further increased in Marbofloxacin tofacitinib\treated subjects (17), although multidermatomal or disseminated HZ cases have been infrequent (8% of HZ cases) in subjects receiving tofacitinib (13). This appears to be a class\specific effect, because use of other JAK inhibitors targeting JAK1 or JAK1/JAK2 has resulted in an increased risk of HZ (18). HZ risk in tofacitinib\treated subjects with RA increases with age, glucocorticoid use, tofacitinib dose, and enrollment within Asia (e.g., subjects from Japan and Korea have 2C3\fold higher rates of HZ versus those from other regions) (19). Similarly, in tofacitinib\treated subjects with PsO, HZ risk increases with age, tofacitinib dose, and Asian descent, and also prior bDMARD use (20). Subjects with UC and those with PsA receiving tofacitinib also experience higher rates of HZ when compared with subjects who have not been treated with tofacitinib (21, 22, 23). The higher HZ rates in Asian subjects observed in the RA and PsO studies (17, 20) could be attributable to multiple factors, including ascertainment bias, prevalence of a genetic clade of virus prone to reactivation, enhanced response to tofacitinib, or an interaction between JAK inhibition and a genetic polymorphism more common in Japan and Korea. Genetic studies have identified variations in the HLA region as being associated with risk of HZ (24). We hypothesized that genetic factors may be associated with tofacitinib\related HZ, and that the genetic variation across ethnicities may contribute to the variance in HZ rates. Identifying such genetic factors could help reveal the mechanisms of, and hence the risk of, varicella zoster virus (VZV) reactivation related to tofacitinib. We therefore conducted a genome\wide.