Interleukin-6 receptor (IL6R) stimulates the inflammatory pathways as part of the acute-phase response to infection. Tocilizumab is a monoclonal antibody that inhibits both membrane-bound and soluble IL6R and is used to treat inflammatory conditions, including COVID-19. Despite the disproportionate incidence of COVID-19 among underserved, racial, and ethnic minority populations, the efficacy of tocilizumab in hospitalized COVID-19 patients from these populations is unclear. In this work, three genetic markers for the IL6R gene were analyzed across diverse ethnic backgrounds to identify population differences in response to tocilizumab treatment. Genetic structure analyses showed that African populations were significantly different from other described populations. In addition, mapped frequencies of these alleles showed that Sub-Saharan African populations were 3.4x more likely to show an impaired response to tocilizumab than East Asian populations, and 1.8x more likely than European ancestry populations. Existing IL6R genotype results may identify populations at increased therapeutic failure risk. As results from current clinical trials on the efficacy of tocilizumab treatment for extreme COVID-19 infections are conflicting, more studies are needed across diverse patient backgrounds to better understand the genetic factors necessary to predict treatment efficacy. This work demonstrates how pharmacogenomics studies can elucidate genetic variation on treatment efficacy on COVID-19.

The COVID-19 global pandemic has led to repurposing of drugs, with little underlying evidence for treatment safety and efficacy. This may increase complications for patients with acute viral respiratory infections. UGT1A1 and CYP2D6 enzymes are involved in the metabolism of atazanavir and fluvoxamine repurposed for COVID-19. This study aimed to elucidate the role of interethnic variation in these enzymes in the efficacy of repurposed drug therapies. A retrospective cohort of 101 Jordanian Arab samples were genotyped using Affymetrix DMET Plus Premier Package. Comprehensive global population genetic structure analyses were performed for CYP2D6 and UGT1A1 allele frequencies across multi-ethnic populations of over 131,000 global subjects from 417 published reports, revealing that Jordanian Arabs share the closest sequence homology to European and Near East populations. The East Asian populations have significantly over-representaiton of individuals with diplotype pairs for reduced atazanavir metabolism compared to the African populations and are more likely to show impaired UGT1A1 metabolism. East Asian populations are also 4.4x more likely to show impaired fluvoxamine metabolism than South Central Asian and Oceanian populations, and 8x more likely than other ancestry populations. The results here support previous findings that interethnic variation should be used for developing proper population-specific dosage guidelines.