LAUSR

Context A sex discordance in COVID exists, with males disproportionately affected. Although sex steroids may play a role in this discordance, no definitive genetic data exist to support androgen-mediated immune suppression for viral susceptibility, nor for adrenally produced androgens. Objective The common adrenal-permissive missense-encoding variant HSD3B1(1245C) that enables androgen synthesis from adrenal precursors and that has been linked to suppression of inflammation in severe asthma was investigated in COVID susceptibility and outcomes reported in the UK Biobank. Methods The UK Biobank is a long-term study with detailed medical information and health outcomes for over 500,000 genotyped individuals. We obtained COVID test results, inpatient hospital records, and death records and tested for associations between COVID susceptibility or outcomes and HSD3B1(1245A/C) genotype. Primary analyses were performed on the UK Biobank Caucasian cohort. The outcomes were identification as a COVID case among all subjects, COVID positivity among COVID-tested subjects, and mortality among subjects identified as COVID cases. Results Adrenal-permissive HSD3B1(1245C) genotype was associated with identification as a COVID case (odds ratio 1.11 per C allele, p=0.0013) and COVID test positivity (OR 1.10, p=0.011) in older (≥ 70 years of age) women. In women identified as COVID cases, there was a positive linear relationship between age and 1245C allele frequency (p < 0.0001). No associations were found between genotype and mortality, or between genotype and circulating sex hormone levels. Conclusion Our study suggests that a common androgen synthesis variant regulates immune susceptibility to COVID infection in women, with increasingly strong effects as women age.