Exploring the genetic link between COVID-19 resistance and diabetes

Infection with SARS-CoV-2 can be asymptomatic or life-threatening, with various clinical forms and levels of clinical severity in between. There is compelling evidence that the proportion of casualties is much higher in humans older than 50 years of age and those with underlying co-morbidities. Patients with type 2 diabetes (T2D) have a four-fold increased risk of having severe/critical COVID-19 illness. The risk of severe disease in patients with type 1 diabetes (T1D) is less clear; there is currently no indication that adolescents with T1D have higher mortality or morbidity than their healthy peers. Life-threatening SARS-CoV-2 infection is associated with inborn errors of immunity, and patients with COVID-19 pneumonia have pre-existing autoantibodies that neutralize type I IFNs. Autoantibodies to type I IFNs have been linked to protection against T1D, but their role in T2D is still unknown. Although most individuals who encounter SARS-CoV-2 become infected, some individuals appear to have a natural resistance to SARS-CoV-2 infection and remain uninfected and seronegative despite confirmed repetitive exposure to the pathogen. This indicates that 'resistors’ may carry monogenic variations that make them naturally resistant to the entry of the virus. In this study, we want to find out if some people have changes in their genes that make them naturally resistant to the virus. We will also explore the genetic link between SARS-CoV-2 resistance and both types of diabetes. Specifically, we aim to ascertain whether such 'resistors’ have a genetic makeup that renders them resistant to developing T2D but genetically predisposed to developing T1D. To this end, we plan to recruit individuals in close contact with confirmed SARS-CoV-2 cases who remain uninfected and do not display any symptoms of infection. A blood sample will be obtained from all eligible participants for whole genome/exon sequencing and for the measurement of anti-SARS-CoV-2 antibodies and autoantibodies. Findings from our study will define key immunity genes involved in host defense against SARS-CoV-2 in the setting of a natural ecosystem and further show how this might be linked to the genetic landscape of diabetes. This will ultimately benefit patients with diabetes who are at increased risk of severe COVID-19.