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Coronavirus disease 2019 (COVID-19), the agent behind the worst global pandemic of the 21st century (COVID-19), is primarily a respiratory-disease-causing virus called SARS-CoV-2 that is responsible for millions of new cases (incidence) and deaths (mortalities) worldwide. Many factors have played a role in the differential morbidity and mortality experienced by nations and ethnicities against SARS-CoV-2, such as the quality of primary medical health facilities or enabling economies. At the same time, the most important variable, i.e., the subsequent ability of individuals to be immunologically sensitive or resistant to the infection, has not been properly discussed before. Despite having excellent medical facilities, an astounding issue arose when some developed countries experienced higher morbidity and mortality compared with their relatively underdeveloped counterparts. Hence, this investigative review attempts to analyze the issue from an angle of previously undiscussed genetic, epigenetic, and molecular immune resistance mechanisms in correlation with the pathophysiology of SARS-CoV-2 and varied ethnicity-based immunological responses against it. The biological factors discussed here include the overall landscape of human microbiota, endogenous retroviral genes spliced into the human genome, and copy number variation, and how they could modulate the innate and adaptive immune systems that put a certain ethnic genetic architecture at a higher risk of SARS-CoV-2 infection than others. Considering an array of these factors in their entirety may help explain the geographic disparity of disease incidence, severity, and subsequent mortality associated with the disease while at the same time encouraging scientists to design new experimental approaches to investigation. Full article