The high mortality rate of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is a critical concern of the Coronavirus Disease 2019 (COVID-19) pandemic. Strikingly, men account for the majority of COVID-19 deaths, with current figures ranging from 59–75% of total mortality. However, despite clear implications in relation to COVID-19 mortality, most research has not considered sex as a critical factor in data analysis. Here, we highlight fundamental biological differences that exist between males and females, and how these may make significant contributions to the male-biased COVID-19 mortality. We present preclinical evidence identifying the influence of biological sex on the expression and regulation of angiotensin-converting enzyme 2 (ACE2), which is the main receptor used by SARS-CoV-2 to enter cells. However, we note that there is a lack of reports showing that sexual dimorphism of ACE2 expression exists and is of functional relevance in humans. In contrast, there is strong evidence, especially in the context of viral infections, that sexual dimorphism plays a central role in the genetic and hormonal regulation of immune responses, both of the innate as well as the adaptive immune system. We review evidence supporting that ineffective anti-SARS-CoV-2 responses, coupled with a predisposition for inappropriate hyperinflammatory responses, could provide a biological explanation for the male bias in COVID-19 mortality. A prominent finding in COVID-19 is the increased risk of death with pre-existing cardiovascular comorbidities such as hypertension, obesity and age. We contextualise how important features of sexual dimorphism and inflammation in COVID-19 may exhibit a reciprocal relationship with comorbidities, and explain their increased mortality risk. Ultimately, we demonstrate that biological sex is a fundamental variable of critical relevance to our mechanistic understanding of SARS-CoV-2 infection and the pursuit of effective COVID-19 preventative and therapeutic strategies.

IMPORTANCEThe association between obesity and diabetic retinopathy (DR) is equivocal, possibly owing to the strong interrelation between generalized and abdominal obesity leading to a mutually confounding effect. To our knowledge, no study in Asia has investigated the independent associations of these 2 parameters with DR to date.OBJECTIVE To investigate the associations of generalized (defined by body mass index [BMI], calculated as weight in kilograms divided by height in meters squared) and abdominal obesity (assessed by waist to hip ratio [WHR]) with DR in a clinical sample of Asian patients with type 2 diabetes mellitus. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional clinic-based study was conducted at the Singapore National Eye Centre, a tertiary eye care institution in Singapore, from December 2010 to September 2013. We recruited 498 patients with diabetes. After exclusion of participants with ungradable retinal images and type 1 diabetes, 420 patients (mean [SD] age, 57.8 [7.5] years; 32.1% women) were included in the analyses.EXPOSURES Body mass index and WHR as waist/hip circumference (in centimeters). MAIN OUTCOMES AND MEASURESThe presence and severity of DR were graded from retinal images using the modified Airlie House Classification into none (n = 189), mild-moderate (Early Treatment Diabetic Retinopathy Study scale score, 20-41; n = 125), and severe DR (Early Treatment Diabetic Retinopathy Study scale score Ն53; n = 118). The associations of BMI and WHR with DR were assessed using multinomial logistic regression models adjusting for age, sex, traditional risk factors, and mutually for BMI and WHR. RESULTS Among the total of 420 patients, the median (interquartile range) for BMI and WHR were 25.7 (5.7) and 0.94 (0.08), respectively. In multivariable models, BMI was inversely associated with mild-moderate and severe DR (odds ratio [OR], 0.90 [95% CI, 0.84-0.97] and OR, 0.92 [95% CI, 0.85-0.99] per 1-unit increase, respectively), while WHR was positively associated with mild-moderate and severe DR (OR, 3.49 [95% CI,] and OR, 2.68 [95% CI, 1.28-5.62] per 0.1-unit increase, respectively) in women (P for interaction = .006). No sex-specific associations were found between BMI and DR (P for interaction >.10). CONCLUSIONS AND RELEVANCEIn Asian patients with type 2 diabetes, a higher BMI appeared to confer a protective effect on DR, while higher WHR was associated with the presence and severity of DR in women. Our results may inform future clinical trials to determine whether WHR is a more clinically relevant risk marker than BMI for individuals with type 2 diabetes.