Genetic association and causal inference converge on hyperglycaemia as a modifiable factor to improve lung function.

Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug-repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise individuals who may benefit from particular drug-repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug-gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug-repurposing opportunities that could improve lung function.

Chronic respiratory disorders like asthma affect around 600 million people worldwide. Although these illnesses are widespread, they can have several different underlying causes, making them difficult to treat. Drugs that work well on one type of respiratory disorder may be completely ineffective on another. Understanding the biological and environmental factors that cause these illnesses will allow them to be treated more effectively by tailoring therapies to each patient. Reduced lung function is a factor in respiratory disorders and it can have many genetic causes. Studying the genes of patients with reduced lung function can reveal the genes involved, some of which may already be targets of existing drugs for other illnesses. So, could a patient's genetics be used to repurpose existing drugs to treat their respiratory disorders? Reay et al. combined three methods to link genetics and biological processes to the causes of reduced lung function. The results reveal several factors that could lead to new treatments. In one example, reduced lung function showed a link to genes associated with high blood sugar. As such, treatments used in diabetes might help improve lung function in some patients. Reay et al. also developed a scoring system that could predict the efficacy of a treatment based on a patient's genetics. The study suggests that COVID-19 infection could be affected by blood sugar levels too. Chronic respiratory disorders are a critical issue worldwide and have proven difficult to treat, but these results suggest a way to identify new therapies and target them to the right patients. The findings also support a connection between lung function and blood sugar levels. This implies that perhaps existing diabetes treatments ­ including diet and lifestyle changes aimed at reducing or limiting blood sugar ­ could be repurposed to treat respiratory disorders in some patients. The next step will be to perform clinical trials to test whether these therapies are in fact effective.

COVID-19 and diabetes: A bidirectional relationship. / COVID-19 y diabetes mellitus: una relación bidireccional.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19). Diabetes is one of the most frequent comorbidities in people with COVID-19 with a prevalence that varies between 7 and 30%. Diabetics infected with SARS-CoV-2 have a higher rate of hospital admission, severe pneumonia, and higher mortality compared to non-diabetic subjects. Chronic hyperglycemia can compromise innate and humoral immunity. Furthermore, diabetes is associated with a low-grade chronic inflammatory state that favors the development of an exaggerated inflammatory response and therefore the appearance of acute respiratory distress syndrome. Recent evidence has shown that SARS-CoV-2 is also capable of causing direct damage to the pancreas that could worsen hyperglycemia and even induce the onset of diabetes in previously non-diabetic subjects. Therapeutic strategies should be aimed at facilitating patient access to the healthcare system. Control of blood glucose and comorbidities must be individualized in order to reduce the incidence of complications and decrease the burden on health systems. In this article we will review the pathophysiological mechanisms that explain the bidirectional relationship between COVID-19 and diabetes mellitus, its implication in the prognosis and management of hyperglycemia in this group of patients.

High admission blood glucose independently predicts poor prognosis in COVID-19 patients: A systematic review and dose-response meta-analysis.

AIMS: To investigate the prognostic value of admission blood glucose (BG) in predicting COVID-19 outcomes, including poor composite outcomes (mortality/severity), mortality, and severity. METHODS: Eligible studies evaluating the association between admission fasting BG (FBG) and random BG (RBG) levels with COVID-19 outcomes were included and assessed for risk of bias with the Quality in Prognosis Studies tool. Random-effects dose-response meta-analysis was conducted to investigate potential linear or non-linear exposure-response gradient. RESULTS: The search yielded 35 studies involving a total of 14,502 patients. We discovered independent association between admission FBG and poor COVID-19 prognosis. Furthermore, we demonstrated non-linear relationship between admission FBG and severity (Pnon-linearity < 0.001), where each 1 mmol/L increase augmented the risk of severity by 33% (risk ratio 1.33 [95% CI: 1.26-1.40]). Albeit exhibiting similar trends, study scarcity limited the evidence strength on the independent prognostic value of admission RBG. GRADE assessment yielded high-quality evidence for the association between admission FBG and COVID-19 severity, and moderate-quality evidence for its association with mortality and poor outcomes. CONCLUSION: High admission FBG level independently predicted poor COVID-19 prognosis. Further research to confirm the prognostic value of admission RBG and to ascertain the estimated dose-response risk between admission FBG and COVID-19 severity are required.