The severity of outcome from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is widely varied, with most individuals remaining asymptomatic while others experience severe life-threatening pneumonia and multi-organ failure. Host genetics play a role in disease progression and prognosis. A paper recently uploaded to the preprint server medRxiv* by Dubé et al. (1st March 2021) identifies several alleles associated with the gene natriuretic peptide receptor C (NPR3) that may impact disease severity.
How was the study performed?
The group worked with 4,488 high-risk COVID-19 outpatients being over 40 years of age and having at least one other comorbidity such as diabetes or obesity. The group was split into two equal sizes, one of which received a placebo, while the other received 0.5 mg colchicine, an anti-inflammatory, daily for a month. The patients were evaluated for disease symptoms 15 and 30 days into the trial.
The same patients were asked to take part in an additional study to help identify genetic determinants in the COVID-19 outcome. Genetic data were collected from those that consented and the outcome of COVID-19 tracked per individual. The dataset was further refined by the removal of genetically related samples or those without positive COVID-19 PCR tests, leaving 1,855 for analysis.
78% of the total participants reported being free of COVID-19 symptoms during the 30 day period, with the authors noting that generally, women experienced longer-lasting symptoms than men. Interestingly, 0.3% and 5.1% of the colchicine trial participants died or were hospitalized, respectively, while only 3.1% of those who went on to be included in the genetic study were hospitalized, with none dying. Unfortunately, as the authors state, healthy participant bias means that less healthy patients are less likely to participate in the additional genetic study.
The time to symptom remission following onset was recorded amongst the genetic analysis group, and in-silico methods were utilized to identify two common genetic variations correlated with shorter disease period.
Manhattan plots for the GWAS of time to remission of COVID-19 symptoms. a. Using a Cox proportional hazards regression with 1723 subjects from the colchicine and placebo arms of the COLCORONA study, controlling for study arm, sex, age, and 10 principal components for genetic ancestry, with 6,392,715 genetic variants of minor allele frequency ≥ 5%.
Which alleles were identified?
Two loci of interest were identified by the group, located at 5p13.3 and 9q33.1. The chromosome 5 locus variant spans the NPR3 gene, which is involved in the extended renin-angiotensin system. Variation in NPR3 has also been associated with height, blood pressure, and the forced expiratory volume of an individual’s lungs. Those with copies of the minor allele had a shorter remission period than those with the major allele, with 44%, 54% and 59% of patients becoming healthy 15 days after infection if they had 0, 1, or 2 copies of the allele, respectively.
The chromosome 9 allele has also been associated with a person's height and is a risk factor for venous abnormalities. In this case, the locus variant only had an observable effect on symptom remission in the non-placebo group, which the authors suggest may be due to the administration of colchicine. Multiple similar inflammatory pathways are activated by both the downstream effects of the chromosome 9 variant and colchicine, potentially occluding the genetic effect in the group receiving the drug. Within the placebo group, 46%, 62% and 64% of patients had symptom remission within 15 days when the individual had 0, 1, or 2 copies of the allele, respectively.
Since symptom duration is a strong predictor of disease severity this newly discovered genetic risk factor could aid in predicting outcome. Deeper categorization of an individual’s risk factors by genetic analysis will allow custom treatments to be devised in future, though in this particular case more follow-up studies with more participants will be required to confirm the findings.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Genetics of symptom remission in outpatients with COVID-19, Marie-Pierre Dube, Audrey Lemacon, Amina Barhdadi, Louis-Philippe Lemieux Perreault, Essaid Oussaid, Geraldine Asselin, Sylvie Provost, Maxine Sun, Johanna Sandoval, Marc-Andre Legault, Ian Mongrain, Anick Dubois, Diane Valois, Emma Dedelis, Jennifer Lousky, Julie Choi, Elisabeth Goulet, Christiane Savard, Lea-Mei Chicoine, Marieve Cossette, Malorie Chabot-Blanchet, Marie-Claude Guertin, Simon de Denus, Nadia Bouabdallaoui, Richard Marchand, Zohar Bassevitch, Anna Nozza, Daniel Gaudet, Philippe L L'Allier, Julie Hussin, Guy Boivin, David Busseuil, Jean-Claude Tardif, medRxiv, 2021.02.24.21252396; doi: https://doi.org/10.1101/2021.02.24.21252396, https://www.medrxiv.org/content/10.1101/2021.02.24.21252396v1