Mining a GWAS of Severe Covid-19 | NEJM - nejm.org

To the Editor

In order to probe the genetic signal associated with severe coronavirus disease 2019 (Covid-19) reported by the Severe Covid-19 GWAS Group (Oct. 15 issue)¹ and to formulate clinically relevant hypotheses, we examined phenomewide associations for rs657152-A (ABO) (see Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).

The variant rs657152-A was associated with risks of deep-vein thrombosis and pulmonary embolism, conditions that are pervasive in patients with severe Covid-19.² Correlated variants were also associated with higher levels of the blood-clotting proteins von Willebrand factor and factor VIII as well as interleukin-6, all of which are frequently elevated in patients with severe Covid-19.³ Evidence from a recent study suggests that persons with blood type A or type B are at a higher risk for thromboembolic events than persons with type O, irrespective of Covid-19 status.⁴ We have observed that higher levels of the soluble lectin CD209 are associated with the single-nucleotide polymorphism rs505922-C (which has an r² of 0.9 with rs657152-A). CD209 facilitates the spread of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) to T lymphocytes through antigen-presenting cells.⁵ These findings raise questions of therapeutic and prognostic relevance. Could a lower threshold for the initiation of thromboprophylaxis be beneficial? Is there a correlation between CD209 levels and SARS-CoV-2 viral load?

Mohd Karim, M.B., B.S.
Maya Ghoussaini, Ph.D.
Wellcome Sanger Institute, Hinxton, United Kingdom
[email protected]

Ian Dunham, D.Phil.
European Bioinformatics Institute, Hinxton, United Kingdom

No potential conflict of interest relevant to this letter was reported.

This letter was published on November 24, 2020, at NEJM.org.

1. 1. The Severe Covid-19 GWAS Group. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med 2020;383:1522-1534.

2. 2. Kerbikov OB, Yu Orekhov P, Borskaya EN, Nosenko NS. High incidence of venous thrombosis in patients with moderate to severe COVID-19. June 14, 2020 (https://www.medrxiv.org/content/10.1101/2020.06.12.20129536v1). preprint.

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3. 3. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020;46:1089-1098.

4. 4. Groot HE, Villegas Sierra LE, Said MA, Lipsic E, Karper JC, van der Harst P. Genetically determined ABO blood group and its associations with health and disease. Arterioscler Thromb Vasc Biol 2020;40:830-838.

5. 5. Jeffers SA, Tusell SM, Gillim-Ross L, et al. CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. Proc Natl Acad Sci U S A 2004;101:15748-15753.

To the Editor

The Severe Covid-19 GWAS Group recently identified variants in two loci that increase the risk of respiratory failure in patients with Covid-19. To determine the mechanisms through which these loci might confer risk, we combined genetic data and measurements of 1305 circulating proteins (with the use of SOMAScan) from 4856 Black and White participants in three studies: the Jackson Heart Study, the Framingham Heart Study, and the Malmö Diet and Cancer Study.¹

Strikingly, the specific Covid-19 risk variant rs657152-A (at the ABO locus) was strongly associated with increased levels of the CD209 antigen (also known as dendritic cell [DC]–specific-intracellular adhesion molecule 3 [ICAM-3]–grabbing nonintegrin [DC-SIGN] (see Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). This dendritic cell-surface protein has been found to facilitate infection by SARS-CoV-2 and other viruses² and can be shed into the bloodstream. Cohort differences emerged. In the Jackson Heart Study, we found associations between rs657152-A and multiple inflammatory proteins, whereas in the Framingham and Malmö studies, we found that rs657152-A was associated with levels of adhesion proteins. We also observed that variants at the 3p21.31 locus were associated with levels of CXCL16, an inflammatory chemokine implicated in alveolitis and atherogenesis (see Table S2).^3,4 These analyses suggest potential mechanisms for genetic risk in patients with Covid-19, including proteins involved in viral binding, endothelial function, and atherothrombosis.

Daniel H. Katz, M.D.
James G. Wilson, M.D.
Robert E. Gerszten, M.D.
Beth Israel Deaconess Medical Center, Boston, MA
[email protected]

for the Jackson, Framingham, and Malmö Heart Study Group

No potential conflict of interest relevant to this letter was reported.

The views expressed in this letter are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the Department of Health and Human Services.

This letter was published on November 24, 2020, at NEJM.org.

The members of the Jackson, Framingham, and Malmö Heart Study Group are listed in the Supplementary Appendix, available at NEJM.org.

1. 1. Benson MD, Yang Q, Ngo D, et al. Genetic architecture of the cardiovascular risk proteome. Circulation 2018;137:1158-1172.

2. 2. Yang Z-Y, Huang Y, Ganesh L, et al. pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN. J Virol 2004;78:5642-5650.

3. 3. Agostini C, Cabrelle A, Calabrese F, et al. Role for CXCR6 and its ligand CXCL16 in the pathogenesis of T-cell alveolitis in sarcoidosis. Am J Respir Crit Care Med 2005;172:1290-1298.

4. 4. Aslanian AM, Charo IF. Targeted disruption of the scavenger receptor and chemokine CXCL16 accelerates atherosclerosis. Circulation 2006;114:583-590.

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