The identification of a gene cluster associated with progression to severe disease in patients with Covid-19 strengthens findings from earlier studies suggesting a prominent role for ABO blood group locus in disease severity.
In the genome-wide association study (GWAS) involving patients hospitalized with Covid-19 in Italy and Spain during the local peak of the pandemic, patients with blood group A had an increased risk for progression to severe disease, while patients with blood group O had a lesser risk for progression.
The strongest signal for severe disease, however, was the rs11385942 insertion-deletion GA or G variant at locus 3p21.31, according to researchers from the Severe Covid-19 GWAS Group.
Blood-group specific analysis showed a higher risk for severe disease among patients with blood group A and a lower risk with blood group O.
In a newly published commentary, researcher Arthur Kaser, MD, of the University of Cambridge Institute of Therapeutic Immunology and Infectious Disease wrote that the genome-wide association study “represents a major leap toward disentangling the molecular mechanisms that cause severe Covid-19.”
Kaser was not involved with the study.
“This genome association study will set directions for research,” he wrote, adding that “a focus on the immunologic synapse between T cells and antigen-presenting cells appears to be warranted” in the search for therapies to address the hyperinflammatory state known as cytokine storm that occurs in some patients with severe Covid-19.
Researchers from the Severe Covid-19 GWAS Group pragmatically compared data from patients hospitalized with severe Covid-19 (defined as respiratory failure), with data from contemporarily recruited blood donors with mostly unknown SARS-CoV-2 status and from historically healthy controls from the same region.
Associations were identified between the risk of developing severe Covid-19 and a multigene locus at 3p21.31 and the ABO blood group locus at 9q34.2.
No association signal was shown for the human leukocyte antigen (HLA) region, which is a regulator of infection immunity and has been suggested as a potential driver of Covid-19 severity.
At locus 3p21.31, the association signal spanned 6 genes: SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1.
“The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group–specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20-1.75; P=1.48×10−4) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53-0.79; P=1.06×10−5),” wrote Tom H. Karlsen of the University of Oslo, and colleagues from the Severe Covid-19 GWAS Group.
In his editorial, Kaser noted that among the 6 candidate genes at 3p21.31, “LZTFL1 might be the most compelling, with the rs11385942 variant and all other fine-mapped association signals that exceeded genome-wide significance located within it.” “LZTFL1 is widely expressed and encodes a protein involved in protein trafficking to primary cilia, which are microtubule-based subcellular organelles acting as antennas for extracellular signals,” he wrote. “In T lymphocytes, LZTFL1 participates in the immunologic synapse with antigen-presenting cells, such as dendritic cells (these cells prime T-lymphocyte responses).”
Kaser noted that of the other 5 candidate genes, 4 (CCR9, FYCO1, CXCR6 and XCR1) have roles in T-cell and dendritic-cell function, while SLC6A20 is a transporter with intestinal expression regulated by the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2).
Earlier research has shown the Covid-19 hyperinflammatory response to resemble secondary hemophagocytic lymphohistiocytosis (HLH), which is a rare and often fatal hyperinflammatory response triggered by autoimmune disorders, certain cancers, and infections.
Kaser wrote that while secondary HLH remains poorly understood, “Mendelian-inherited primary HLH points toward CD8+ T lymphocytes, natural killer cells and dendritic cells triggering a cytokine storm involving macrophages.”
“Other shared features between secondary HLH and severe Covid-19 are cytopenia, hyperferritinemia, disseminated intravascular coagulation, acute respiratory distress syndrome, multiple organ dysfunction, excessive expansion of T lymphocytes, and bone marrow histiocytic hyperplasia with hemophagocytosis with aggregates of interstitial CD8+ lymphocytes,” he noted.
The Severe Covid-19 GWAS Group concluded that “further exploration of the (study) findings both as to their usefulness in clinical risk profiling of patients with Covid-19 and toward a mechanistic understanding of the underlying pathophysiology, is warranted.”
In his commentary, Kaser concluded that the clinical success of treating Covid-19 patients on mechanical ventilation with the corticosteroid dexamethasone “provides strong evidence that death may be caused by a late hyperinflammatory phase.”
“A therapeutic agent that converts severe Covid-19 into a manageable, nonfatal infection would render this pandemic a lesser concern,” he wrote.
“Because it is impossible to predict mechanisms straight from genomic coordinates, experimental testing of the biology of implicated genetic risk pathways is a route, albeit a potentially challenging one, toward that goal.”
- The identification of a gene cluster associated with progression to severe disease in patients with Covid-19 strengthens findings from earlier studies suggesting a prominent role for ABO blood group locus in disease severity.
- The strongest signal for severe disease, however, was the rs11385942 insertion-deletion GA or G variant at locus 3p21.31, according to researchers from the Severe Covid-19 GWAS Group
Salynn Boyles, Contributing Writer, BreakingMED™
Karlsen reported grants from Stein Erik Hagen (via Canica A/S) during the conduct of the study; personal fees from Gilead Sciences, personal fees from Novartis, personal fees from Engitix, and personal fees from Intercept outside the submitted work.
Kaser had no disclosures.
Cat ID: 497
Topic ID: 495,497,282,497,125,190,926,192,927,151,59,928,925,934