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DOCK2 is involved in the host genetics and biology of severe COVID-19

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1-5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

 

Comments:

The passage you provided describes a significant scientific finding related to the genetic factors influencing the severity of COVID-19 in a specific population. Here's a summary of the key points:

1. **Research Focus**: The study aimed to identify genetic factors associated with severe COVID-19 in a Japanese population.

2. **Study Design**: The researchers conducted a Genome-Wide Association Study (GWAS) involving 2,393 severe COVID-19 cases and 3,289 unaffected individuals as controls.

3. **Genetic Variant Identified**: The study pinpointed a specific genetic variant (rs60200309-A) located on chromosome 5 at 5q35, close to the DOCK2 gene, which was associated with severe COVID-19 in patients under 65 years old.

4. **Population Specificity**: This risk allele was found to be common in East Asian individuals but rare in Europeans, highlighting the importance of conducting genetic studies in diverse populations.

5. **Gene Expression Analysis**: RNA-sequencing analysis of blood samples revealed that the risk allele was linked to decreased expression of the DOCK2 gene. This decreased expression was particularly notable in non-classical monocytes, a specific type of immune cell.

6. **Biological Role of DOCK2**: The study demonstrated that DOCK2 plays a crucial role in the immune response to SARS-CoV-2. Suppressed DOCK2 expression was observed in severe COVID-19 cases, both in blood samples and lung tissues from affected patients.

7. **Animal Model Validation**: In a Syrian hamster model of SARS-CoV-2 infection, inhibiting DOCK2 function led to more severe pneumonia. This was evidenced by weight loss, lung edema, increased viral loads, impaired macrophage recruitment, and disrupted type I interferon responses.

8. **Implications**: The findings suggest that DOCK2 could serve as a biomarker for predicting severe COVID-19 and might also be a potential therapeutic target. Further research is needed to explore its therapeutic implications fully.

In summary, this research provides valuable insights into the genetic basis of severe COVID-19 in a specific population, shedding light on the role of the DOCK2 gene and its potential as a target for therapeutic interventions and a biomarker for disease severity.

Related Products

Cat.No. Product Name Information
S0899 CPYPP CPYPP is an inhibitor of dedicator of cytokinesis 2 (DOCK2). CPYPP inhibits the guanine nucleotide exchange factor (GEF) activity of DOCK2DHR-2 for Rac1 in a dose-dependent manner with IC50 of 22.8 μM. CPYPP also inhibits DOCK180, DOCK5 and less DOCK9.

Related Targets

DOCK