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The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis

Our take —

This case-control study from Spain and Italy, available as a preprint and thus not yet peer reviewed, provides the first large-scale evidence of host genetic influence in severe COVID-19 disease, and identifies biological targets for further investigation. This analysis was only conducted in European populations, however these genetic variants do not vary widely between ancestries, and therefore should be similar across populations. Furthermore this study does not support a biological explanation for racial/ethnic disparities in COVID-19 morbidity and mortality both within the United States and globally. Finally, replication studies are needed with better control definitions and clinical characterizations to clarify the role of human genetics in COVID-19 severity, instead of overall frailty.

Study design

Case-Control

Study population and setting

A total of 1,610 patients with severe COVID-19 defined by hospitalization with respiratory failure were recruited from seven medical centers in Spain and Italy, and compared to 2,205 randomly selected blood donors. Population based-controls were significantly younger than cases; data were unavailable regarding pre-existing comorbidities or other relevant risk factors for COVID-19.

Summary of Main Findings

A genome-wide association study (GWAS) estimated the association between ~8 million single nucleotide polymorphisms (SNPs) across the human genome, adjusting for population substructure, age, and sex separately by country and then combined with a fixed-effects meta-analysis. Two regions were identified and met the threshold of genome-wide significance (P<10^-8): a region on chromosome 3 upstream of a solute carrier (SLC6A209) and a region on chromosome 9 overlapping the ABO blood group gene. Further analyses found a protective effect for blood group O, and an elevated risk for A positive individuals.

Study Strengths

By limiting cases to those hospitalized with documented COVID-19, the analysis is more likely to capture the host genetics underlying severe disease sequelae.

Limitations

This study uses population controls that are not documented to be exposed or tested for COVID-19, which could dilute the true effect size. Additionally, the combination of different age distributions in cases and controls (controls being significantly younger), and the lack of availability of additional clinical information such as comorbidities, makes the association inference unclear. The associated genetic regions may reflect a COVID-19-specific morbidity, an existing co-morbidity, or generally poorer health in an older population.

Value added

This study provides evidence that genetic variants may be partially responsible for differences in COVID-19 severity.

This review was posted on: 25 June 2020