A multigene locus at 3p21.31 and the ABO blood group locus at 9q34.2 were identified as potential genetic factors involved in the development of severe coronavirus disease 2019 (COVID-19) with respiratory failure, according to study results published in the New England Journal of Medicine.

In this genomewide association study, researchers analyzed single nucleotide polymorphisms (SNPs) to identify genetic factors associated with severe COVID-19 and respiratory failure, defined as the need for supplemental oxygen or ventilator-assisted respiration, in patients from 7 hospitals in the pandemic epicenters in Italy and Spain. They conducted a meta-analysis of case-control data sets from each country: 835 patients and 1255 control participants from Italy with a total of 8,965,091 SNPs; and, 775 patients and 950 control participants from Spain with a total of 9,140,716 SNPs.

Researchers found a genomewide significance at 2 loci to be associated with severe COVID-19-induced respiratory failure: the rs11385942 insertion-deletion GA or G variant at locus 3p21.31 (odds ratio [OR] for the GA allele, 1.77; 95% CI, 1.48-2.11; P =1.15 x 10−10) and the rs657152 A or C SNP at locus 9q34.2 (OR for the A allele, 1.32; 95% CI, 1.20-1.47; P =4.95 x 10−8). This observation was further confirmed when the analyses were corrected for age and sex.

At locus 3p21.31, the association signal spanned 6 genes: SLC6A20, LZTFL1, CCR9, FYC01, FYCO1, CXCR6, and XCR1. In both the main meta-analysis and the meta-analysis adjusted for age and sex, the frequency of the risk allele of the lead variant at 3p21.31 (rs11385942) was higher among patients who received mechanical ventilation than among those who received only oxygen supplementation.

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At locus 9q34.2, the association signal coincided with the ABO blood group locus. In the meta-analysis adjusted for age and sex, patients with blood group A had a higher risk for severe COVID-19 with respiratory failure compared with other blood groups (OR, 1.45; 95% CI, 1.20-1.75; P =1.48 x 10−4), and patients with blood group O had a decreased risk compared with other blood groups (OR, 0.65; 95% CI, 0.53-0.79; P =1.06 x 10−5).

When researchers scrutinized the extended human leukocyte antigen region, they did not find any association signal.

A key limitation of this study included an inability to adjust for all potential sources of bias such as underlying cardiovascular and metabolic factors relevant to COVID-19.

“Further exploration of current 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,” concluded the researchers.


Ellinghaus D, Degenhardt F, Bujanda L, et al; Severe Covid-19 GWAS Group. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med. 2020;383(16):1522-1534. doi:10.1056/NEJMoa2020283