Table 1

Genetic variants and disease severity

AuthorStudy typePopulationBlood type distributionOther findingsRoB
Rhesus and ABO
Ellinghaus et al17GWAS1980 severe COVID-19
vs
2381 HD
Italian
Spanish
NA
  • rs657152 A or C SNP at locus 9q34.2 (OR for the A allele 1.32; 95% CI 1.20 to 1.47; p<0.0001)

  • Higher risk of severe COVID-19 in blood group A vs other blood groups (OR 1.45; 95% CI 1.20 to 1.75; p=0.0148)

  • Lower risk of severe COVID-19 in blood group O vs other blood groups (OR 0.65; 95% CI 0.53 to 0.79; p<0.0001)

  • No significant difference in blood group distribution between patients receiving supplemental oxygen only and those receiving mechanical ventilation of any kind

Low
HLA
Novelli et al16Sequencing and genotyping of HLA genes99
COVID-19
vs
1017 normal
Italian subjects
Haplotypes more prevalent in COVID-19
B*27:07
DRB1*15:01
DQB1*06:02
 p value vs HD
 0.004
 0.048
 0.016
Unclear
Ellinghaus et al17GWAS1980 severe COVID-19
vs
2381 HD
Italian
Spanish
  • No SNP association signals at the HLA complex that met the significance threshold of suggestive association

  • No significant allele associations with either COVID-19 infection or disease severity

High
Genes encoding molecules involved in the host immune response
Zhang et al12Sequencing and genotyping of IFITM3 rs12252 sequence80 COVID-19
(56 mild, 24 severe)
vs
Beijing population (International Genome Sample Resource)
  • Association between homozygosity for the C allele (CC vs CT/TT) and disease severity (OR 6.37; p<0.0001)

  • 2 of the 3 patients who died carried the CC genotype

  • The frequency of CC genotype in mild patients is similar to that in the general Beijing population

Unclear
Cabrera-Marante et al14Sequencing and genotyping of PRF1 rs35947132 (A91V) sequence22 severe young COVID-19
vs
22 HD
(14 Latin-American, 7 Spanish and 1 Polish)
  • Both A91V-positive patients died

High
Ellinghaus et al17GWAS1980 severe COVID-19
vs
2381 HD
Italian
Spanish
  • Cross-replicating associations with rs11385942 at locus 3p21.31 (spanning the genes LZTFL1, CCR9, FYCO1, CXCR6 and XCR1)

High
Zhang et al11RNA Seq659 life-threatening COVID-19 pneumonia
vs
534 asymptomatic or benign
SARS-CoV-2 infection
  • Known variants of Toll-like receptor 3 (TLR3)–and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity associated with life-threatening influenza are present in a subset of patients with life-threatening COVID-19

  • New variants within the same loci have been identified in life-threatening COVID-19

  • Patients showing these variants have hampered IFN immunity in vivo and in vitro

Low
Pairo-Castineira et al13GWAS2244 critical (ICU) COVID-19
vs
11220 HD
  • Significant associations in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3) near the gene encoding tyrosine kinase 2 (TYK2) and in the interferon receptor gene IFNAR2

  • Using Mendelian randomisation, evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease

  • Transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe COVID-19

Low
ACE-2
Benetti et al19Whole exome seq131 COVID-19
vs
258 HD
  • Different distributions of variants vs controls

  • Lower ACE2 allelic variability vs controls (p value<0.029)

Unclear
Novelli et al16Whole
exome
seq
131 hospitalised COVID-19
vs
1000 HD
  • No evidence of consistent association of ACE2 variants with COVID-19 severity

Unclear
Gomez et al20ACE2 gene seq and SNP assessment204 COVID-19
(137 non-severe and 67 severe)
vs 536 HD
  • Low ACE2 allelic variability

  • ACE I/D DD phenotype more prevalent in severe diseases but not significant at multivariable analysis

  • The ACE2 rs2285666 alleles did not differ based on severity nor vs controls

  • Both polymorphisms are associated with hypertension

Unclear
Ellinghaus et al17GWAS1980
severe COVID-19
vs
2381 HD
Italian
Spanish
  • No evidence identified in ACE-2 loci

  • Cross-replicating associations with rs11385942 at locus 3p21.31 (spanning the SLC6A20 gene among others)

High
  • GWAS, genome-wide association study; HD, healthy donor; HLA, human leucocyte antigens; JAK, Janus kinase; NA, not available; RoB, risk of bias; SNP, single nuclear polymorphism; TYK, tyrosine kinase.