BACKGROUND
There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.
METHODS
We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case–control panels.
RESULTS
We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10−8) in the meta-analysis of the two case–control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.15×10−10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P=4.95×10−8, respectively). At locus 3p21.31, the association signal spanned the 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 to 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 to 0.79; P=1.06×10−5).
CONCLUSIONS
We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system.
Using a pragmatic approach with simplified inclusion criteria and a complementary team of clinicians at the European Covid-19 epicenters in Italy and Spain and scientists in the less-burdened countries of Germany and Norway, we performed a GWAS that included de novo genotyping for Covid-19 with respiratory failure in approximately 2 months. We detected a novel susceptibility locus at a chromosome 3p21.31 gene cluster and confirmed a potential involvement of the ABO blood-group system in Covid-19.
On chromosome 3p21.31, the peak association signal covered a cluster of six genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, and XCR1), several of which have functions that are potentially relevant to Covid-19. A causative gene cannot be reliably implicated by the present data. One candidate is SLC6A20, which encodes the sodium–imino acid (proline) transporter 1 (SIT1) and which functionally interacts with angiotensin-converting enzyme 2, the SARS-CoV-2 cell-surface receptor.However, the locus also contains genes encoding chemokine receptors, including the CC motif chemokine receptor 9 (CCR9) and the C-X-C motif chemokine receptor 6 (CXCR6), the latter of which regulates the specific location of lung-resident memory CD8 T cells throughout the sustained immune response to airway pathogens, including influenza viruses. Flanking genes (e.g., CCR1 and CCR2) also have relevant functions,and further studies will be needed to delineate the functional consequences of detected associations.
The preliminary results from the Covid-19 Host Genetics Consortium include suggestive associations within the same locus at chromosome 3p21.31, which lend considerable support to our findings. The consortium analysis also used population-based controls, but the patients included persons with mild Covid-19 and those with severe Covid-19. The parallel findings nevertheless underscore an important point about the ascertainment of patients and controls in genetic studies of Covid-19. Because the majority of patients with SARS-CoV-2 infection are asymptomatic, any sample involving patients with a positive nasopharyngeal RNA test is likely to hold a bias toward some degree of symptomatic burden. Two of the identifiers for inclusion in the current study were a positive result for the presence of SARS-CoV-2 according to PCR testing and receipt of respiratory support (an extreme Covid-19 phenotype). As such, it seems reasonable to conclude that the chromosome 3p21.31 locus is involved in Covid-19 susceptibility per se, with a possible enrichment in patients with severe disease. This latter interpretation is supported by the significantly higher frequency of the risk allele among patients who received mechanical ventilation than among those who received supplemental oxygen only as well as by the finding of younger age among patients who were homozygous for the risk allele than among patients who were heterozygous or homozygous for the nonrisk allele.
Nongenetic studies that were reported as preprints have previously implicated the involvement of ABO blood groups in Covid-19 susceptibility, and ABO blood groups have also been implicated in susceptibility to SARS-CoV-1 infection.Our genetic data confirm that blood group O is associated with a risk of acquiring Covid-19 that was lower than that in non-O blood groups, whereas blood group A was associated with a higher risk than non-A blood groups.The biologic mechanisms undergirding these findings may have to do with the ABO group per se (e.g., with the development of neutralizing antibodies against protein-linked N-glycans) or with other biologic effects of the identified variant,including the stabilization of von Willebrand factor.The ABO locus holds considerable risk for population stratification,which is increased by the inclusion of randomly selected blood donors in the current study (for which there is an inherent risk of blood group O enrichment). Alignment of the allele frequencies at the ABO locus in our control population with those in several non–blood-donor control populations would suggest that this is not a major bias, and at least one study that tested for association with blood type used disease controls with no affiliation to blood donors.
The pragmatic aspects leading to the feasibility of this massive undertaking in a very short period of time during the extreme clinical circumstances of the pandemic imposed limitations that will be important to explore in follow-up studies. For example, to enable the recruitment of study participants, a bare minimum of clinical metadata was requested. For this reason, extensive genotype–phenotype elaboration of current findings could not be conducted, and adjustments for all potential sources of bias (e.g., underlying cardiovascular and metabolic factors relevant to Covid-19) could not be performed. Furthermore, we have limited information about the SARS-CoV-2 infection status in the control participants; this concern is mitigated by the fact that the presence of susceptible persons in the control group would only bias the tests toward the null. In addition, few restrictions were imposed during inclusion, which led to genotyped samples having to be excluded owing to differing ethnic groups (population outliers). 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.
Reference & Source information: https://www.nejm.org
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