Genetic association at the genomic level (genomewide association study - GWAS),requencing by NGS (whole exome sequencing) and gene expression studies to identify themain ones hereditary genetic determinants of predisposition to the development of SARS(symptomatic pathology associated with development of insufficiency respiratory diseaseof any degree) in Italian subjects affected by SARSCoV-2.
Lombardy region in Northern Italy is now in the midst of an outbreak of severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus
disease 2019 (COVID-19) . The COVID-19 epidemic situation needs little introduction and
represent a global world-wide emergency with mortality rates rapidly increasing in Europe
and the US. Evidence is accumulating that the majority of individuals infected by
SARS-CoV-2 are asymptomatic and the major source of viral spread 3, and that a
considerable fraction of these has active viral replication 4,5. Furthermore, disease
behavior is variable, with the majority of patients experiencing only mild symptoms or no
symptoms at all. Some patients develop severe pulmonary affection, with aggressive and
extensive inflammatory destruction of lung parenchyma and associated inflammatory
responses and superinfections, driving large fractions of the COVID-19 related mortality.
What exactly drives this development of severe lung disease remains unknown, but old age,
obesity, diabetes and other co-morbidities increase the risk, while the role played by
specific medications is still uncertain. Variation in virus genetics and patient
immunology are also likely involved. As to the latter point, the investigators
hypothesize that host genetics may play a role in determining development of severe lung
disease in SARS-CoV-2 infection. Genome-wide association studies (GWAS) have been applied
to decipher the genetic predisposition in thousands of disease traits since the study
design was invented in 2005. The genetic signals detected vary from very strong effects
that can be detected in a few hundred individuals, to very weak effects requiring cohorts
of tens of thousands for detection. By 2020, the study design is now a robust,
off-the-shelf, easyto-perform industry-standard screening tool for genetic
predisposition, even available through "consumer genetics" online-based companies. The
study design is simple: testing for genetic variants throughout the genome (single
nucleotide polymorphisms, SNPs) using SNP microarrays, comparing their frequencies in
patients versus controls (or across other variables). For inflammatory phenotypes in
particular, GWAS has proven an efficient tool, delineating hundreds of susceptibility
loci in many conditions, some of which has provided novel and surprising disease
insights. GWAS serve two purposes. Most importantly they allow to determine biological
factors involved in disease development, thus potentially guiding drug development and
therapy. This would be particularly relevant during the current COVID-19 emergency, when
hundreds of trials have begun and there is an urgent need to prioritize well-conducted
collaborative studies based on robust pathophysiological data. Secondly, and increasingly
popular, they allow for the calculation of a "polygenic risk score" to predict disease
development. Both aspects appear crucial to clarify for COVID-19 lung disease: (a) are
there genetic signatures suggesting which biological mechanisms are involved that may
suggest relevant therapeutic approaches, and (b) can we predict those at risk (or those
with very low risk)?
Genetic: genetic determinants to develop respiratory failure
To identify the main common genetic determinants of severe COVID-19 by conducting a GWAS:
in first phase we will compare SARS-CoV-2 positive patients with severe lung affection to
healthy controls from the same geographic area, in order to provide initial data
informing the research in the field in a timely fashion. This will be conducted in close
collaboration with the University of Kiel COVID-19 genomic initiative. Later on, we will
proceed to assess objectives 1 and 2 in the full cohort, including also infected controls
who did not developed clinically significant symptoms
Genetic: genetic determinants to develop respiratory failure
To provide extensive genetic characterization of all patients managed at the Fondazione
in order to facilitate other groups working on specific projects (e.g. on candidate genes
such as SERPINA1 and ACE2 by the Intensive Care and Cardiology Units and other that may
emerge from upcoming projects), in a large population and in a very timely fashion, and
without incurring in any additional expenses for the Fondazione research network, and
coordinate research efforts.
Genetic: genetic determinants to develop respiratory failure
To provide a coordination to manage the collaboration with other research consortia in
the field, e.g. the "An anonymized GWAS to urgently query host genetic predisposition to
severe COVID-19 (SARS-CoV-2 infection) lung disease, and the COVID-19 Host Genetic
Initiative (https://www.covid19hg.org). Indeed, collaboration among large networks
analyzing several thousand cases will be ultimately necessary to clarify the genetic
basis of COVID-19 susceptibility, and large collaborative networks are essential
instruments for conducting human genetic research.
Inclusion Criteria:
Cohort 1 inclusion criteria:
- SARS-CoV-2 positive patients (no age limit) with severe pulmonary compromise,
hospitalized with failure respiratory that requires support of any kind
- Signature of informed consent
Cohort 2 inclusion criteria:
- Blood donors (18-70 years old) who donated between 24/02/2020 and 31/12/2021
- exposure to the SARS-CoV-2 virus confirmed by viremia positive and presence of
IgG/IgM
- Signature of informed consent
Cohort 3 inclusion criteria:
Healthy controls available from previous studies (n=5,000, ages 14-80 years), whose data
are already available for genetic association analyses within the Kiel University
database.
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica
Milan 3173435, Milano, Italy
Not Provided