新型コロナウィルスに関する人の包括的な遺伝子分析

//Background//---
 On any diseases, understanding and finding the most upstream cause is crucial. In SARS-CoV-2, virus entering from oral and nasal cavity is clear etiology. However, the (degree of) symptoms is widely various for each patient from asymptomatic to life-threating, viral pneumonia and acute respiratory distress syndrome(2). Several risk factors, such as obesity, diabetes, renal dysfunction, cardiovascular diseases, cancer, aging, are pointed out, but in these categories, severity is changed for each patient. To grasp precise symptomatic trait, statistical genetic analysis and building genetic architecture are prerequisite. If we can find the gene specific to severe symptom, we can choose several strategies. We could prevent SARS-CoV-2 prophylactically. We can find the important pathway related to this risk gene, and find the important proteins in line with the pathway. If so, we could develop the effective drug, and find the repurposed drug.
COVID-19 Host Genetics Initiative investigate the correlation between a degree of symptom and gene, risk factor through gathering huge genome data of SARS-CoV-2(1). I hope to share these important contents with the #Global important readers in an accelerated manner.
 
//Condition(1)//---
Patient number: 49,562
The meta-analysis from 46 studies
Across 19 countries (European, Admixed American, African, Middle Eastern, South Asian and East Asian)
 
//Previous important data//---
 Variants in genes involved in type 1 interferon response is related to severe symptom(3-6). The delay of type-1 interferon response may lead to large virus load and immune dysfunction.
 Important genomic locus: 3p21.31(7-11)(*Two of loci in this report(1) are very close.)
 
//Result(1)//---
(Special note)
*The strongest susceptibility for infection: ABO locus(rs912805253)
Same locus was previously reported(7,8,10,11).
*Plausible genes: TYK2(19p13.2)-Immunodeficiency(12)
(The gene related to “Hospitalized” case) (See Fig.2)
*Chromosome 3
 rs10490770: LZTFL1, CXCR6
*Chromosome 6
 rs1886814: FOXP4
*Chromosome 8
 rs72711165: TMEM65 (Hospitalized only)
*Chromosome 9
 rs912805253:ABO
*Chromosome 12
 rs10774671:OAS1, OAS2, OAS3
*Chromosome 17
 rs1819040: KANSL1, ARHGAP27, PLEKHM1, LINC022-CRHR1, CRHR1, SPPL2C, MAPT, STH, LRRC37A, ARL17B, LRRC37A2, ARL17A, NSF, WNT3
*Chromosome 19
 rs2109069: DPP9
 rs74956615: RAVER1, TYK2, ICAM5, ICAM1, ICAM4, ZGLP1, FDX2, ICAM3
  ICAM: intercellular adhesion molecule
 ICAM is highly related to vascular system and immune system.
*Chromosome 21
 rs13050728:IFNAR2
(The gene related to “Critically ill” case) (See Fig.2)
*Chromosome 3
 rs10490770: LZTFL1, CXCR6
*Chromosome 12
 rs10774671:OAS1, OAS2, OAS3
*Chromosome 17
 rs77534576:TAC4, DLX3, FLJ45513, KAT7 (Critically ill only)
 TAC4: Tachykinin-4
 This regulates peripheral endocrine and paracrine function including blood pressure, the immune system and endocrine gland secretion.
 DLX3
 This regulates hair follicle differentiation.
 KAT7
 This regulates origin licensing (Cell differentiation) and DNA replication.
*Chromosome 19
 rs2109069: DPP9
 rs74956615: RAVER1, TYK2, ICAM5, ICAM1, ICAM4, ZGLP1, FDX2, ICAM3
*Chromosome 21
 rs13050728:IFNAR2
(Severity vs risk factor)(See Fig.3)
 BMI, Smoking
(Severity vs disease liability)(See Fig.3)
 ADHD, Diabetes, Idiopathic pulmonary fibrosis
 
 //Discussion//---
 Whether the gene related to hospitalized and severe case is epigenetic or not is controversial. However, the dysfunction relating to gene is obvious. For example, dysfunction of intercellular adhesion molecule which functions to immune and vascular cells could be confirmed. Endocrine and paracrine system are alike. Therefore, we may be able to develop the efficient therapy and drug through scrutinizing the pathway of the genes highly related to hospitalized patients and severe symptoms.
 
(Reference)
(1)
COVID-19 Host Genetics Initiative (See below for detail)
Mapping the human genetic architecture of COVID-19
Nature (2021)
---
See additional articles in my blog:
Covid-19 Host Genetics Initiative List - Contributors
Covid-19 Host Genetics Initiative List - Affiliations
(2)
Buitrago-Garcia, D. et al.
Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: A living systematic review and meta-analysis.
PLoS Med. 17, e1003346 (2020).
(3)
van der Made, C. I. et al.
Presence of Genetic Variants Among Young Men With Severe COVID-19.
JAMA (2020) https://doi.org/10.1001/jama.2020.13719.
(4)
Zhang, Q. et al.
Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.
Science 370, (2020).
(5)
Bastard, P. et al.
Autoantibodies against type I IFNs in patients with life-threatening COVID-19.
Science 370, (2020).
(6)
Povysil, G. et al.
Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19.
J. Clin. Invest. (2021) https://doi.org/10.1172/JCI147834.
(7)
Severe Covid-19 GWAS Group et al.
Genomewide Association Study of Severe Covid-19 with Respiratory Failure.
N. Engl. J. Med. 383, 1522–1534 (2020).
(8)
Shelton, J. F. et al.
Trans-ethnic analysis reveals genetic and non-genetic associations with COVID-19 susceptibility and severity.
bioRxiv (2020) https://doi.org/10.1101/2020.09.04.20188318.
(9)
Pairo-Castineira, E. et al.
Genetic mechanisms of critical illness in Covid-19.
Nature (2020) https://doi.org/10.1038/s41586-020-03065-y.
(10)
Roberts, G. H. L. et al.
AncestryDNA COVID-19 host genetic study identifies three novel loci.
bioRxiv (2020) https://doi.org/10.1101/2020.10.06.20205864.
(11)
Kosmicki, J. A. et al.
Genetic association analysis of SARS-CoV-2 infection in 455,838 UK Biobank participants.
bioRxiv (2020) https://doi.org/10.1101/2020.10.28.20221804.
(12)
Dendrou, C. A. et al.
Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity.
Sci. Transl. Med. 8, 363ra149 (2016).