ABSTRACT
Background: Although it is common knowledge that the coronavirus disease of 2019 (COVID-19) and other viral infections have an uneven impact globally, the reasons for this are still indistinct. The absence of equivalent capacities worldwide in screening, testing, and reporting of cases is one of the ideas put forward to explain this discrepancy. The molecular developments are noteworthy, particularly the role played by single nucleotide polymorphisms (SNPs) in ACEs (ACE1 and ACE2). The virus can enter the host cell thanks to the transmembrane protein ACE2, which is a homolog of ACE1. Objectives: With a focus on the I/D genotype of ACE1 and the rs2285666 SNV of ACE2, we elucidated the prevalence of SNPs in ACE1 and ACE2 in various geographic locations. We examined the relationship between these SNPs and the global patterns of COVID-19 prevalence. Methods: 66 of the 127 articles obtained using PubMed, Google Scholar, and Google directly conformed to the search terms; geographical distribution of viral infections, the prevalence of COVID-19, ACE1, ACE2, SNPs, and prevalence of the DD genotype, and rs2285666. Results: The DD genotype of ACE1 and the rs2285666 SNV of ACE2 are vital in their gene expression and contribute greatly to viral disease susceptibility, development, and severity. There was generally a high prevalence of the DD genotype in Europe and America, where COVID-19 had a more devastating effect than in Asia and Africa. The prevalence of the SNV rs2285666 varied in the following order: East Asia> South Asia >America>Europe >Africa. However, there were conflicting agreements in the association of rs2285666 with COVID-19 susceptibility and prevalence. Conclusion: The ACE1 DD genotype and COVID-19 prevalence have been positively linked in a number of studies. The ACE2 rs2285666 SNV, however, has yielded no definitive results. To determine the relationship between these SNVs and COVID-19 incidence, more research is required.
Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , COVID-19/genetics , Angiotensin-Converting Enzyme 2/genetics , SARS-CoV-2/genetics , Prevalence , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Polymorphism, Single Nucleotide/genetics , Angiotensins/genetics , NucleotidesABSTRACT
The clinical condition COVID-19, caused by SARS-CoV-2, was declared a pandemic by the WHO in March 2020. Currently, there are more than 5 million cases worldwide, and the pandemic has increased exponentially in many countries, with different incidences and death rates among regions/ethnicities and, intriguingly, between sexes. In addition to the many factors that can influence these discrepancies, we suggest a biological aspect, the genetic variation at the viral S protein receptor in human cells, ACE2 (angiotensin I-converting enzyme 2), which may contribute to the worse clinical outcome in males and in some regions worldwide. We performed exomics analysis in native and admixed South American populations, and we also conducted in silico genomics databank investigations in populations from other continents. Interestingly, at least ten polymorphisms in coding, noncoding and regulatory sites were found that can shed light on this issue and offer a plausible biological explanation for these epidemiological differences. In conclusion, there are ACE2 polymorphisms that could influence epidemiological discrepancies observed among ancestry and, moreover, between sexes.
Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Polymorphism, Single Nucleotide/genetics , COVID-19/virology , Exome/genetics , Female , Humans , Male , Open Reading Frames/genetics , RNA, Untranslated/genetics , Regulatory Sequences, Ribonucleic Acid/genetics , South AmericaABSTRACT
ERAP2 is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to Yersinia pestis, have marked changes in allele frequency of the single-nucleotide polymorphism (SNP) rs2549794, with the T allele suggested to be deleterious during this period, while ERAP2 is also implicated in autoimmune diseases. This study explored the association between variation at ERAP2 and (1) infection, (2) autoimmune disease, and (3) parental longevity. Genome-wide association studies (GWASs) of these outcomes were identified in contemporary cohorts (UK Biobank, FinnGen, and GenOMICC). Effect estimates were extracted for rs2549794 and rs2248374, a haplotype tagging SNP. Additionally, cis expression and protein quantitative trait loci (QTLs) for ERAP2 were used in Mendelian randomization (MR) analyses. Consistent with decreased survival in the Black Death, the T allele of rs2549794 showed evidence of association with respiratory infection (odds ratio; OR for pneumonia 1.03; 95% CI 1.01-1.05). Effect estimates were larger for more severe phenotypes (OR for critical care admission with pneumonia 1.08; 95% CI 1.02-1.14). In contrast, opposing effects were identified for Crohn disease (OR 0.86; 95% CI 0.82-0.90). This allele was shown to associate with decreased ERAP2 expression and protein levels, independent of haplotype. MR analyses suggest that ERAP2 expression may be mediating disease associations. Decreased ERAP2 expression is associated with severe respiratory infection with an opposing association with autoimmune diseases. These data support the hypothesis of balancing selection at this locus driven by autoimmune and infectious disease.
Subject(s)
Autoimmune Diseases , Plague , Humans , Genome-Wide Association Study , Genotype , Haplotypes/genetics , Autoimmune Diseases/genetics , Polymorphism, Single Nucleotide/genetics , Genetic Predisposition to Disease , Aminopeptidases/genetics , Aminopeptidases/metabolismABSTRACT
OBJECTIVE: Coronavirus disease 2019 (COVID-19) has caused a global pandemic in the last three years. The lack of reliable evidence on the risk of miscarriage due to COVID-19 has become a concern for patients and obstetricians. We sought to identify rigorous evidence using two-sample Mendelian randomization (MR) analysis. METHODS: Seven single-nucleotide polymorphisms (SNPs) associated with COVID-19 were used as instrumental variables to explore causality by two-sample MR. The summary data of genetic variants were obtained from the Genome Wide Association Study (GWAS) among European populations in the UK Biobank and EBI database. Inverse variance weighting (IVW) method was taken as the gold standard for MR results, and other methods were taken as auxiliary. We also performed sensitivity analysis to evaluate the robustness of MR. RESULTS: The MR analysis showed there was no clear causal association between COVID-19 and miscarriage in the genetic prediction [OR 0.9981 (95% CI, 0.9872-1.0091), p = 0.7336]. Sensitivity analysis suggested that the MR results were robust [horizontal pleiotropy (MR-Egger, intercept = 0.0001592; se = 0.0023; p = 0.9480)]. CONCLUSIONS: The evidence from MR does not support COVID-19 as a causal risk factor for miscarriage in European populations. The small probability of direct placental infection, as well as the inability to stratify the data may explain the results of MR. These findings can be informative for obstetricians when managing women in labor.
Subject(s)
Abortion, Spontaneous , COVID-19 , Pregnancy , Humans , Female , Mendelian Randomization Analysis , Genome-Wide Association Study , Abortion, Spontaneous/epidemiology , Abortion, Spontaneous/genetics , COVID-19/epidemiology , COVID-19/genetics , Placenta , Polymorphism, Single Nucleotide/geneticsABSTRACT
Proximal genetic variants are frequently correlated, implying that the corresponding effect sizes detected by genome-wide association studies (GWAS) are also not independent. Methods already exist to account for this when aggregating effects from a single GWAS across genes or pathways. Here we present a rigorous yet fast method for detecting genes with coherent association signals for two traits, facilitating cross-GWAS analyses. To this end, we devised a new significance test for the covariance of datapoints not drawn independently but with a known inter-sample covariance structure. We show that the distribution of its test statistic is a linear combination of χ2 distributions with positive and negative coefficients. The corresponding cumulative distribution function can be efficiently calculated with Davies' algorithm at high precision. We apply this general framework to test for dependence between SNP-wise effect sizes of two GWAS at the gene level. We extend this test to detect also gene-wise causal links. We demonstrate the utility of our method by uncovering potential shared genetic links between the severity of COVID-19 and (1) being prescribed class M05B medication (drugs affecting bone structure and mineralization), (2) rheumatoid arthritis, (3) vitamin D (25OHD), and (4) serum calcium concentrations. Our method detects a potential role played by chemokine receptor genes linked to TH1 versus TH2 immune response, a gene related to integrin beta-1 cell surface expression, and other genes potentially impacting the severity of COVID-19. Our approach will be useful for similar analyses involving datapoints with known auto-correlation structures.
Subject(s)
COVID-19 , Genome-Wide Association Study , COVID-19/genetics , Calcium , Humans , Integrins , Polymorphism, Single Nucleotide/genetics , Receptors, Chemokine , Vitamin DABSTRACT
Background: Single nucleotide polymorphisms provide information on individuals' potential reactions to environmental factors, infections, diseases, as well as various therapies. A study on SNPs that influence SARS-CoV-2 susceptibility and severity may provide a predictive tool for COVID-19 outcomes and improve the customized coronavirus treatment. Aim: To evaluate the role of human leukocyte antigens DP/DQ and IFNλ4 polymorphisms on COVID-19 outcomes among Egyptian patients. Participants and Methods: The study involved 80 patients with severe COVID-19, 80 patients with mild COVID-19, and 80 non-infected healthy volunteers. Genotyping and allelic discrimination of HLA-DPrs3077 (G/A), HLA-DQrs7453920 (A/G), and IFNλ4 rs73555604 (C/T) SNPs were performed using real-time PCR. Results: Ages were 47.9 ± 8, 44.1 ± 12.1, and 45.8 ± 10 years in severe, mild and non-infected persons. There was a statistically significant association between severe COVID-19 and male gender (p = 0.002). A statistically significant increase in the frequency of HLA-DPrs3077G, HLA-DQrs7453920A, and IFNλ4rs73555604C alleles among severe COVID-19 patients when compared with other groups (p < 0.001). Coexistence of these alleles in the same individual increases the susceptibility to severe COVID-19 by many folds (p < 0.001). Univariate and multivariate logistic regression analysis for the studied parameters showed that old age, male gender, non-vaccination, HLA-DQ rs7453920AG+AA, HLA-DPrs3077GA+GG, and IFNλ4rs73555604CT+CC genotypes are independent risk factors for severe COVID-19 among Egyptian patients. Conclusion: HLA-DQ rs7453920A, HLA-DPrs3077G, and IFNλ4rs73555604C alleles could be used as markers of COVID-19 severity.
Subject(s)
COVID-19 , HLA-DP Antigens , HLA-DQ Antigens , Interleukins , Humans , Male , Alleles , Case-Control Studies , COVID-19/genetics , Genetic Predisposition to Disease , Genotype , HLA-DP Antigens/genetics , HLA-DQ Antigens/genetics , Polymorphism, Single Nucleotide/genetics , SARS-CoV-2 , Interleukins/geneticsABSTRACT
Vitamin D requires activation to show its pharmacological effect. While most studies investigate the association between vitamin D and disease, only a few focus on the impact of vitamin D metabolism gene polymorphisms (vitDMGPs). This bibliometric study aims to provide an overview of current publications on vitDMGPs (CYP27B1, CYP24A1, CYP2R1, CYP27A1, CYP2R1, DHCR7/NADSYN1), compare them across countries, affiliations, and journals, and inspect keywords, co-citations, and citation bursts to identify trends in this research field. CiteSpace© (version 6.1.R3, Chaomei Chen), Bibliometrix© (R version 4.1.3 library, K-Synth Srl, University of Naples Federico II, Naples, Italy), VOSviewer© (version 1.6.1, Nees Jan van Eck and Ludo Waltman, Leiden University, Leiden, Netherlands) and Microsoft® Excel 365 (Microsoft, Redmond, Washington, USA) classified and summarized Web of Science articles from 1998 to November 2022. We analyzed 2496 articles and built a timeline of co-citations and a bibliometric keywords co-occurrence map. The annual growth rate of vitDMGPs publications was 18.68%, and their relative research interest and published papers were increasing. The United States of America leads vitDMGPs research. The University of California System attained the highest quality of vitDMGPs research, followed by the American National Institutes of Health and Harvard University. The three productive journals on vitDMGPs papers are J. Steroid. Biochem. Mol. Biol., PLOS ONE, and J. Clin. Endocrinol. Metab. We highlighted that the vitDMGPs domain is relatively new, and many novel research opportunities are available, especially those related to studying single nucleotide polymorphisms or markers in a specific gene in the vitamin D metabolism cycle and their association with disease. Genome-wide association studies, genetic variants of vitDMGPs, and vitamin D and its role in cancer risk were the most popular studies. CYP24A1 and CYB27A1 were the most-studied genes in vitDMGPs. Insulin was the longest-trending studied hormone associated with vitDMGPs. Trending topics in this field relate to bile acid metabolism, transcriptome and gene expression, biomarkers, single nucleotide polymorphism, and fibroblast growth factor 23. We also expect an increase in original research papers investigating the association between vitDMGPs and coronavirus disease 2019, hypercalcemia, Smith-Lemli-Opitz syndrome, 27-hydroxycholesterol, and mendelian randomization. These findings will provide the foundations for innovations in the diagnosis and treatment of a vast spectrum of conditions.
Subject(s)
COVID-19 , Genome-Wide Association Study , Humans , Vitamin D3 24-Hydroxylase , Polymorphism, Single Nucleotide/genetics , Vitamin D/genetics , Vitamins , BibliometricsABSTRACT
The elevated levels of inflammatory cytokines have attracted much attention during the treatment of COVID-19 patients. The conclusions of current observational studies are often controversial in terms of the causal effects of COVID-19 on various cytokines because of the confounding factors involving underlying diseases. To resolve this problem, we conducted a Mendelian randomization analysis by integrating the GWAS data of COVID-19 and 41 cytokines. As a result, the levels of 2 cytokines were identified to be promoted by COVID-19 and had unsignificant pleiotropy. In comparison, the levels of 10 cytokines were found to be inhibited and had unsignificant pleiotropy. Among down-regulated cytokines, CCL2, CCL3 and CCL7 were members of CC chemokine family. We then explored the potential molecular mechanism for a significant causal association at a single cell resolution based on single-cell RNA data, and discovered the suppression of CCL3 and the inhibition of CCL3-CCR1 interaction in classical monocytes (CMs) of COVID-19 patients. Our findings may indicate that the capability of COVID-19 in decreasing the chemotaxis of lymphocytes by inhibiting the CCL3-CCR1 interaction in CMs.
Subject(s)
COVID-19 , Cytokines , Humans , Mendelian Randomization Analysis , COVID-19/genetics , Sequence Analysis, RNA , Genome-Wide Association Study , Polymorphism, Single Nucleotide/geneticsABSTRACT
COVID-19 has a broad spectrum of clinical manifestations, from asymptomatic or mild/moderate symptoms to severe symptoms and death. The mechanisms underlying its clinical evolution are still unclear. Upon SARS-CoV-2 infection, host factors, such as the inflammasome system, are activated by the presence of the virus inside host cells. The search for COVID-19 risk factors is of relevance for clinical management. In this study, we investigated the impact of inflammasome single-nucleotide polymorphisms (SNPs) in SARS-CoV-2-infected individuals with distinct severity profiles at clinical presentation. Patients were divided into two groups according to disease severity at clinical presentation based on the WHO Clinical Progression Scale. Group 1 included patients with mild/moderate disease (WHO < 6; n = 76), and group 2 included patients with severe/critical COVID-19 (WHO ≥ 6; n = 357). Inpatients with moderate to severe/critical profiles were recruited and followed-up at Hospital Center for COVID-19 Pandemic - National Institute of Infectology (INI)/FIOCRUZ, RJ, Brazil, from June 2020 to March 2021. Patients with mild disease were recruited at Oswaldo Cruz Institute (IOC)/FIOCRUZ, RJ, Brazil, in August 2020. Genotyping of 11 inflammasome SNPs was determined by real-time PCR. Protection and risk estimation were performed using unconditional logistic regression models. Significant differences in NLRP3 rs1539019 and CARD8 rs2043211 were observed between the two groups. Protection against disease severity was associated with the A/A genotype (ORadj = 0.36; P = 0.032), allele A (ORadj = 0.93; P = 0.010), or carrier-A (ORadj = 0.45; P = 0.027) in the NLRP3 rs1539019 polymorphism; A/T genotype (ORadj = 0.5; P = 0.045), allele T (ORadj = 0.93; P = 0.018), or carrier-T (ORadj = 0.48; P = 0.029) in the CARD8 rs2043211 polymorphism; and the A-C-G-C-C (ORadj = 0.11; P = 0.018), A-C-G-C-G (ORadj = 0.23; P = 0.003), C-C-G-C-C (ORadj = 0.37; P = 0.021), and C-T-G-A-C (ORadj = 0.04; P = 0.0473) in NLRP3 genetic haplotype variants. No significant associations were observed for the other polymorphisms. To the best of our knowledge, this is the first study demonstrating an association between CARD8 and NLRP3 inflammasome genetic variants and protection against COVID-19 severity, contributing to the discussion of the impact of inflammasomes on COVID-19 outcomes.
Subject(s)
COVID-19 , Inflammasomes , Apoptosis Regulatory Proteins/genetics , Brazil/epidemiology , CARD Signaling Adaptor Proteins/genetics , COVID-19/genetics , Genetic Predisposition to Disease/genetics , Humans , Inflammasomes/genetics , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neoplasm Proteins/genetics , Pandemics , Polymorphism, Single Nucleotide/genetics , SARS-CoV-2Subject(s)
COVID-19 , DNA, Complementary , Genome, Viral , RNA, Viral , COVID-19/genetics , DNA, Complementary/chemistry , DNA, Complementary/genetics , Genetic Variation , Genome, Viral/genetics , Humans , Nucleotides/genetics , Polymorphism, Single Nucleotide/genetics , RNA, Viral/chemistry , RNA, Viral/geneticsABSTRACT
BACKGROUND AND AIMS: Interferon-induced transmembrane protein 3 (IFITM3) plays a critical role in the adaptive and innate immune response by preventing membrane hemifusion between the host and viral cell cytoplasm. This study aimed to evaluate whether IFITM3 rs12252 polymorphism is related to an increased mortality rate of coronavirus disease 2019 (COVID-19). METHODS: The IFITM3 rs12252 polymorphism was genotyped using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 548 dead and 630 improved patients positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RESULTS: In the present study, the minor allele frequency of IFITM3 rs12252 (C) was significantly more frequent in dead patients than in improved cases. The results of the multivariate logistic regression analysis indicated that the lower lipid profiles, PCR Ct value, 25-hydroxyvitamin D, and uric acid and higher levels of erythrocyte sedimentation rate (ESR), liver enzymes, and creatinine, and IFITM3 rs12252 CC genotypes were related to the COVID-19 infection mortality. CONCLUSIONS: In summary, our findings suggested a possible link between the mortality of COVID-19 infection, the CC genotypes of IFITM3 rs12252, and clinical parameters. Further investigations are required worldwide to prove the link relationship of COVID-19 mortality with host genetic factors.
Subject(s)
COVID-19 , Influenza, Human , COVID-19/genetics , Genetic Predisposition to Disease , Humans , Interferons/genetics , Membrane Proteins/genetics , Polymorphism, Single Nucleotide/genetics , RNA-Binding Proteins/genetics , SARS-CoV-2ABSTRACT
OBJECTIVES: COVID-19 continues to range around the world and set morbidity and mortality antirecords. Determining the role of genetic factors in the development of COVID-19 may contribute to the understanding of the pathogenetic mechanisms that lead to the development of complications and fatalities in this disease. The aim of our study was to analyze the effect of TNF-α (rs1800629), IL-6 (rs1800795) and VDR (rs731236 and rs1544410) genes variants on the development risk and the course of COVID-19 in intensive care patients. METHODS: The study group included 31 patients with diagnosis "viral COVID-19 pneumonia". All patients underwent standard daily repeated clinical, instrumental and laboratory examinations. Determination of IL-6, TNF-α, and VDR genes variants was performed using the PCR-RFLP method. RESULTS: It was found a significant increase in the rate of the CC genotype and C allele (38.7 vs. 12.0% and 0.6 vs. 0.4%, respectively) of the IL-6 gene in all patients of the study in comparison with population frequencies. There was a significantly higher rate of heterozygous genotypes TC and GA of the VDR gene in group of died patients. The rs1800629 variant of the TNF-α gene is associated with the need for respiratory support and its longer duration in patients with COVID-19. CONCLUSIONS: The obtained results support a hypothesis about the influence of variants of IL-6, TNF-α and VDR genes on severity of COVID-19. However, in order to draw definite conclusions, further multifaceted research in this area are need.
Subject(s)
COVID-19 , Interleukin-6/genetics , Tumor Necrosis Factor-alpha/genetics , COVID-19/genetics , Case-Control Studies , Genetic Predisposition to Disease , Genotype , Humans , Pilot Projects , Polymorphism, Single Nucleotide/genetics , Receptors, Calcitriol/geneticsABSTRACT
Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
Subject(s)
COVID-19 , Genome-Wide Association Study , Female , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , COVID-19/genetics , Sex Characteristics , Genetic Loci , Genetic Predisposition to DiseaseABSTRACT
CONTEXT: Estradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism, but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels. OBJECTIVE: Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD). DESIGN: We performed GWAS for estradiol in males (nâ =â 147 690) and females (nâ =â 163 985) from UK Biobank. Estradiol was analyzed as a binary phenotype above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization. RESULTS: We identified 14 independent loci associated (Pâ <â 5â ×â 10-8) with estradiol levels in males, of which 1 (CYP3A7) was genome-wide and 7 nominally (Pâ <â 0.05) significant in females. In addition, 1 female-specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS (eg, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7, which encode enzymes likely to be involved in estradiol elimination). The allele that tags the O blood group at the ABO locus was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (Pâ =â 1.58â ×â 10-11) and females (Pâ =â 7.48â ×â 10-6). CONCLUSION: Our findings further support the importance of the body's own estrogen to maintain skeletal health in males and in females.
Subject(s)
Bone Density/genetics , Estradiol/blood , Estradiol/genetics , Genome-Wide Association Study , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics , ABO Blood-Group System/genetics , Bone Density/physiology , Cohort Studies , Cross-Sectional Studies , Cytochrome P-450 CYP3A/genetics , Estrogens/genetics , Estrogens/physiology , Female , Genotype , Glucuronosyltransferase/genetics , Humans , Male , Membrane Proteins/genetics , Mendelian Randomization Analysis , Middle Aged , N-Acetylglucosaminyltransferases/genetics , Polymorphism, Single Nucleotide/genetics , United KingdomABSTRACT
The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.
Subject(s)
COVID-19 , Veterans , COVID-19/epidemiology , COVID-19/genetics , Genetic Association Studies , Genome-Wide Association Study/methods , Humans , Polymorphism, Single Nucleotide/geneticsABSTRACT
Multiple COVID-19 genome-wide association studies (GWASs) have identified reproducible genetic associations indicating that there is a genetic component to susceptibility and severity risk. To complement these studies, we collected deep coronavirus disease 2019 (COVID-19) phenotype data from a survey of 736,723 AncestryDNA research participants. With these data, we defined eight phenotypes related to COVID-19 outcomes: four phenotypes that align with previously studied COVID-19 definitions and four 'expanded' phenotypes that focus on susceptibility given exposure, mild clinical manifestations and an aggregate score of symptom severity. We performed a replication analysis of 12 previously reported COVID-19 genetic associations with all eight phenotypes in a trans-ancestry meta-analysis of AncestryDNA research participants. In this analysis, we show distinct patterns of association at the 12 loci with the eight outcomes that we assessed. We also performed a genome-wide discovery analysis of all eight phenotypes, which did not yield new genome-wide significant loci but did suggest that three of the four 'expanded' COVID-19 phenotypes have enhanced power to capture protective genetic associations relative to the previously studied phenotypes. Thus, we conclude that continued large-scale ascertainment of deep COVID-19 phenotype data would likely represent a boon for COVID-19 therapeutic target identification.
Subject(s)
COVID-19 , Genome-Wide Association Study , COVID-19/genetics , Genetic Predisposition to Disease , Humans , Phenotype , Polymorphism, Single Nucleotide/geneticsABSTRACT
Critical coronavirus disease 2019 (COVID-19) is associated with high mortality and potential genetic factors have been reported to be involved in the development of critical COVID-19. We performed a genome-wide association study to identify the genetic factors responsible for developing critical COVID-19. 632 critical patients with COVID-19 and 3021 healthy controls from the Chinese population were recruited. First, we identified a genome-wide significant difference of IL-6 rs2069837 (p = 9.73 × 10-15, OR = 0.41) between 437 critical patients with COVID-19 and 2551 normal controls in the discovery cohort. When replicated these findings in a set of 195 patients with critical COVID-19 and 470 healthy controls, we detected significant association of rs2069837 with COVID-19 (p = 8.89 × 10-3, OR = 0.67). This variant surpassed the formal threshold for genome-wide significance (combined p = 4.64 × 10-16, OR = 0.49). Further analysis revealed that there was a significantly stronger expression of IL-6 in the serum from patients with critical COVID-19 than in that from patients with asymptomatic COVID-19. An in vitro assay showed that the A to G allele changes in rs2069837 within IL-6 obviously decreased the luciferase expression activity. When analyzing the effect of this variant on the IL-6 in the serum based on the rs2069837 genotype, we found that the A to G variation in rs2069837 decreased the expression of IL-6, especially in the male. Overall, we identified a genetic variant in IL-6 that protects against critical conditions with COVID-19 though decreasing IL-6 expression in the serum.
Subject(s)
COVID-19 , Interleukin-6/genetics , COVID-19/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Humans , Male , Polymorphism, Single Nucleotide/geneticsABSTRACT
Genetic polymorphisms at the IFNL4 loci are known to influence the clinical outcome of several different infectious diseases. Best described is the association between the IFNL4 genotype and hepatitis C virus clearance. However, an influence of the IFNL4 genotype on the adaptive immune system was suggested by several studies but never investigated in humans. In this cross-sectional study, we have genotyped 201 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive participants for 3 IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) and stratified them according to the IFNλ4 activity. Based on this stratification, we investigated the association between the IFNL4 genotype and the antibody as well as the CD8+ T cell response in the acute phase of the SARS-CoV-2 infection. We observed no differences in the genotype distribution compared with a Danish reference cohort or the 1,000 Genome Project, and we were not able to link the IFNL4 genotype to changes in either the antibody or CD8+ T cell responses of these patients.