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Haplotypic variants of COVID-19 related genes are associated with blood pressure and metabolites levels

Morteza Gholami

Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

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Marziyeh Zoughi,

Marziyeh Zoughi

Metabolomics and genomics research center endocrinology and metabolism molecular-cellular sciences institute, Tehran University of medical sciences, Tehran, Iran

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Mandana Hasanzad,

Mandana Hasanzad

Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

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Bagher Larijani,

Bagher Larijani

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

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Mahsa M. Amoli,

Corresponding Author

Mahsa M. Amoli

[email protected]

orcid.org/0000-0002-9168-9223

Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

Correspondence Mahsa M. Amoli, Metabolic Disorders Research Center, Endocrinology and Metabolism Research Institute, 5th floor, Shariati Hospital, North Kargar Ave., Tehran, Iran.

Email: [email protected]

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Morteza Gholami,

Morteza Gholami

Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

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Marziyeh Zoughi,

Marziyeh Zoughi

Metabolomics and genomics research center endocrinology and metabolism molecular-cellular sciences institute, Tehran University of medical sciences, Tehran, Iran

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Mandana Hasanzad,

Mandana Hasanzad

Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

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Bagher Larijani,

Bagher Larijani

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

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Mahsa M. Amoli,

Corresponding Author

Mahsa M. Amoli

[email protected]

orcid.org/0000-0002-9168-9223

Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

Correspondence Mahsa M. Amoli, Metabolic Disorders Research Center, Endocrinology and Metabolism Research Institute, 5th floor, Shariati Hospital, North Kargar Ave., Tehran, Iran.

Email: [email protected]

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First published: 28 November 2022

https://doi.org/10.1002/jmv.28355

Citations: 1

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Abstract

The genetic association of coronavirus disease 2019 (COVID-19) with its complications has not been fully understood. This study aimed to identify variants and haplotypes of candidate genes implicated in COVID-19 related traits by combining the literature review and pathway analysis. To explore such genes, the protein-protein interactions and relevant pathways of COVID-19-associated genes were assessed. A number of variants on candidate genes were identified from Genome-wide association studies (GWASs) which were associated with COVID-19 related traits (p ˂ 10^-6). Haplotypic blocks were assessed using haplotypic structures among the 1000 Genomes Project (r² ≥ 0.8, D′ ≥ 0.8). Further functional analyses were performed on the selected variants. The results demonstrated that a group of variants in ACE and AGT genes were significantly correlated with COVID-19 related traits. Three haplotypes were identified to be involved in the blood metabolites levels and the development of blood pressure. Functional analyses revealed that most GWAS index variants were expression quantitative trait loci and had transcription factor binding sites, exonic splicing enhancers or silencer activities. Furthermore, the proxy haplotype variants, rs4316, rs4353, rs4359, and three variants, namely rs2493133, rs2478543, and rs5051, were associated with blood metabolite and systolic blood pressure, respectively. These variants exerted more regulatory effects compared with other GWAS variants. The present study indicates that the genetic variants and candidate haplotypes of COVID-19 related genes are associated with blood pressure and blood metabolites. However, further observational studies are warranted to confirm these results.

1 INTRODUCTION

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), which is classified as RNA viruses. High infection rates and the emergence of numerous clinical manifestations are the hallmarks of COVID-19 infection. Many international and observational studies have focused on these issues over the past 2 years.^1-4 These studies will help to better understand COVID-19 infection, reduce its complications, and find effective treatments. The respiratory tract, blood metabolites, and cardiovascular system are commonly affected by COVID-19 infection.

Many studies have shown the impact of different genetic variants on blood metabolites, as well as respiratory or cardiovascular diseases.^5-7 The Genome-wide association study (GWAS) is one of the most important approaches used for identifying the association between genetic variants and complex disorders. The identification of disease-causing genes to understand the genetic function, communication, and pathways has always been a challenge in genetic studies. Several bioinformatics studies have been performed to identify and predict the effect of genetic variants in a number of diseases.^{8, 9}

Several studies have been performed to characterize variants and haplotype involved in COVID-19 related traits.^{10, 11} The understanding of these factors will help to seek correlations between COVID-19 infection and its associated characteristics and genetic variants, as well as genetically related mechanisms, for effective targeted treatments. This study hypothesized that previously identified polymorphisms by GWAS could provide major clues about the genetic association of COVID-19 and its associated diseases or traits. Therefore, this study aimed to find genetic variants and haplotypes among candidate genes associated with COVID-19 related traits by combining the literature review and pathway analysis.

2 METHODS

This study was based on the combinatory assessment of the literature reviews and pathway analysis approaches. To achieve this goal, candidate genes associated with COVID-19 infection were identified by the literature review and pathway analysis, and then previous GWAS results and their significant variants associated with the candidate genes were identified from the National Human Genome Research Institute-European Bioinformatics Institute(NHGRI-EBI) GWAS catalog (https://www.ebi.ac.uk/gwas/). Finally, the haplotypic blocks associated with these candidate variants were characterized, and their functional relevance was analyzed. An overview of the workflow is shown in Figure 1. The detailed method is described in the following sections.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Study workflow

3 CANDIDATE GENES ASSOCIATED WITH COVID-19 INFECTION

To investigate the significant genes associated with COVID-19, a literature review was performed on experimental human studies available in PubMed. We used “COVID-19,” “gene,” “expression,” “polymorphism,” and their equivalent terms to identify the main genes whose expression levels or one of their polymorphic variants were correlated with coronavirus infection, mortality, or severity of disease in both male and female adult patients. To this aim, the kyoto encyclopedia of genes and genomes (KEGG) pathways (https://www.genome.jp/kegg/pathway.html)¹² and protein−protein interactions (https://string-db.org/)¹³ were assessed according to the highest confidence score (0.9), coexpression, experimentally determined, curated databases, and text mining interactions. Based on the literature review and pathway analysis, a list of candidate genes associated with COVID-19 infection was obtained.

4 GWAS VARIANTS ASSOCIATED WITH COVID-19 RELATED TRAITS

The most important COVID-19 related traits listed in previous studies were identified. GWAS variants associated with these identified traits were obtained from GWAS results listed in the EBI-NHGRI GWAS catalog (https://www.ebi.ac.uk/gwas/). The catalog format was tab-separated values containing the results of 3875 GWA studies and 111 406 variants. Based on traits, SNPs, and p values, a data set of index variants (GWAS statistically significant variants(p ˂ 10⁻⁶)) in candidate genes associated with COVID-19 infection was obtained from the EBI-NHGRI GWAS catalog. The sample size of the studied populations was obtained from the sum of the initial and replication of the sample size. Then, GRCh38 genomic positions of these variants were extracted from single nucleotide polymorphism database (https://www.ncbi.nlm.nih.gov/snp/). The GRCh38 genomic position of candidate genes associated with COVID-19 infection (identified based on statements previously mentioned) was obtained from the National Center for Biotechnology Information gene (https://www.ncbi.nlm.nih.gov/gene). Then, variants whose genomic positions were placed inside the candidate genes were characterized using the Galaxy web-based platform.¹⁴

5 HAPLOTYPE OF CANDIDATE VARIANTS

Candidate variants associated with COVID-19 related traits were used to obtain haplotype blocks. These variants were integrated with the data obtained from population-specific haplotypic structures from the 1000 Genomes Project. Haplotypes associated with each COVID-19 related trait were separately analyzed using HaploReg v4.1. For this purpose, all GWAS variants associated with COVID-19 related traits (identified in the previous step) were included in the analysis. Variants with high correlation ratios (r² ≥ 0.8, D′ ≥ 0.8) were recorded for COVID-19 and its related traits influencing haplotype blocks.

6 FUNCTIONAL ANALYSIS

To assess the impact of variants in haplotype blocks, their functional effects were investigated. A comprehensive set of micro RNAs (miRNA) targets were prepared to find variants located in miRNA binding sites, including the information about the binding sites confirmed by experimental studies, such as CLIP-seq and CLASH studies. Two online tools, namely targetScan (version 7.1; http://www.targetscan.org/vert_71/),¹⁵ StarBase (version 2; http://starbase.sysu.edu.cn/starbase2/index.php)¹⁶ were used to explore variants located at the miRNA−messenger RNA binding site. The impact of variants on gene expression was evaluated by expression quantitative trait loci (eQTL) using the GTEx Portal (https://www.gtexportal.org/). RegulomeDB (https://regulomedb.org/) was applied to assess the potential regulatory functions of haplotype variants outside the coding region. The scores can range from 1 to 7, and lower scores are more likely to be related to regulatory variants. The range of probability is between 0 and 1, in which 1 denotes the most probability of being a regulatory variant.¹⁷ Also, the SNPInfo (SNP Function Prediction [FuncPred], https://snpinfo.niehs.nih.gov/) analysis was performed for all variants.¹⁸

7 RESULTS

7.1 COVID-19 associated genes

The literature review showed that angiotensin-converting enzymes (ACE and ACE2), as well as TMPRSS2, play main roles in COVID-19 infection. The protein−protein interaction analysis revealed the most important interacting genes associated with ACE. The results showed AGT (Angiotensinogen), AGTR2 (Angiotensin II Receptor Type 2), AGTR1 (Angiotensin II Receptor Type 1), KNG1 (Kininogen 1), REN (Renin), RHOA (Ras Homolog Family Member A), and RHOC (Ras Homolog Family Member C) were associated with ACE. The detailed results are shown in Figure 2A.

The AGT had a stronger association with ACE2 in protein-protein interactions, similar to protein−protein interactions in ACE (Figure 2A,B). The ACE2 and TMPRSS2 had strong association with each other (Figure 2B,C). The protein−protein interaction of AGT confirmed its associations with ACE2 and ACE (Figure 3). However, according to the interactions and also based on the pathway analysis, the results revealed that ACE, ACE-2, and AGT are involved in similar pathways, including the renin-angiotensin system (RAS) (KEGG, https://www.pharmgkb.org/pathway/PA165110622), and ACE Inhibitor pathways, (https://www.ncbi.nlm.nih.gov/biosystems/198763, https://www.pharmgkb.org/pathway/PA2023).

7.2 COVID-19 associated genes and variants involved in COVID-19 related traits

The GWA studies were mined to find variants of the candidate genes associated with COVID-19 related traits. ACE gene variants showed 10 unique polymorphisms, all of which were significantly associated with COVID-19 related traits including systolic and diastolic blood pressure, blood protein, and serum metabolite. Results are shown in Table 1. We also investigated GWAS variants located in the proximity of the genomic position of ACE. Two intragenic variants, rs4968782 and rs4277405, very close to the PPIAP55 pseudo gene, were associated with COVID-19 related traits (Table 2). No GWAS-associated variants were found in ACE2, and GWAS variants of TMPRSS2 were not associated with COVID-19 related traits (Table 3).

Table 1. Significant ACE gene variants based on GWA studies

Traits	Study population	Sample size	Variants	Type of variant	p Value	References
ACE activity	Han Chinese	1023	rs4343	Synonymous	3e-25	19
Blood metabolite levels	European	7824	rs4351	Intron	4e-22, 1e-19, 3e-17, 1e-14	20
		7824	rs4362	Synonymous	1e-21	20
Blood metabolite ratios	European	7358	rs4343	Synonymous	1e-37	20
Blood protein levels	European	3200	rs4344	Intron	9e-136	21
Diastolic blood pressure	European, Latino, Africa, East Asian, South Asian, mixed and unknown	321262	rs4295	Intron	4e-8	22
	European	331204	rs4308	Intron	7e-14	22
		378379	rs4459609	Intergenic	2e-7,2e-14	23
Metabolic traits	European	2820	rs4329	Intron	8e-20	24
Metabolite levels	European	891	rs4351	Intron	9.00e-13	25
Serum metabolite levels	European	1678	rs4325	Intron	1e-11, 3e-12	26
	African, European	2938	rs4343	Synonymous	9-25, 1e-18, 8e-14, 1e-16	26, 27
		1678	rs4351	Intron	4e-14, 5e-15	26
Systolic blood pressure	European, African, Hispanic, Asian, Native American	776078	rs4291	Regulatory_region	1e-9	28
	European, Latino, Africa, East Asian, South Asian, mixed and unknown	321262	rs4295	Intron	1e-8	22

Table 2. Significant PPIAP55 gene variants based on GWA studies

Traits	Study population	Sample size	Variants	Type of variant	p Value	References
CSF levels of AD proteins	Unknown	574	rs4968782	Intragenic	4e-12	29
Diastolic blood pressure and alcohol interaction	European, African, Asian, Hispanic, or Latino American	574163	rs4277405	Intragenic	1e-12	30
Diastolic blood pressure and smoking	European, African, Asian, Hispanic	1191328	rs4968782	Intragenic	3-e16, 3e-14, 7e-16, 4e-13	31
Systolic blood pressure and alcohol interaction	European, African, Asian, Hispanic, or Latin American	574117	rs4277405	Intragenic	2e-12	30
Systolic blood pressure and smoking status	European, African, Asian, Hispanic	1191328	rs4968782	Intragenic	8e-15, 2e-13, 6e-14, 3e-12	31

Table 3. Significant TMPRSS2 gene variants based on GWA studies

TraitS	Study population	Sample size	Variants	Type of variant	p Value	References
3-hydroxypropyl mercapturic acid levels in smokers	European, African, Hawaiian, Asian, Latino	2282	rs183026840	Intron	9e-6	32
Prostate cancer	European, African, Asian, Latino	87040	rs1041449	Intron	3e-8,3e-7	33

In addition, GWAS results were mined to identify genes having interactions with ACE. The results identified 39 GWAS variants. All KNG1 variants (12 variants), 6 polymorphisms in the AGT gene, 2 in the REN gene, 1 in the BDKRB2, and 1 in the RHOA gene were significantly associated with COVID-19 related traits. The results are shown in Table 4. Most of the associated traits were similar to those identified in association with ACE gene variants (Table 1). Polymorphisms within RHOC, BDKRB2, AGTR1, and AGTR2 genes were not related to COVID-19 related traits. GWAS variants of other COVID-19 related traits, including cold, respiratory diseases, and cardiovascular diseases, were assessed; however, no association was found for these traits.

Table 4. GWAS variants of genes with high confidence protein−protein interactions with AEC (identified in Figure 1)

Genes	Traits or diseases	Study population	Sample size	Variants	Type of variant	p Value	References
REN	Systolic blood pressure	European	422000	rs72749713	Intron	9E-10	34
	Blood protein levels	European	3301	rs193280350	Intron	1E-15	35
	Psychosis proneness	European	3967	rs7513165	Intron	3E-7, 2E-6	36
BDKRB2	Mumps	European	85380	rs11160318	Regulatory_region	5E-12	37
	Coronary artery calcified atherosclerotic plaque in type 2 diabetes	African	896	rs7158214	Regulatory_region	4E-06	38
	Subcutaneous adipose tissue	European	2513	rs4384548	Regulatory_region	5E-08	39
	Corneal astigmatism	European	86335	rs56274409	Intron	7E-06	40
	Cerebrospinal fluid AB1-42 levels	unknown	3146	rs76881547	Regulatory_region	5E-06	41
	Gout	Han Chinese	62	rs2069590	3_prime_UTR	1E-07	42
AGTR2	Cystic fibrosis severity	European	3476	rs1403543	Intron	2E-06	43
AGTR1	Adolescent idiopathic scoliosis	Chinese	499	rs12695894	Intron	5E-12	44
AGT	Diastolic blood pressure	European, Latino, African, African, East Asian, South Asian, mixed and unknown	699641	rs2004776	Intron	9E-7, 2E-11	22, 23
	Mean arterial pressure	European, African, Hispanic	146562	rs699	Missense	4E-12	45
	Systolic blood pressure	European	342415	rs2493134	Intron	1E-12	46
	Diastolic blood pressure	European	342415	rs2493134	Intron	1E-14	46
	Coronary artery disease	unknown	547261	rs699	Missense	2E-08	47
	Diastolic blood pressure and alcohol interaction	European, African, Asian, Hispanic, or Latin American	535163	rs2004776	Intron	9E-13	30
	Diastolic blood pressure and smoking interaction	European, African, Asian, Hispanic	610091	rs2004776	Intron	2E-14	31
	Systolic blood pressure and smoking interaction	European, African, Asian, Hispanic	610091	rs2004776	Intron	3E-10	31
	Blood protein levels	European	3200	rs3789678	Intron	2E-16	21
	Pancreatic ductal adenocarcinoma	European	21536	rs1326889	Intron	4E-07	48
	Systolic blood pressure	European, African, Hispanic, Asian, Native American	776078	rs699	Missense	6E-26	28
	Systolic blood pressure	European, Latino, African, African, East Asian, South Asian, mixed and unknown	321262	rs2004776	Intron	1E-09	22
	Cardiovascular disease	European	459000	rs943580	Intergenic	4E-16	34
	Systolic blood pressure	European	422000	rs2478539	Intron	3E-30	34
RHOC	Glomerular filtration rate (creatinine)	European	110517	rs12144044	5_prime_UTR	3E-8	49
	Cerebral amyloid deposition in APOEe4 non-carriers	European and other	370	rs76570619	Intron	3E-7	50
RHOA	Educational attainment	European	280007	rs148734725	Intron	5E-12	51
	Cognitive ability				Intron
	High intelligence	European	87740	rs1987628	Intron	4E-8	52
	Morning person	European	651295	rs62259941	Intron	1E-17	53
	Household income	European, unknown	505541	rs11716948	Intron	1E-10
	Intelligence	European	269867	rs7623659	Intron	1E-27	54
	Educational attainment	European	1131881	rs116656374	Intron	3E-10	55
	Cognitive performance	European	402382	rs7623659	Intron	4E-57	55
	Coronary artery disease	European, unknown	547261 340599 304591	rs7623687	Intron	1E-8, 4E-10, 2E-8	47, 56, 57
KNG1	Activated partial thromboplastin time	European, Japanese	377667 1431 9240	rs2304456	Missense	4E-45, 3E-199 2E-36	58-60
	Blood metabolite levels	European	7824	rs4686799	Intron	9E-6	20
	Blood protein levels	European	3301 997 3200	rs5030081 rs3856930 rs2304456 rs5030049 rs5030062 rs138610068 rs710446 rs5030044	Intron Intron Intron Intron Exon Intron Missense Intron	4E-49 8E-15 3E-97 1E-96 6E-13 1E-13 2E-302 1E-300	21, 35, 61
	Factor XI	European	18214	rs5030062	Exon	3E-40	62
	Plasma renin activity	European	5275	rs5030062	Exon	2E-35	63
	Small vessel stroke	Chinese	3526	rs1403694	Intron	1E-12	64
	Thrombosis	European	258962	rs698078	Intron	5E-7	65
	Venous thromboembolism	European	187204	rs710446	Missense	2E-203	66

7.3 Haplotype analysis of COVID-19 related traits

The haplotype analysis was performed based on 1000 Genomes Project haplotypes. First, all common variants in the ACE gene and its near genomic positions, related to blood metabolite levels, were analyzed (Tables 1 and 2). The results showed that all of these variants (rs4329_rs4325_rs4343_rs4351_rs4344_rs4362) were in strong linkage disequilibrium (LD) (r² ≥ 0.90 and D′ ≥ 0.98). To examine the functional effect of these variants, the annotation of polymorphisms with eQTL was performed, and except for rs4343, all other variants were eQTL. The haplotype analysis was carried out on other variants associated with COVID-19 related traits. The results showed that rs4295_rs4968782_rs4308_rs4459609_rs4277405_rs4291 in the ACE gene and its near genomic positions (Tables 1 and 2) were in strong LD (r² ≥ 0.88 and D′ ≥ 0.95). All these variants were eQTL and associated with blood pressure. Also, the haplotype analysis of AGT variants was conducted, and it was found that rs2478539_rs699_rs2493134_rs943580 were in a haplotype block (r² ≥ 0.87 and D′ ≥ 0.96) for systolic blood pressure variations. All variants in this haplotype were also eQTL, showing the functional importance of this haplotype. Finally, the online tools targetScan and StarBase were used to find the miRNA binding site variants, while RegulomeDB and SNPinfo were applied to assess the potential regulatory functions of haplotype variants. The results are shown in Table 5. The RegulomeDB analysis indicated that except for three polymorphisms, other variants had a probability of 0.61≥ (ranked 4 or less) for the potential regulatory functions. The SNPinfo analysis showed that many of the index variants among identified haplotypes were located in the transcription factor binding sites (TFBS), exonic splicing enhancers (ESE), or silencer (ESS) activity variants. The three index polymorphisms (rs4968782, rs4277405, and rs4459609) had low probability scores in RegulomeDB and were TFBS variants based on SNPinfo.

Table 5. RegulomeDB results for candidate haplotypic variants

Haplotype	Type of SNP	rsID	Probability	Ranking	TFBSa	Splicing (ESE or ESS)b	RegPotenti alc	eQTL
Haplotype		rsID	RegulomeDB			SNPinfo		eQTL
ACE associated with blood metabolite variations	Index	rs4325	0.85	3a			NA	Yes
		rs4329	0.61	4			0.13	Yes
		rs4343	0.87	2b		Yes	0	-
		rs4344	0.61	4			0.05	Yes
		rs4351	0.61	4			0	Yes
		rs4362	0.64	3a		Yes	0.33	Yes
	Proxy	rs4316	0.83	2a			0.37	Yes
		rs4320	0.61	4			0	Yes
		rs4321	0.13	5			0.04	Yes
		rs4323	0.13	5			NA	Yes
		rs4324	0.59	5			NA	Yes
		rs4326	0.61	4			NA	Yes
		rs4327	0.61	4			NA	Yes
		rs4330	0.61	4			0	Yes
		rs4332	0.61	4			0.17	Yes
		rs4333	0.61	4			0.11	Yes
		rs4334	0.13	5			0	Yes
		rs4335	0.13	5			0	Yes
		rs200491776	0.13	5				-
		rs4336	0.13	5			0.18	Yes
		rs201390711	0.13	5				-
		rs4337	0.13	5			0.20	Yes
		rs1987692	0.61	4			NA	Yes
		rs4341	0.61	4			0	-
		rs4342	0.61	4			0	-
		rs4353	0.74	2b			0	Yes
		rs4359	0.78	3a			0	Yes
		rs4363	0.61	4			0.59	Yes
		rs1055086	0.61	4			0	Yes
ACE haplotype associated with blood pressure variations	Index	rs4968782	0.18	7	Yes		0	Yes
		rs4277405	0.13	5	Yes		0	Yes
		rs4459609	0.13	5	Yes		0.12	Yes
		rs4291	0.61	4	Yes		0.42	Yes
		rs4295	0.61	4			0.12	Yes
		rs4308	0.61	4			0	Yes
	Proxy	rs6504163	0.36	3a			NA	Yes
		rs8077276	0.13	5			NA	Yes
		rs4968783	0.59	5			NA	Yes
		rs4292	0.70	4	Yes		059	Yes
AGT haplotype associated with systolic blood pressure variations	Index	rs943580	0.61	4			0	Yes
		rs2478539	0.61	4			0	Yes
		rs699	0.61	4		Yes	0.46	Yes
		rs2493134	0.61	4	Yes		0	Yes
	Proxy	rs2493126	0.61	4			0.19	Yes
		rs2493128	0	5			0	Yes
		rs2006765	0.61	4			NA	Yes
		rs2493133	0.79	2b			0.10	Yes
		rs2478543	0.79	3a			0.07	Yes
		rs5051	1.0	2b			0.23	Yes
		rs2493135	0.61	4			NA	Yes
		rs2493136	0.61	4			NA	Yes

Note: Bold values shows proxy variants with more regulatory effects. Ranking/supporting data: 2a/TF binding + matched TF motif + matched DNase Footprint + DNase peak; 2b/TF binding + any motif + DNase Footprint + DNase peak; 3a/TF binding + any motif + DNase peak; 4/TF binding + DNase peak; 5/TF binding or DNase peak; 7/Other.
^a affecting the transcription factor binding sites (TFBS) activity (transcriptional regulation);
^b exonic splicing enhancers (ESE) or silencers (ESS);
^c Regulatory Potential Score only for SNPs that are outside of the coding region in SNP selection.

The haplotype analysis showed proxy haplotypic variants were associated with described traits. Most of the proxy haplotype variants identified form the GWA studies were eQTL. Three variants, including rs4316, rs4353, and rs4359, and three variants rs2493133, rs2478543, and rs5051, were correlated with blood metabolite levels and systolic blood pressure, respectively. These variants showed more regulatory effects compared with other GWAS variants, suggesting the potential effects of these variants on blood metabolite and blood pressure.

8 DISCUSSION

Genetic factors play a key role in the susceptibility and severity of COVID-19. In this study, we tried to identify variants and haplotypes associated with COVID-19 related traits by the identification of genes and GWAS variants associated with COVID-19. The literature review showed that ACE, ACE2, and TMPRSS2 genes play fundamental roles in COVID-19 infection.⁶⁷ The results showed GWAS variants in ACE and AGT genes were the most significant variants associated with COVID-19 related traits. These variants contribute to the development of blood pressure and blood metabolite levels and are potentially involved in COVID-19 severity. Two specific haplotypes were found in the ACE gene, closely related to blood metabolites levels and blood pressure. GWAS index variants of these haplotypes functionally affect the ACE expression. Three candidate proxy variants, including rs4316, rs4353, and rs4359, were identified to be associated with blood metabolite levels. The effect of these variants on blood metabolites levels was not assessed in previous studies. Studies have shown that the ACE-2 and ACE genes are correlated with COVID-19 infection.^{1, 2, 6, 7, 68, 69} For example, infected individuals with COVID-19 receiving ACE inhibitors or the angiotensin receptor blocker (ACEis/ARBs) had a lower risk of mortality than other COVID-19 patients.⁶⁸ Several studies have been performed on the role of ACE inhibitors in the development of blood pressure or blood metabolic levels,^70-74 confirming the results obtained in this study. Also, a relationship between blood pressure control and its role in the mortality of COVID-19 patients has been observed, implying the role of systolic and diastolic blood pressure controlling drugs in COVID-19 infection.⁶⁸ Another study examined ACE gene haplotypes in the African American population and their close association with blood pressure. The study identified rs4313-rs4337 haplotype in association with hypertension.⁷⁵ The relationship between blood metabolites and ACE gene polymorphisms has been investigated in previous studies. Also, the correlation of ACE I/D polymorphisms with nitric oxide metabolite and blood pressure levels in Mexican men has been identified.⁷⁶ A recent study carried out on the effect of the ACE gene on mortality rate in COVID-19 shows that in the European population, ACE Del/Del polymorphism is significantly involved in COVID-19-associated mortality. The authors suggested further research on this variant and level of ACE as prognostic biomarkers for the severity of COVID-19. They have identified both ACE and Ang II could act as potential targets for the treatment of COVID-19.⁶ In addition, recent studies identified variants in the ACE gene, which are implicated in COVID-19 outcome.⁷ Recently, a pilot study suggested that the rs4343 variant in ACE may be a predictive marker for the severity of COVID-19 in patients with hypertension.⁵ Also, this variant is associated with angiotensin-converting enzyme inhibitors.⁷⁷ In addition, rs4343, rs4329, and rs4351 are associated with blood metabolic measurements.^{20, 24, 25} A recent study showed the role of rs699 in the prediction of the clinical outcome of SARS-CoV-2 infection.⁷⁸ These findings confirm the importance of variants identified as haplotypes in the current study. Also, the ACE2 gene was assessed as the receptor of COVID-19.^{79, 80} It was revealed that its polymorphisms are associated with the genetic susceptibility of COVID-19.⁸¹ No GWAS-associated variants were found to be related to ACE2.

In this study, ACE and AGT variants had associations with blood pressure. As shown in Figures 2 and 3, AGT is closely associated with both COVID-19 related genes (ACE, ACE2), which is in agreement with the previous study.³ The study identified a haplotype and three rs2493133, rs2478543, and rs5051 variants in the AGT gene associated with systolic blood pressure. The role of rs2493133 and rs2478543 variants in blood pressure was not evaluated in previous studies, and the results of previous studies on the role of rs5051 in hypertension were not similar.^82-84 The role of AGT gene polymorphisms in blood pressure was investigated in previous studies.^85-87 Polymorphisms in this gene play a role in respiratory distress syndrome.⁸⁸ This gene is co-expressed with renin in the brain.⁸⁹ AGT, ACE, and ACE2 are related to vasoconstriction, vasodilation, and angiogenesis, as well as the risk of developing ischemic stroke. The ACE2-Ang-(1-7)-Mas axis lowers the ACE-Ang II-AT1R axis and, accordingly, exerts a protective effect against stroke and shows anti-hypertensive properties.³ However, there was no study on the association of AGT levels with the severity of COVID-19.⁹⁰ The AGT protein is a potential therapeutic target to decrease infection.⁴ Recent studies found an association between the expression of AGT and ACE2 expression.⁴ Both of these genes are involved in RAS.² The inhibition of this system may be a therapeutic option and an important pathway for COVID-19 treatment.^{1, 91}

9 CONCLUSION

According to the results, all three index variants in candidate haplotypes had important effects on blood pressure and blood metabolite levels. The findings were completely specific, and variants are effective in gene expression. Furthermore, three candidate variants, rs4316, rs4353, and rs4359, and three candidate variants, rs2493133, rs2478543, and rs5051 were identified to be involved in blood metabolite levels and systolic blood pressure, respectively. More observational studies on identified variants are needed to confirm the association of these candidate variants with blood metabolite levels, blood pressure, and COVID-19 severity.

AUTHOR CONTRIBUTIONS

All authors contributed to the conception and design of the study. The literature review and pathway analysis were performed by Mandana Hasanzad and Bagher Larijani. GWAS variants associated with COVID-19-related traits were identified by Marziyeh Zoughi and Morteza Gholami. Haplotype and functional analyses were conducted by Mahsa M. Amoli and Morteza Gholami. The manuscript was drafted by Morteza Gholami and Marziyeh Zoughi with the help of Mahsa M. Amoli. All authors commented on previous versions of the manuscript and discussed the results. Mahsa M. Amoli supervised the project and approved the final version. All authors read and approved the final version of the manuscript.

ACKNOWLEDGMENT

This study was supported by the Tehran University of Medical Sciences (Grant No. 51229-221-3-99).

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ETHICS STATEMENT

This study was approved by the Research Ethics Committee of Tehran University of Medical Sciences.

Open Research

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Volume95, Issue1

January 2023

e28355

Haplotypic variants of COVID-19 related genes are associated with blood pressure and metabolites levels

Abstract

1 INTRODUCTION

2 METHODS

3 CANDIDATE GENES ASSOCIATED WITH COVID-19 INFECTION

4 GWAS VARIANTS ASSOCIATED WITH COVID-19 RELATED TRAITS

5 HAPLOTYPE OF CANDIDATE VARIANTS

6 FUNCTIONAL ANALYSIS

7 RESULTS

7.1 COVID-19 associated genes

7.2 COVID-19 associated genes and variants involved in COVID-19 related traits

7.3 Haplotype analysis of COVID-19 related traits

8 DISCUSSION

9 CONCLUSION

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENT

CONFLICT OF INTEREST

ETHICS STATEMENT

Open Research

DATA AVAILABILITY STATEMENT

REFERENCES

Citing Literature

Figures

References

Information

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Haplotypic variants of COVID-19 related genes are associated with blood pressure and metabolites levels

Abstract

1 INTRODUCTION

2 METHODS

3 CANDIDATE GENES ASSOCIATED WITH COVID-19 INFECTION

4 GWAS VARIANTS ASSOCIATED WITH COVID-19 RELATED TRAITS

5 HAPLOTYPE OF CANDIDATE VARIANTS

6 FUNCTIONAL ANALYSIS

7 RESULTS

7.1 COVID-19 associated genes

7.2 COVID-19 associated genes and variants involved in COVID-19 related traits

7.3 Haplotype analysis of COVID-19 related traits

8 DISCUSSION

9 CONCLUSION

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENT

CONFLICT OF INTEREST

ETHICS STATEMENT

Open Research

DATA AVAILABILITY STATEMENT

REFERENCES

Citing Literature

Figures

References

Related

Information