Invest Clin 65(2): 169 - 178, 2024 https://doi.org/10.54817/IC.v65n2a04

Autor de Correspondencia Francisco Álvarez-Nava. Carrera de Biología. Facultad de Ciencias Biológicas. Universi-

dad Central del Ecuador. Quito, Ecuador. Tel: +593-252-8810. Fax: +593-252-8810. E-mail: fjalvarez@uce.edu.ec

Genetic association study of the rs10774671

variant of the OAS1 gene with the severity

of COVID-19 in an Ecuadorian population.

Kathya Pilataxi

, Thalía Balarezo

, Erik Chávez, Camila Acosta

, Ivonne Z. Peña

Katherin Narváez

and Francisco Álvarez-Nava

Facultad de Ciencias Biológicas, Universidad Central del Ecuador, Quito, Ecuador.

Hospital Quito Sur del Instituto Ecuatoriano de Seguridad Social, Quito, Ecuador.

Keywords: complex trait; COVID-19; genetic association study; genetic variant;

Hardy-Weinberg equilibrium; innate immune processes.

Abstract. COVID-19 exhibits a wide range of phenotypic manifestations,

from asymptomatic to severe phenotypes with fatal complications. The exis-

tence of risk factors cannot entirely explain the variance in the phenotypic vari-

ability of COVID-19. Genome-wide association analyses have identified target

human genes related to virus transmission and the clinical phenotype observed

in COVID-19 patients. Genetic variants on the OAS1 gene have been associ-

ated with innate immune processes (entry phase and viral replication in host

cells). The A or G alleles of rs10774671 in OAS1 encode isoforms with different

antiviral activities. One hundred COVID-19 patients were genotyped for the

rs10774671 using RFLP-PCR (severe form, n = 43; asymptomatic-mild, n =

57). The susceptibility of the two groups to the severe phenotype of COVID-19

was compared. The allele frequency for A was 0.8. The genotypic frequencies

for AA and GG homozygotes were 0.62 and 0.02, respectively. A Hardy-Weinberg

equilibrium deviation was found in both groups. No statistically significant as-

sociations were found in genetic models adjusted for sex (for the additive model

OR = 1.18, 95% CI = (0.53-2.61), p = 0.69). A relatively recent mix of different

ethnic groups and sample size may influence these findings.

170 Pilataxi et al.

Investigación Clínica 65(2): 2024

Estudio de asociación genética de la variante rs10774671

del gen OAS1 con la severidad de COVID-19 en una población

ecuatoriana.

Invest Clin 2024; 65 (2): 169 – 178

Palabras clave: estudio de asociación genética; equilibrio Hardy-Weinberg; rasgo

complejo; variante genética; procesos inmunes innatos.

Resumen. La COVID-19 presenta una amplia gama de manifestaciones clí-

nicas, desde asintomáticas hasta formas graves con complicaciones mortales.

La variabilidad fenotípica de la COVID-19 no puede explicarse totalmente por

la existencia de factores de riesgo. Se han identificado genes humanos diana

relacionados con la transmisión del virus y el fenotipo clínico observado en

pacientes con COVID-19 mediante análisis de asociación de genoma completo.

Las variantes genéticas del gen OAS1 se han asociado con procesos inmunita-

rios innatos (fase de entrada y replicación viral en las células hospedadoras).

Los alelos A o G de rs10774671 en OAS1 codifican isoformas con diferentes

actividades antivirales. Cien pacientes con COVID-19 fueron genotipados para

el rs10774671 mediante RFLP-PCR (forma grave, n = 43; asintomática-leve, n

= 57). Se comparó la susceptibilidad de los dos grupos al fenotipo severo de

COVID-19. La frecuencia alélica para A fue de 0,8. Las frecuencias genotípicas

para los homocigotos AA y GG fueron 0,62 y 0,02, respectivamente. Se observó

una desviación del equilibrio de Hardy-Weinberg en ambos grupos. No se encon-

traron asociaciones estadísticamente significativas en los modelos genéticos

ajustados por sexo (para el modelo aditivo OR = 1,18, IC 95% = (0,53-2,61),

p = 0,69). La mezcla relativamente reciente de diferentes grupos étnicos y el

tamaño de la muestra pueden influir en estos resultados.

Received: 24-06-2023 Accepted: 13-02-2024

INTRODUCTION

COVID-19 is a human-to-human trans-

missible viral infectious disease

. Until the

beginning of 2023, it had been responsible

for about 7 million deaths worldwide

. Sub-

jects infected with SARS-CoV-2, the etiologi-

cal agent of COVID-19, have a wide range of

phenotypic variability, from asymptomatic

to severe forms of the disease

. This broad

clinical variability is partially explained by

risk factors that include age (> 65 years),

male sex, and the presence of comorbidi-

ties such as obesity, cardiovascular diseases,

diabetes mellitus, and respiratory disorders,

among others

. Therefore, the variance in

the clinical phenotype of COVID-19 may be

caused by additional host-specific factors

Genome-wide association studies have

reported associations between the severe

form of COVID-19 and chromosomal re-

gions, including 12q24.13, which harbors

a gene cluster encoding antiviral restric-

tion enzyme activators (OAS1, OAS2, and

OAS3). These activators are involved in vi-

ral RNA degradation and viral replication

inhibition

6,7

. The OAS1 gene encodes the

enzyme 2′-5′ oligoadenylate synthetase 1

COVID-19 and OAS1 Gene in Ecuadorian Population 171

Vol. 65(2): 169 - 178, 2024

(2-5A), an activator of the ribonuclease L

(RNaseL), which degrades viral RNA within

the host cell, blocks viral replication and

inhibits viral protein synthesis. The genetic

variant rs10774671 is a G→A transition in

the last nucleotide of intron 5 of the OAS1

gene, which affects the nonsense-mediated

decay and the splicing site and controls

the differential expression of isoforms with

lesser enzymatic activity

7,8

. Different allele

and genotype frequencies have been report-

ed in studies, including those of European,

African, and Latin American Afro-Caribbe-

an populations, likely due to the influence

of the ancestral factor

9,10

. Despite being a

multiethnic society composed of different

communities with South American, West

Eurasian, and Sub-Saharan ancestries, the

Ecuadorian population has a strong Native

South American ancestral influence, which

is considered the second highest for this re-

gion’s population

The percentage of severe cases and

deaths among individuals of Hispanic an-

cestry was higher than that reported for the

general population. For instance, in New York

City, one of the communities hardest hit by

the SARS-CoV-2 virus globally, more Hispan-

ics per capita have died from COVID-19 than

any other ethnic group. Infection rates on

the Navajo Nation Indian Reservation have

also been reported to be particularly high

Native Americans represent more than a

third of the COVID-19 cases in the state of

New Mexico, despite making up only 9% of

the population

. These ethnic differences

do not appear to be caused by socioeconomic

conditions or access to health services since

Latin American non-Sub-Saharan ancestry

was reported as a factor associated with

morbidity and mortality from COVID-19 in a

study that included health professionals with

similar economic and educational status

Latin America is one of the regions

where the impact of COVID-19 has been

most severe. Poor sanitary conditions of in-

frastructure, health personnel, and an im-

munologically vulnerable population are two

factors that influenced this impact. Ecua-

dor was one of the countries that was dra-

matically impacted at the beginning of the

pandemic. However, sustained vaccination

campaigns were able to mitigate this impact

partially. Fifteen million people, or 86% of

the population, have received at least one

dose

, with 14 million (or 79%) receiving

two or more doses

. Few genetic associa-

tion studies between COVID-19 and suscep-

tibility genes have been reported for the

Latin American populations. For this reason,

we examined the association between the

rs10774671 variant of the OAS1 gene and

the severe form of COVID-19 among Ecua-

dorian individuals.

METHODS

Design and Study Subjects

In this observational, analytical, and

case-control study, a total of 100 Ecuadorian

individuals with COVID-19 were analyzed.

The individuals were divided into two groups:

43 patients with the severe clinical picture

(group A) enrolled from October 2021 to

March 2022 and 57 subjects with the asymp-

tomatic-mild form (group B) enrolled in Jan-

uary 2021 at the Quito Sur Hospital of the

Ecuadorian Institute of Social Security, Qui-

to, Ecuador. Group A consisted of individuals

without regard to sex who had a diagnosis of

COVID-19 severe form confirmed by a posi-

tive RT-PCR test specific for SARS-CoV-2; a

chest computed tomography image showing

a pattern of viral pneumonia due to diffuse

infiltration of both lungs greater than 50%

(CORADS 6); and the presence of respirato-

ry failure and the need for mechanical venti-

lation (PaO2/FiO2 ≤ 100mmHg (with PEEP

≥ 5cm H2O) and SpO2/FiO2 ratio <315).

This group had received at least two doses of

SARS-CoV-2 vaccines. Group B subjects pre-

sented the disease’s asymptomatic or mild

clinical form, validated by a positive RT-PCR

test for SARS-CoV-2. Group B was made up of

health workers from the same hospital who

provided care for patients with the severe

172 Pilataxi et al.

Investigación Clínica 65(2): 2024

form of COVID-19 admitted to the intensive

care unit. When the subjects from Group B

were diagnosed with COVID-19, they had not

received any vaccination against COVID-19.

This method of subject selection was carried

out to identify COVID-19 protective alleles.

The exclusion criteria for both groups in-

cluded consanguineous individuals, minors,

pregnant or nursing women, and refugees or

displaced with little or no knowledge of the

Spanish language.

Molecular Analysis

Ten milliliters of peripheral blood were

drawn from each subject in an EDTA tube. In

order to reduce bias in the laboratory phase,

each tube was assigned a unique code with-

out discriminating to which clinical group

it belonged. The Column-Pure Blood Ge-

nomic DNA (ABM, Vancouver, Canada) kit

was used to extract DNA according to the

manufacturer´s instructions. The Qubit ds-

DNA BR ASSAY Kit (21000 ng 100RX (Invi-

trogen, Massachusetts, USA) was then used

to quantify the DNA using the Qubit fluo-

rometer (Invitrogen, Massachusetts, USA).

The DNA quality was determined by elec-

trophoresis in 1.5% agarose gels at 80V for

an hour, with the bands visualized using the

Microtek Bio-1000F program scanner (Mi-

crotek International Inc., Hsinchu City, Tai-

wan). The forward primer 5’-TCC-AGA-TGG-

CAT-GTC-ACA-GT-3’ and the reverse primer

5’-TAG-AAG-GCC-AGG-AGT-CAG-GA-3´ were

used to carry out the PCR, based on earlier

research

. The master mix and thermocy-

cler settings (Applied Biosystems MiniAmp,

Thermo Fisher Scientific Inc., Massachu-

setts, USA) for PCR were performed based

on a previously published

method with

modifications. PCR products were examined

by electrophoresis on 1.5% agarose gels in

the blueGelTM system (48V, 45 minutes)

(MiniPCR Bio, Massachusetts, USA). Subse-

quently, these products were digested with

10 U of AluI at 37°C for 16 hours, in a total

volume of 20 μl, following the manufactur-

er’s instructions. They were electrophoresed

in 3% agarose gels in the Thermo Scienti-

ficTM equipment (120V, 2 hours) (Thermo

Fisher Scientific Inc., Massachusetts, USA).

Ten percent of all samples were randomly se-

quenced to control the reproducibility and

quality of genotyping of PCR-RFLP, which

showed complete matching of results.

Statistical Analysis

Used software included InfoStat, Micro-

soft Excel 2019, SNPStats

(https://www.

snpstats.net/), and the Hardy-Weinberg sta-

tistical package for R Studio

. Allelic and

genotypic frequencies were calculated by

direct counting and expressed in propor-

tions and percentages. The exact test ex-

amined genotypic and allelic frequencies

to determine whether the groups were in

Hardy-Weinberg equilibrium (HWE)

. The

Fisher’s exact test was then used to compare

allele frequencies between group A (severe

COVID-19 phenotype) and group B (mild

and moderate COVID-19 phenotype). The

association between the rs10774671 alleles

and the severe phenotype of COVID-19 was

estimated considering different inheritance

models (codominant, dominant, recessive,

overdominant, and additive)

, expressed in

frequencies and percentages. For each analy-

sis, the odds ratios (OR), 95% confidence in-

tervals (95% CI), and corresponding p values

were calculated. An association was consid-

ered significant when the p-value was < 0.05

in all two-tailed statistical tests.

Ethical Considerations

Participants gave their written consent

to sample extraction, the use of clinical

histories, and the processing of biological

samples. Hospital staff members collected

the samples and data; they had no interac-

tion with the researchers who conducted the

molecular tests. The data were collected ac-

cording to the WHO “COVID-19 Case Reg-

istration Form”, and the information was

handled confidentially. This study had the

ethical, legal, and methodological endorse-

COVID-19 and OAS1 Gene in Ecuadorian Population 173

Vol. 65(2): 169 - 178, 2024

ment of the Ethics Committee for the Ex-

pedited Review of COVID-19 Investigations

of the Ministry of Public Health of Ecuador

(MSP-CGDES-2020-0244-O1).

RESULTS

Table 1 shows the allelic and genotypic

frequencies discriminated by groups (whole

group, groups A and B). Alleles and geno-

types were not found in HWE in the ana-

lyzed groups. Likewise, no allele or genotype

was significantly associated with the severe

phenotype of COVID-19 enough to be con-

sidered an associated factor (risk or protec-

tive) (OR (95% CI) = 1.17 (0.43-1.72), 1.04

(0.46-2.35), respectively). Although it was

not statistically significant, this estimation

revealed that the additive model had the

best fit (OR (95% CI) = 1.18 (0.53-2.61); p

= 0.69; Table 2).

DISCUSSION

In the current study, a higher frequency

of the A allele was found in the three groups

analyzed, with a value around 0.8 for the

rs10774671 variant of the OAS1 gene in a

mestizo population with a high Native South

American influence. The contrast between

these values and those observed in other re-

search conducted in various ethnic settings

is striking. In a sample of 301,842 individu-

als from all continents, a higher frequency

of the A allele of 0.6346 was reported

. In

this same database, for Latin American in-

dividuals of Afro-Caribbean ancestry (n =

1,394) and subjects with primarily European

and Native American ancestry (n = 6,656),

the frequencies of the A allele were reported

at 0.5703 and 0.7763, respectively

. A fre-

quency similar to that of the present study

for the A allele (0.796) was reported by a

Mexican study with similar methodological

features

. The allele A determines the differ-

ential expression of isoforms depending on

the virus type. This allele has been the sub-

ject of study for other viral diseases, finding

significant associations as a risk factor for

initial infection with West Nile virus (WNV)

as well as hepatitis C virus (HCV)

Conversely, the worldwide genotype fre-

quencies for AA and GG homozygotes and

heterozygotes were 41%, 18.1%, and 40.9%,

respectively

. These genotype frequencies

are very different from those found in the

present study and in the data from the Mexi-

can population, whose respective genotype

frequencies were 61.2%, 2%, and 36.7%

Both studies analyzed populations (Mexican

Table 1

Allele and genotypic frequencies for the rs10774671 genetic variant

in the OAS1 gene in the groups analyzed.

Variable

General sample

n=100

Group A

n=43

Group B

n=57

(CI 95%)

Alelle§

0.8

0.2

0.81

0.19

0.79

0.21

0.723

1.17 (0.43-1.72)

Genotype§§

A/A

A/G

G/G

62 (62)

36 (36)

2 (2)

27 (62.8)

16 (37.2)

0 (0)

35 (61.4)

20 (35.1)

2 (3.5)

0.347

0.312

1.04 (0.46-2.35)

Group A: individuals with a diagnosis of COVID-19 severe form. Group B: individuals with a diagnosis of COVID-19

asymptomatic or mild clinical severe form. Allelic frequencies are expressed in proportions. Genotypic frequen-

cies are expressed in number of cases and percentages.

p-value of Fisher’s exact test (2x2 contingency table).

§§

p-value of the Exact test (R Studio).

174 Pilataxi et al.

Investigación Clínica 65(2): 2024

and Ecuadorian) composed of several ethnic

groups that underwent a complex process

of biological mixing but with a solid Native

South American component in their popu-

lation structure

27,28

. However, despite their

close geographic and evolutionary proxim-

ity, the genotype frequencies reported for a

Peruvian population (78.8%, 1.2%, and 20%,

respectively) were very different from those

of the present study. This difference could be

explained by the fact that the data collected

for the Peruvian population belongs to the

results published by the 1000 Genomes Proj-

ect (1 KGP) with a study design different

from the one used in our study

. Similarly,

the effect of the study’s sample size cannot

be ignored. Despite this, the results for the

Mexican and Peruvian populations and the

current study show a similar frequency of

homozygotes for the minor allele (GG). The

high Native South American component of

these mixed populations could explain this

observation.

No statistically significant differences

were found for allele and genotypic frequen-

cies between groups A and B. Genetic models

developed from the sex-adjusted frequencies

did not support a possible association with

the severe form of COVID-19 in Ecuador-

ian patients. Significant associations were

reported between the rs10774671 allele of

the OAS1 gene and the severe phenotype of

COVID-19 for European populations (OR =

1.33 (1.13-1.56), p = 6.45x10

−4

)

. By con-

trast, for individuals with Sub-Saharan an-

cestry, no significant association was found

(OR = 1.23 (0.98-1.55), p = 0.079) for the

allele A. These findings suggest the possibil-

ity that ethnic differences in genotype and

allele frequencies may account for the in-

consistent results when examining the asso-

ciation between genotype and phenotype for

this locus and COVID-19.

The evolutionary history of South

American ethnic groups may help clarify the

epidemiological findings that suggest these

populations are more susceptible to develop-

ing the severe form of COVID-19. In this con-

text, the G allele of rs10774671 of the OAS1

gene has been associated with a protective

effect against the severe form of COVID-19

for this haplotype in patients of European

ancestry

. The G allele probably has a Nean-

derthal origin, whereas the A allele (which

confers risk in the European population)

is predominantly of Denisovan ancestry

Table 2

Genetic Models for the Estimation of the Association of the rs10774671 genetic variant

of the OAS1 gene and the severe phenotype of COVID-19.

Genetic Models† Group A (n=43) Group B (n=57) p§ OR (CI 95%)

Co A/A

G/G

A/G

27 (62.8)

0 (0)

16 (37.2)

35 (61.4)

2 (3.5)

20 (35.1)

0.34 NC‡

Do A/A+A/

G G/G

43 (100)

0 (0)

55 (96.5)

2 (3.5)

0.14 NC

Re A/A+G/

G A/G

27 (62.8)

16 (37.2)

37 (64.9)

20 (35.1)

0.94 1.04 (0.44-2.42)

Overdo A/G+G/

G A/A

16 (37.2)

27 (62.8)

22 (38.6)

35 (61.4)

0.79 1.12 (0.48-2.60)

- - - 0.69 1.18 (0.53-2.61)

Group A refers to individuals with a diagnosis of COVID-19 severe form and Group B refers to subjects who presen-

ted the asymptomatic or mild clinical form of the disease, § p-value of Fisher’s exact test (2x2 contingency table).

† Genetic Models: codominant (Co), dominant (Do), recessive (Re), overdominant (Over-do) and additive (Ad). ‡

NC: Not calculated.

COVID-19 and OAS1 Gene in Ecuadorian Population 175

Vol. 65(2): 169 - 178, 2024

It is proposed that Sapiens, Neanderthals,

and Denisovans cohabited 100,000 years

ago based on evolutionary history and gene

flow

. Data from genetic analyses of human

fossils indicate that hybridization events oc-

curred between modern humans and Nean-

derthals between 37,000 and 86,000 years

ago

. This hybridization led to the recom-

bination of adaptive alleles that provided

resistance against viruses. However, these

genomic segments of Neanderthal origin

were rapidly eliminated by selective environ-

mental pressure among modern humans

These haplotypes of Neanderthal ancestry

in the Homo sapiens genomes of European

and Asian populations dropped consider-

ably from 10% to 4% and 2%, respectively

Hence, the decline in the frequency of the

GG homozygotes with a protective effect for

the severe form of COVID-19 reported in

Latin American populations could be attrib-

utable to the selective environmental pres-

sure when modern humans migrated to the

Americas from Asia. However, the fixation of

alleles in populations with recent admixture,

such as the Ecuadorian population, may be

influenced by other factors, such as genetic

drift, including bottle-neck and founder ef-

fects. Our investigation’s design study and

statistical power were inadequate to assess

this hypothesis.

The present study has several limita-

tions. None of the analyzed groups presented

HWE for the alleles and genotypes evaluated.

Precautions were taken to avoid genotyping

errors, as different researchers tested molec-

ular analyses to confirm the results separate-

ly. In addition, we have randomly sequenced

10% of the samples to verify the results of

the PCR-RFLP analysis, which showed com-

plete matching of results. Sample size and

stratification might be two more potential

sources of this HWE deviation. We wanted to

take advantage of the outbreak produced by

the Omicron variant of SARS-CoV-2, which

increased the number of patients hospital-

ized in our intensive care unit, selecting

those who had received at least two doses of

the COVID-19 vaccine and contrasting them

with subjects who presented COVID-19 in

the asymptomatic and mild forms. This

would make it possible to find protective al-

leles. However, this selection method intro-

duces a selection bias that may distort the

genetic composition of the groups studied.

Such selection bias could explain the lack of

homozygous genotypes for the minor allele

(GG). The sample size was small, resulting

in even smaller sample sizes when broken

down into two groups for analysis. Thus, the

main limitations of our study were the small

sample size and the lack of a replication-in-

dependent cohort to verify our findings. The

statistical interpretation of the associations

is limited by the reduced sample size in our

study. We know our results may have a type II

error (false negative). Thus, although we did

not find a significant association between

the rs10774671 variant of the OAS1 and the

severe phenotype of COVID-19 in the Ecua-

dorian population, we cannot rule out such

an association. Therefore, we suggest these

associations be further investigated and rep-

licated in other Latin American cohorts with

a more significant number of individuals.

To the best of our knowledge, this study

is the first effort to identify an association

between the rs10774671 of the OAS1 gene

and COVID-19 in mestizo Latin American

groups, as previous studies that involved the

genotyping of this genetic variant did not

assess this relationship. Due to the existing

ethnic heterogeneity, new strategies will be

needed to assess the genetic components

implicated in emerging viral infections in

the Latin American population.

ACKNOWLEDGEMENTS

This study was supported by the Bureau

Direction of Central University of Ecuador,

Quito, Ecuador (Grant No. DI-COVID19-26).

Statement of ethics

The Ethics Committee reviewed and

approved the study protocol for the Expe-

176 Pilataxi et al.

Investigación Clínica 65(2): 2024

dited Review of COVID-19 Investigations

of the Ministry of Public Health of Ecuador

(MSP-CGDES-2020-0244-O1). The ethical

principles of the 1964 Declaration of Hel-

sinki for medical research were adhered to

throughout this research. Before beginning

the study, the procedures and possible dis-

comfort/risks were fully explained to all par-

ticipating subjects. Each then voluntarily

decided to participate in the study, approved

their participation, and signed an informed

written consent form in front of a witness.

Subjects were allowed to withdraw their par-

ticipation in the study at any time without

consequence.

ORCID numbers

• Kathya Pilataxi:

0009-0002-3701-5284

• Thalía Balarezo:

0000-0002-5985-8525

• Erik Chávez:

0000-0001-5571-2441

• Camila Acosta:

0000-0001-6555-4627

• Francisco Álvarez-Nava:

0000-0002-4673-3643

Author Contributions

The authors’ contributions to the paper

are as follows: KP: study concepts and de-

sign, data analysis and interpretation, statis-

tical analysis, critical revision of the manu-

script for important intellectual content and

manuscript preparation; TB: molecular stud-

ies and data analysis; CA: biochemical stud-

ies and data analysis; IZP: acquisition of data

and data analysis; KN: acquisition of data

and data analysis; and FAN: study concepts

and design, data analysis and interpretation,

statistical analysis, obtaining funding, criti-

cal revision of the manuscript for important

intellectual content and manuscript prepa-

ration. All authors read and approved the fi-

nal manuscript.

Conflict of interest

The authors declare that the research

was conducted without any commercial or

financial relationships that could be con-

strued as a potential conflict of interest.

Data Availability Statement

The data supporting this study’s find-

ings are openly available in DOI: 10.5281/

zenodo.7672228 at https://zenodo.org. The

data are publicly available privacy and ethi-

cal restrictions, as stipulated by the Central

University of Ecuador Institutional Review

Board.

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