The His131Arg substitution in the FCGR2A gene (rs1801274) is not associated with the severity of influenza A(H1N1)pdm09 infection
Maestri et al. BMC Res Notes
The His131Arg substitution in the FCGR2A gene (rs1801274) is not associated with the severity of influenza A(H1N1)pdm09 infection
Alvino Maestri 0 3
Vinicius Albuquerque Sortica 2
Deimy Lima Ferreira 1
Jessylene de Almeida Ferreira 1
Marcos Antônio Trindade Amador 5
Wyller Alencar de Mello 1
Sidney Emanuel Batista Santos 2 5
Rita Catarina Medeiros Sousa 4
0 Alvino Maestri Neto, Laboratório de Genética Humana e Médica, Universidade Federal do Pará , Cidade Universitária Prof. José da Silveira Neto, Rua Augusto Corrêa, 01, BOX 8615, CEP 66.075-970 Belém, Pará , Brazil
1 Laboratório de Vírus Respiratórios, Seção de Virologia Instituto Evandro Chagas , Ananindeua, Pará , Brazil
2 Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará , Belém, Pará , Brazil
3 Alvino Maestri Neto, Laboratório de Genética Humana e Médica, Universidade Federal do Pará , Cidade Universitária Prof. José da Silveira Neto, Rua Augusto Corrêa, 01, BOX 8615, CEP 66.075-970 Belém, Pará , Brazil
4 Instituto Evandro Chagas, Universidade Federal do Pará , Belém, Pará , Brazil
5 Laboratório de Genética Humana e Médica, Universidade Federal do Pará , Belém, Pará , Brazil
Background: The virulence and pathogenicity of different influenza strains are responsible for a more or less severe disease. Recent studies have attempted to understand how host genetic factors may influence the clinical presentation of the disease. In the present study, the His131Arg (rs1801274) polymorphism was investigated in individuals from a Brazilian admixed population with a diagnosis of influenza A(H1N1)pdm09 infection. Methods: In the present study, the influence of the His131Arg (rs1801274) polymorphism, a variant of the FCGR2A gene, was investigated in 436 patients with a diagnosis of influenza A(H1N1)pdm09, evaluated at health services in the northern and northeastern regions of Brazil between June 2009 and August 2010. Patients were divided into a group of non-hospitalized patients (n = 192) and a group of hospitalized patients (n = 244; 100 of them died). Results: No significant difference in the allele or genotype frequencies of the rs1801274 polymorphism was observed between groups (p = 0.952 and p = 0.388). Multinomial logistic regression showed no effect of the rs1801274 polymorphism on severity or death of patients from the Brazilian admixed population (p = 0.368 and p = 0.469). Conclusions: The rs1801274 polymorphism is not associated with severe disease in patients infected with influenza A(H1N1)pdm09.
A(H1N1)pdm09 infection; Influenza; FCGR2A
Influenza, or the flu, is an acute respiratory tract
infection caused by the influenza virus, which shows a global
distribution and high transmissibility. In April 2009,
the Centers for Disease Control and Prevention (CDC)
reported two cases of influenza in children from
California, USA [
], caused by a new influenza strain. This
strain originated from the genetic rearrangement of four
other circulating viruses and resulted in the first
influenza pandemic in the 21st century [
]. The increase in
severe cases and deaths among children and young adults
called attention during the pandemic period [
the death rate exceeding annual figures [
]. The estimated
rate of deaths caused by the 2009 pandemic influenza
A(H1N1)pdm09 worldwide was 65 % in individuals
aged 18–64 years [
]. In contrast, in southern Brazil, the
median annual rate of underlying respiratory/circulatory
deaths was 70 % in patients aged ≥60 years between 2000
and 2008 [
Although the virulence and pathogenicity of different
viral strains are responsible for a more or less severe
disease, recent studies have attempted to understand how
host genetic factors may influence the clinical presentation
of the disease, considering signaling pathways activated
by viral infection [
], as well as pathways activated by the
immune system in an attempt to promote viral clearance
]. Recent studies have tried to identify host genetic
variants that could explain severe cases of the disease: TNF [
], CCR5 [
], and ST3GAL1 .
In 2012, a case–control study was published in which
91 patients who developed severe pneumonia caused by
influenza A(H1N1)pdm09 were compared to 98
asymptomatic household contacts. The results showed that 36.6 %
of the patients with severe pneumonia were homozygous
for allele A of the rs1801274 variant of the FCGR2A gene,
which encodes a histidine (His) at position 131 of the
protein, while only 13.2 % of the contacts who did not develop
the disease carried this variant. The authors concluded
that this variant of the FCGR2A gene may be related to
greater susceptibility to severe forms of the disease [
FCGR is a glycoprotein that binds to the Fc region of
immunoglobulin G, triggering immune responses such as
pathogen phagocytosis, clearance of immune complexes,
antigen presentation, and degranulation [
]. Five genes are
found on chromosome 1 (FCGR2A, FCGR2B, FCGR2C,
FCGR3A, and FCGR3B), which encode five receptors with
low affinity for this glycoprotein. The activation or
inhibition of these receptors determines the local inflammatory
]. The genetic variant of the IgG Fc receptor
at position 131 has been associated with susceptibility to
inflammatory and infectious diseases [
]. In the
present study, the His131Arg (rs1801274) polymorphism was
investigated in individuals from a Brazilian admixed
population with a diagnosis of influenza A(H1N1)pdm09 infection.
In the present study, the His131Arg substitution in the
FCGR2A gene (rs1801274) was studied in nasopharyngeal
swab samples obtained from 436 subjects that were
randomly selected among 1524 cases from the northern and
northeastern regions of Brazil diagnosed with influenza
caused by strain A(H1N1)pdm09 between June 2009 and
August 2010. Collection of the material during the study
was accompanied by filling out a notification form of the
Brazilian National System of Medical Care (SINAM),
which contained the clinical data of the patient.
Viral detection was carried out at the Laboratory of
Respiratory Viruses, virology section of the Evandro
Chagas Institute (Seção de Virologia do Instituto Evandro
Chagas—SEVIR/IEC), Ananindeua, Pará, Brazil, using
the SuperScript III™ One-Step RT-qPCR System with
Platinum® Taq (Invitrogen Life Technologies). Using the
same material, genomic DNA was extracted from patient
samples with the QIAamp DNA Mini Kit (Qiagen)
according to manufacturer instructions. The extracted DNA was
quantified in a NanoDrop spectrophotometer
(Uniscience®) at 260 to 280 nm and submitted to real-time PCR
using the C__9077561_20 TaqMan® assay (Applied
Biosystems) according to manufacturer instructions. The
proportions of African, European and Amerindian genetic
ancestry of the patients were estimated using a panel of 48
ancestry informative markers as described elsewhere [
The allele and genotype frequencies of the
polymorphism studied were estimated by direct counting. The
individual proportions of genetic ancestry were
estimated using the STRUCTURE 2.3.3 software [
Differences in the main characteristics between the groups
of patients were verified using the Student t test, Fisher’s
exact test and Kruskal–Wallis test. Fisher’s exact test was
also applied to evaluate differences in the allele and
genotype frequencies of the His131Arg (rs1801274)
polymorphism between the groups of patients. Multinomial
logistic regression controlling for age, comorbidities and
European and African ancestry was performed to evaluate
the existence of an association between the polymorphism
and severity of infection. Statistical analysis was performed
using the SPSS18.0 software, adopting a level of
significance of p < 0.05.
Ethics approval and consent to participate
All patients enrolled in the study provided their written
informed consent. The study was approved by the Ethics
Committee of the Center of Tropical Medicine, Federal
University of Pará (Núcleo de Medicina Tropical,
Universidade Federal do Pará).
The sample of 436 subjects with the disease was divided
into two groups (Table 1) according to disease
progression: a group of non-hospitalized patients (n = 192)
and a group of hospitalized patients (n = 244; 100
of them died). The characteristics of the subjects are
shown in Table 1. There was a predominance of women
(62.8 %, n = 247), with a mean age of 24.6 years. Of
these (n = 247), 193 were of child-bearing age, 63 were
pregnant, and 40 required hospitalization (22 died). The
absence of comorbidities in non-hospitalized patients
was significant (p = 0.007). Among patients with
comorbidities (n = 150), metabolic disorders (p = 0.001),
immunosuppression (p < 0.001) and obesity (p = 0.001)
were the most frequent in severe cases of the disease.
The study of genetic ancestry in the population
studied showed a median European contribution of 61.3 %, an
Age is reported as the mean ± SD, genetic ancestry is reported as the median (minimum; maximum), and all other variables are reported as absolute number (%)
a Fisher’s exact test
b Student t-test
c Kruskal–Wallis test
Amerindian contribution of 20.1 %, and an African
contribution of 13.2 %. The frequency of the homozygous AA
genotype of the His131Arg polymorphism was 38 % in
nonhospitalized patients, 32.6 % in hospitalized patients who
survived, and 37 % in hospitalized patients who died, with
no significant difference among groups (p = 0.388).
Multinomial logistic regression controlling for European and
African genetic ancestry, comorbidities and age revealed
no significant association between the FCGR2A genotypes
and severity of the disease (hospitalization) or death of the
patients (p = 0.368 and p = 0.469, respectively).
A case–control study followed by a meta-analysis
demonstrated an increased risk of developing Kawasaki
disease in carriers of allele A in the Chinese Han population
]. In another meta-analysis, the His131Arg
polymorphism in the FCGR2A gene was found to be associated
with susceptibility to systemic lupus erythematosus and
lupus nephritis in Asian populations [
polymorphism was also associated with bacteremia and the
severity of pneumonia in patients hospitalized in Spain
]. In contrast, in intensive care unit patients with a
diagnosis of invasive Streptococcus pneumoniae
infection (202 with pneumonia and 55 with meningitis), the
GG genotype (guanine) of the FCGR2A His131Arg
polymorphism exerted a protective effect (OR 0.32) [
Although allele A of the FCGR2A gene (rs1801274) has
recently been associated with greater susceptibility to severe
forms of infection with influenza A(H1N1)pdm09 in the
Mexican population in which the Amerindian contribution
is high (approximately 60 %) [
], the present study found
no association of this polymorphism with more severe
influenza infection in the Brazilian admixed population. These
discordant results may be attributed to differences in the
genetic composition of the populations studied.
The present study included a large sample and the
symptoms of the patients were rigorously
characterized, facts that support the results found. Some studies
have reported an association between the His131Arg
(rs1801274) polymorphism in the FCGRA gene and more
severe influenza infection. Our findings demonstrate that
the polymorphism is not associated with an unfavorable
outcome in patients infected with influenza A(H1N1)
pdm09 in the Brazilian admixed population. Further
studies are needed to better understand the effects of
host genetic variants on the susceptibility to and severity
of infections caused by influenza A(H1N1)pdm09.
CDC: Centers for Disease Control and Prevention; IEC: Evandro Chagas
Institute; SEVIR: virology section; WHO: World Health Organization; A: adenine; G:
AMN conceived the study, conducted the study, and prepared the
manuscript. VAS performed the data analysis and interpretation and drafted the
manuscript. DLF, JAF and MATA participated in sample and data collection.
WAS, SEB and RCM conceived the study and drafted the manuscript. All
authors read and approved the final manuscript.
AMN was the recipient of a Doctoral fellowship from the Brazilian Ministry
of Health (Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior—CAPES) and the Abroad Sandwich Doctorate Program (Programa de
Doutorado Sanduíche no Exterior—PDSE).
The authors declare that they have no competing interests.
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