SP-A1, SP-A2 and SP-D gene polymorphisms in severe acute respiratory syncytial infection in Chilean infants

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Abstract

Respiratory syncytial virus (RSV) is the principal pathogen that causes acute lower respiratory tract infection (ALRI) in infants. Severe RSV-ALRI has been associated with the host genetic susceptibility. To assess whether severe RSV disease in infants is associated with certain single nucleotide polymorphism (SNP) into the gene of SP-A1, SP-A2 and SP-D, a prospective study was performed among blood donors and RSV-infected infants aged < or = 6 months, considering their severity, according to a strict scoring system. Allele and genotype frequencies were compared using χ2-test. Association studies and haplotype analysis were tested by using Armitagës trend test and Unphased 3.0 program.

A total of 118 RSV-infected infants and 104 blood donors were enrolled into the study; 59 infants had a severe respiratory disease, 34 children developed a moderate illness and 25 had a mild disease. There was no difference in the allelic and genotypic frequencies of SP-A1, but intragenic haplotypes showed significant differences among infected infants and blood donors (p = 0.0021). 1A0 variant of SP-A2 was the most frequent allele in all groups. Thr11 allele of SP-D is significantly higher in RSV infants (p = 0.028), as given by its higher frequency in severe disease (p = 0.046). Heterozygous Thr11/Met11 was significantly more common in infected infants (p = 0.037), because it has higher frequency in critically ill children (p = 0.017). Thr160 allele was significantly higher in severe infants compared with blood donors (p = 0.046) and infants with mild disease (p = 0.018). Thr11-Thr160-Ser270 haplotype was significantly more common in RSV-infants, due to severe (p = 0.00000034) and moderate disease (p = 0.000009). Differences were also found among severe and mild disease (p = 0.026). Differences found with other authors, indicate the need for local studies to identify genetic biomarkers of severity.

Highlights

► In this work, polymorphisms of SP-A1, SP-A2 and SP-D genes, was performed in Chilean infants with RSV-ALRI. ► Infants- SNP comparison was done according to their clinical severity and with general population. ► This is a study of genetic susceptibility for RSV infection in South-American population. ► Differences found with other authors, indicates the need to identify local biomarkers of severity.

Introduction

Worldwide, respiratory syncytial virus (RSV) is the principal pathogen that causes acute lower respiratory tract infection (ALRI) in infants (Collins and Graham, 2008, Hall, 2001). During the first year of life, over 80% of children got infected with RSV, whereas less than 3% of infants will require hospitalization and 0.5–1% died because of severe bronchiolitis or pneumonia (Boyce et al., 2000, DeVincenzo, 2004, Glezen et al., 1986, Hodes, 1998, Shay et al., 1999). Infants younger than 6 months of age are the major risk group to have severe illness, but many other conditions including premature birth, chronic pulmonary disease, congenital heart disease, immunodeficiency, home-smokers and low levels of maternal RSV antibodies increase the risk of developing severe RSV disease (Collins and Graham, 2008). In Chile, RSV is the most frequent cause of ALRI causing yearly winter outbreaks with a fatality rate of 0.1%. Bronchiolitis is the principal clinical diagnosis at admission (Avendaño et al., 2003, Palomino et al., 2004).

Natural RSV infection is manifested differently in each individual. Although 100% of the children would have acquired the infection by 2 years of age, only a small proportion will have a respiratory disease that endangers their lives. Although there are certain risk conditions, these factors are still controversial in previously healthy children (Kingma and Whitsett, 2010). In the last few years severe RSV-ALRI has been associated with the host genetic susceptibility, which involves many genes related to the human immune response and surfactant proteins (Hill, 2006, Hoebee et al., 2003, Miyairi and DeVincenzo, 2008, Puthothu et al., 2006, Puthothu et al., 2007a, Rämet et al., 2011).

Pulmonary surfactant is composed of 90% phospholipids and 10% proteins, including the hydrophilic surfactant proteins A (SP-A) and D (SP-D), and the hydrophobic surfactant B (SP-B) and C (SP-C). This complex is essential for normal ventilatory functions, because it reduces the surface tension at the air–liquid interface of the alveoli and to prevent generalized lung collapse. Surfactant proteins not only perform pulmonary functions, but also contribute with lung innate immune response, like SP-A and SP-D proteins (Floros et al., 2009, Pastva et al., 2007). Both proteins are colagenous proteins, belonging to the C-lectines family or “collectins” (collagen-lectin family). SP-A gene is located on chromosome 10q22-q23 and two functional genes are recognized, the SP-A1 and SP-A2 gene and a pseudogen. SP-D gene is also located on chromosome 10q22-q23 and is associated with several immunomodulatory functions, including bind and aggregate several pathogens as bacterial, fungal, virus and mycobacterial (McCormack and Whitsett, 2002, Pastva et al., 2007). Several surfactant gene polymorphism candidates have been proposed to explain the association between host susceptibility and respiratory disease (Haataja and Hallman, 2002). SP-A and SP-B have been associated with respiratory distress syndrome in preterm infants, congenital alveolar proteinosis and chronic obstructive pulmonary disease (Rämet et al., 2000a, Lahti et al., 2002, Löfgren et al., 2002, Haataja and Hallman, 2002, Puthothu et al., 2007b). Certain alleles and genotypes of SP-A and SP-D gene have been associated with a high risk of severe RSV infection (El Saleeby et al., 2010, Lahti et al., 2002, Löfgren et al., 2002, McCormack and Whitsett, 2002). At least two single nucleotide polymorphisms (SNPs) in SP-D gene have been associated with severe RSV infection (Lahti et al., 2002, Thomas et al., 2009).

The aim of the present study was to evaluate the susceptibility of previously healthy Chilean infants to develop severe RSV infection, according to the presence of certain alleles and genotypes into the SNPs of the SP-A1, SP-A2 and SP-D genes.

Section snippets

Subjects

We have established a surveillance for community-acquired respiratory viruses in children < 2 years of age, admitted for ALRI to the Roberto del Rio Children's Hospital, in Santiago of Chile since 1988 as previously described in detail (Avendaño et al., 1991, Larrañaga et al., 2000, Larrañaga et al., 2007, Larrañaga et al., 2009). For the purpose of this study, 118 previously healthy term infants, between 28 days of life and 6 months old, with a normal weight at birth, hospitalized in a regular

Demographic and clinical results

Demographic and clinical data are presented in Table 2. There were no differences in sex, or age between children with severe, moderate and mild RSV infection. Similarly there were no gender differences between infants and controls. A total of 118 infants enrolled were confirmed as positive for RSV. They were classified according to the previously implemented clinical scoring system (Larrañaga et al., 2009): 59 of these had a severe respiratory disease, 34 developed moderate illness and 25 had

General framework of the study

The studies of biomarkers of genetic risk of the host, such as the analysis of single nucleotide polymorphisms, are an emerging tool in recent years that also finds its place in the field of infectious diseases (Hill, 2006, Miyairi and DeVincenzo, 2008). Genetic variability of different human populations requires local or regional studies, to validate the condition of risk or increased host-susceptibility in certain disease, as is the case of serious infectious diseases with certain pathogens.

Conclusions

Although we did not obtain parental samples, which can be considered a limitation of this study, in our view this paper is a contribution in two issues. First, we study host-genetic susceptibility against severe RSV infection, by analyzing SNPs previously described, but in a different population as the Admixture of Caucasian and South Amerindian population. Second, it provides a new look, which is to characterize clinically the RSV disease that allows us validating or rejecting differences in

Acknowledgements

This study was supported by Fondo Nacional de Ciencia y Tecnología: Grant FONDECYT 1050513. We thank Dr. José Suazo of the Programa de Genética Humana, ICBM, for their support in the genetic analysis of the data.

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