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Original Research: Chest Infections |

Surfactant Protein B Gene Polymorphism Is Associated With Severe InfluenzaSurfactant Protein B and Influenza FREE TO VIEW

Kelvin K. W. To, MD; Jie Zhou, PhD; You-Qiang Song, PhD; Ivan F. N. Hung, MD; Whitney C. T. Ip, BSc; Zhong-Shan Cheng, MPhil; Andy S. F. Chan, BSc; Richard Y. T. Kao, PhD; Alan K. L. Wu, MD; Sandy Chau, MD; Wei-Kwang Luk, MD; Mary S. M. Ip, MD, FCCP; Kwok-Hung Chan, PhD; Kwok-Yung Yuen, PhD
Author and Funding Information

From the State Key Laboratory for Emerging Infectious Diseases (Drs To, Kao, K.-H. Chan, and Yuen), Carol Yu Centre for Infection (Drs To, Hung, K.-H. Chan, and Yuen), Research Centre of Infection and Immunology (Drs To, Zhou, Hung, Kao, K-H. Chan, and Yuen), Department of Microbiology (Drs To, Zhou, Kao, K.-H. Chan, and Yuen; Ms W. C. T. Ip; and Messrs Cheng and A. S. F. Chan), Department of Biochemistry (Dr Song), and Department of Medicine (Drs Hung and M. S. M. Ip), The University of Hong Kong, Pokfulam; Department of Pathology (Dr Wu), Pamela Youde Nethersole Eastern Hospital, Hong Kong Special Administrative Region; Department of Pathology (Dr Chau), United Christian Hospital, Hong Kong Special Administrative Region; and the Department of Pathology (Dr Luk), Tseung Kwan O Hospital, Hong Kong Special Administrative Region, China.

Correspondence to: Kwok-Yung Yuen, PhD, Carol Yu Centre for Infection and Division of Infectious Diseases, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Rd, Pokfulam, Hong Kong Special Administrative Region, China; e-mail: kyyuen@hku.hk


For editorial comment see page 1186

Funding/Support: This study is supported by the Health and Medical Research Fund of the Food and Health Bureau of the Hong Kong SAR Government [Project No. 13120842] and the Providence Foundation Limited, in memory of the late Dr Lui Hac Minh.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(6):1237-1243. doi:10.1378/chest.13-1651
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Background:  Surfactant proteins play a key role in alveolar stability. We examined whether single nucleotide polymorphisms (SNPs) related to the surfactant protein genes are associated with severe influenza.

Methods:  In the first cohort, 12 SNPs related to surfactant protein genes were compared between Chinese patients with severe and mild pandemic 2009 influenza A(H1N1) (A[H1N1]pdm09) infection who were matched for age, sex, and underlying risk conditions. The SNP rs1130866, which was significantly different between the two groups, was further genotyped in a second cohort of patients. Multivariate analysis was performed to control for confounding factors. The genotype frequencies were also compared with those of the general Han Chinese population.

Results:  This study consisted of 380 patients with A(H1N1)pdm09 infection. In the first cohort of 84 patients, the C allele of rs1130866, an SNP in the surfactant protein B gene (SFTPB), was significantly associated with severe disease (OR = 3.37, P = .0048), although the P value was .057 after Bonferroni correction. In the second cohort of 296 patients, the C/C genotype was confirmed in the univariate analysis to be associated with severe disease. Multivariate analysis of the second cohort showed that genotype C/C was an independent risk factor for severe A(H1N1)pdm09 infection (second cohort: OR = 2.087, P = .023). Compared to the general Han Chinese population, the C/C genotype was overrepresented in patients with severe A(H1N1)pdm09 infection (OR = 3.232, P = .00000056).

Conclusions:  SFTPB polymorphism is associated with severe influenza. The role of SFTPB in influenza warrants further studies.

Figures in this Article

There are an estimated 3 million to 5 million severe influenza cases annually worldwide.1 The avian influenza virus subtypes A(H5N1) and A(H7N9), and the pandemic 2009 influenza A(H1N1) (A[H1N1]pdm09) virus with D222G mutation are particularly virulent.25 Most patients with severe infection have risk factors including extremes of age, pregnancy, and underlying diseases.6 Obesity was identified as a new risk factor during the 2009 pandemic influenza, and leptin was found to be an important pathogenic mediator in a mouse model of diet-induced obesity.7,8 A lower IgG2 level was found in patients with severe A(H1N1)pdm09 infection.9 However, it remains unexplained why many young healthy individuals without these risk factors developed life-threatening illnesses, especially during influenza pandemics.1012

Differences in host genetic background may affect disease outcome. In recent years, single nucleotide polymorphisms (SNPs) have been used to determine genetic predisposition to infectious diseases.13,14 In our previous study, conducted during the A(H1N1)pdm09 influenza pandemic, we performed a small-scale genomewide association study comparing patients with severe A(H1N1)pdm09 infection and those with mild A(H1N1)pdm09 infection and subsequently identified that genotype T/T of the SNP rs2564978, which is linked to a functional variant of the CD55 promoter, was associated with severe disease.15 Other genetic polymorphisms associated with severe influenza were identified in SNPs related to Fc fragment of IgG, low-affinity IIA receptor; RPA interacting protein; complement component 1, q subcomponent binding protein; toll-like receptor 3; killer-cell Ig-like receptors; and interferon-inducible transmembrane 3.1620

Previous studies have shown the association between polymorphisms in the surfactant protein genes and severe respiratory diseases,2123 and surfactant proteins can affect influenza virus replication in vitro.24,25 Furthermore, surfactant therapy has been used as the salvage therapy in a child with severe A(H1N1)pdm09 infection.26 In the current study, we used a candidate gene approach to evaluate whether SNPs related to surfactant protein genes are related to severe influenza.

Patients

Patients with A(H1N1)pdm09 virus infection were diagnosed between May 2009 and January 2012. Patients were included if their respiratory tract specimens were positive for A(H1N1)pdm09 virus by reverse transcription-polymerase chain reaction or viral culture.11,27 Clinical information was retrieved from the clinical management system as described previously.15 Patients were excluded if they were aged < 18 years, were non-Chinese, their archived specimens were not sufficient for testing, or the essential clinical information could not be retrieved from the clinical management system. Patients with severe disease were defined by at least one of the following criteria, as we described previously15: required oxygen supplementation, required admission to the ICU, or died. Patients with mild disease were those who did not satisfy the criteria for severe disease. Underlying risk conditions for severe disease were classified according to the definitions of the World Health Organization.6 The first cohort consisted of patients with severe infection and patients with mild infection, matched by age, sex, and number of underlying risk conditions (Table 1).6 The second cohort consisted of patients not included in the first cohort but who fulfilled the inclusion criteria. Patients with severe or mild disease in the second cohort were not matched for age, sex, and underlying risk factors. This study was approved by the institutional review board of the University of Hong Kong/Hospital Authority of Hong Kong West Cluster (reference number UW 10-411).

Table Graphic Jump Location
Table 1 —Demographics and Underlying Risk Conditions of Patients With A(H1N1)pdm09 Infection in This Study

Data are given as No. (%) unless otherwise stated. A(H1N1)pdm09 = pandemic 2009 influenza A(H1N1); IQR = interquartile range; na = not applicable.

DNA Extraction and Genotyping

Genomic DNA was extracted from archived ethylenediaminetetraacetic acid blood specimens using the QIAamp DNA blood minikit (Qiagen NV) or from respiratory tract specimens using the QIAamp DNA kit (Qiagen NV) as described previously.9,28 Genotyping was performed as described previously.15 The first cohort was genotyped using Genome-Wide Human SNP Array 6.0 (Affymetrix Inc). The SNP rs1130866 was genotyped in the second cohort of patients using Sequenom MassARRAY System (Sequenom Inc).

Statistical Analysis

Genetic association was analyzed using PLINK29 and PASW Statistics 18, release 18.0.0 (IBM). Bonferroni multiple-test correction was performed to correct for multiple testing. Severe cases were compared with mild cases or with the general population using the Han Chinese genotypes in the 1000 Genomes Project sequencing database (Beijing Han Chinese and Southern Han Chinese).30 The Fisher exact test and Mann-Whitney U test were used for the comparison of categorical variables and continuous variables, respectively. To determine whether an SNP was independently associated with severe disease, backward stepwise multivariate regression analysis was used to control for confounding clinical risk conditions. Colinearity diagnostic testing was performed to exclude variables that may be highly correlated. A P value < .05 was considered statistically significant.

A(H1N1)pdm09 Infection

In the first cohort, 42 patients with severe disease were compared with 42 patients with mild disease who were matched for age, sex, and number of risk conditions (Table 1). There was no significant difference between severe and mild cases in the demographics and different underlying conditions. The median age was 48 years with an interquartile range of 39 to 56 years; the male to female ratio was 1:1. Among the 42 severe cases, 31 required positive pressure ventilation (73.8%), 31 required admission to the ICU (73.8%), and 10 died (23.8%). The SNP rs1130866, which is related to the surfactant protein B gene (SFTPB), was the only SNP related to surfactant protein that was significantly different between severe and mild cases with a P value < .05 in the allelic χ2 test (OR = 3.37; 95% CI, 1.404-8.097; P = .0048) (Fig 1A, e-Table 1), although the P value was slightly > .05 after Bonferroni correction (P = .0576). Other nonsignificant SNPs related to surfactant protein B (SP-B) included in the first cohort were rs7316, rs3024811, rs2118177, and rs4616480. The tested SNPs related to surfactant protein C (rs4715 and rs8192325) and surfactant protein D (rs721917, rs2181204, rs6413523, rs726289, and rs2819096) were not significantly different between the severe and mild cases. Although the corrected P value for rs1130866 was borderline for statistical significance, it was still much stronger than the next most likely candidate, rs726289 (before Bonferroni correction P = .1598). Therefore, we decided to proceed with further investigation of rs1130866.

Figure Jump LinkFigure 1. A, Single nucleotide polymorphisms (SNPs) in surfactant proteins. SNPs in the surfactant proteins examined in the first cohort of 84 patients. P values are results of comparison between the 42 severe and 42 mild cases. B, The rs1130866 genotype distribution in patients with pandemic 2009 influenza A(H1N1) infection (n = 380) and in the general Han Chinese population (n = 197). Data of the Beijing and Southern Han Chinese population were obtained from the 1000 Genomes Project.30 SFTPB = surfactant protein B gene; SFTPC = surfactant protein C gene; SFTPD = surfactant protein D gene; UTR = untranslated region.Grahic Jump Location

Next, we determined the rs1130866 genotype of an additional 296 patients (111 patients with severe disease and 185 with mild disease) using the Sequenom MassARRAY analysis (Sequenom Inc). Older age, male sex, chronic pulmonary disease, chronic cardiac disease, metabolic disorders, chronic renal disease, neurologic conditions, and obesity were associated with severe disease (Table 1). C/C genotype of rs1130866 was significantly associated with severe disease in univariate analysis (OR = 1.928; 95% CI, 1.152-3.227; P = .012) (Table 2) and multivariate analysis (OR = 2.087; 95% CI, 1.107-3.934; P = .023) (e-Table 2).

Table Graphic Jump Location
Table 2 —Distribution and Univariate Analysis of rs1130866 Genotypes of Patients With A(H1N1)pdm09 in This Study

See Table 1 legend for expansion of abbreviation.

a 

Fisher exact test.

Since obesity was a very strong risk factor for severe disease, we analyzed whether there would any relationship between the rs1130866 C/C genotype and obesity in the second cohort of patients. χ2 Test results showed that there was no significant difference in the rs1130866 C/C genotype between obese and nonobese patients (72.7% vs 64.2%, P = .422). A colinearity diagnostics test showed that there was no multicolinearity problem (tolerance: 0.998). We performed the multivariate analysis after excluding all 22 obese patients and found that the rs1130866 C/C genotype remained a significant risk factor for severe disease (OR = 2.087; 95% CI, 1.107-3.934; P = .023) (e-Table 3).

Comparison With the General Han Chinese Population

We compared the frequency of rs1130866 in the patients with that of the general Han Chinese population using the data from the 1000 Genomes Project (Fig 1B, Table 3).30 The C allele was significantly associated with severe A(H1N1)pdm09 infection for both recessive pattern (OR = 3.232; 95% CI, 2.033-5.139; P = .00000056) and dominant pattern of inheritance (OR = 6.223; 95% CI, 1.401-27.640; P = .006).

Table Graphic Jump Location
Table 3 —Comparison of the rs1130866 Genotypes Between Patients With Laboratory-Confirmed A(H1N1)pdm09 Infection and General Han Chinese Population Obtained From the 1000 Genomes Project Database

See Table 1 legend for expansion of abbreviation.

a 

Fisher exact test.

Human epidemiologic and animal studies suggest that genetic variations may contribute to severe influenza.15,3134 The influenza A(H1N1)pdm09 pandemic provided a unique opportunity to study host genetic susceptibility, as many patients were young healthy individuals without specific preexisting immunity against the influenza A(H1N1)pdm09 virus.10,35 Previous studies have compared genetic differences between severe and mild cases of influenza and have identified several polymorphisms in genes associated with the immune system.9,1520,3638 In the current study, we specifically examined the SNPs associated with the surfactant protein genes. In the first cohort of carefully selected patients, in which the severe and mild cases were well-matched for age, sex, and underlying conditions, only the C allele of the SFTPB SNP rs1130866 was significantly associated with severe A(H1N1)pdm09 infection, although the P value was slightly > .05 after Bonferroni correction. In the second cohort, we confirmed that the C/C genotype of rs1130866 was an independent risk factor for severe disease using multivariate analysis. The C/C genotype was also overrepresented when compared between patients with severe A(H1N1)pdm09 infection and the general Han Chinese population. Thus, we showed an association between a SNP in a gene directly related to pulmonary function and severe influenza.

SP-B is one of the four major surfactant proteins that line the alveoli and lower the surface tension at the alveolar air-epithelial cell interface, thereby avoiding the collapse of the alveoli. Knockout mice lacking SP-B have increased surfactant surface tension, resulting in the narrowing of alveolar capillaries and oxygen desaturation.39 Previous studies have shown that the SNP rs1130866 related to SP-B was associated with severe pneumonia and ARDS in children and adults2123,40 and interstitial lung disease in Japanese patients with systemic sclerosis.41 The association with COPD is controversial.42,43 Other genetic variants of SFTPB have been associated with severe respiratory syncytial virus infection,44 respiratory distress syndrome in neonates,45 congenital alveolar proteinosis46 and squamous cell carcinoma of the lung.47 In our study involving patients with influenza, the C allele of the rs1130866 is overrepresented in the severe-disease group. The SNP rs1130866 is located on chromosome 2 p11.2 in the exon region of the SP-BN region.21 The C allele, but not the T allele, of rs1130866 is associated with glycosylation at position 129 of the SP-B protein, and that glycosylation may affect the processing, folding, or secretion of the SP-B, which may affect the function of this protein.48 It has been shown that glycosylated proSP-B retards the secretion of SP-B in vitro.49 In addition to the effect of surface tension, the N-terminal of the SP-B proprotein also has direct antimicrobial effect.50,51 Furthermore, knockdown of SFTPB with small interfering RNA reduces influenza virus replication in vitro,24 suggesting that the expression of SFTPB is important in the life cycle of influenza A virus.

In the second cohort of patients, obesity was a very strong risk factor for severe disease (19.8% for severe disease vs 0% for mild disease, P < .001). However, the χ2 test, the colinearity diagnostics test, and the multivariate analysis after excluding obesity all showed that obese patients did not affect our finding that C/C genotype of rs1130866 was an independent risk factor for severe disease. Furthermore, previous large-scale, genomewide association studies did not identify any SNPs related to the SP-B that were associated with obesity.52

Our study differs from previous studies in several aspects. First, this study uses well-matched cohorts of severe and mild cases for the first cohort. This would minimize confounding effect from age, sex, or underlying diseases. Second, we only included Han Chinese patients, and, therefore, avoided the potential differences in SNP frequency among different ethnic groups. A limitation of our study is the small number of patients for the first cohort, which limits the power. However, we have carefully chosen the two groups of patients to minimize potential confounding factors. Furthermore, we confirmed our results with a second cohort of patients.

In conclusion, we demonstrated an association between genetic polymorphism in SFTPB and severe influenza infection. Our results supplement other studies in the understanding of the host factors affecting the outcome of influenza. Further functional studies on the rs1130866 will shed light on why this SNP is associated with disease severity.

Author contributions: Drs To and Yuen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr To: contributed to the conception and design of the study; data acquisition, analysis, and interpretation; drafting of the manuscript; and approval of the final version of the manuscript and served as principal author.

Dr Zhou: contributed to the conception and design of the study; data acquisition, analysis, and interpretation; drafting of the manuscript; and approval of the final version of the manuscript.

Dr Song: contributed to the conception and design of the study, interpretation of data, revision of the manuscript for important intellectual content, and approval of the final version of the manuscript.

Dr Hung: contributed to the conception and design of the study, interpretation of data, revision of the manuscript for important intellectual content, and approval of the final version of the manuscript.

Ms W. C. T. Ip: contributed to data acquisition, analysis, and interpretation; revision of the manuscript for important intellectual content; and approval of the final version of the manuscript.

Mr Cheng: contributed to data acquisition, analysis, and interpretation; revision of the manuscript for important intellectual content; and approval of the final version of the manuscript.

Mr A. S. F. Chan: contributed to data acquisition, analysis, and interpretation; revision of the manuscript for important intellectual content; and approval of the final version of the manuscript.

Dr Kao: contributed to the revision of the data analysis and interpretation, revision of the manuscript for important intellectual content, and approval of the final version of the manuscript.

Dr Wu: contributed to data acquisition, analysis, and interpretation; revision of the manuscript for important intellectual content; and approval of the final version of the manuscript.

Dr Chau: contributed to data acquisition, analysis, and interpretation; revision of the manuscript for important intellectual content; and approval of the final version of the manuscript.

Dr Luk: contributed to data acquisition, analysis, and interpretation; revision of the manuscript for important intellectual content; and approval of the final version of the manuscript.

Dr M. S. M. Ip: contributed to revision of the data analysis and interpretation, revision of the manuscript for important intellectual content, and approval of the final version of the manuscript.

Dr K.-H. Chan: contributed to the conception and design of the study, interpretation of data, revision of the manuscript for important intellectual content, and approval of the final version of the manuscript.

Dr Yuen: contributed to the conception and design of the study; data acquisition, analysis, and interpretation; drafting of the manuscript; and approval of the final version of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Additional information: The e-Tables can be found in the “Supplemental Materials” area of the online article.

A(H1N1)pdm09

pandemic 2009 influenza A(H1N1)

SFTPB

surfactant protein B gene

SNP

single nucleotide polymorphism

SP-B

surfactant protein B

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Tredano M, Griese M, de Blic J, et al. Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to SFTPB. Am J Med Genet A. 2003;119A(3):324-339. [CrossRef]
 
Mildenberger E, deMello DE, Lin Z, Kössel H, Hoehn T, Versmold HT. Focal congenital alveolar proteinosis associated with abnormal surfactant protein B messenger RNA. Chest. 2001;119(2):645-647. [CrossRef]
 
Ewis AA, Kondo K, Dang F, et al. Surfactant protein B gene variations and susceptibility to lung cancer in chromate workers. Am J Ind Med. 2006;49(5):367-373. [CrossRef]
 
Wang GR, Christensen ND, Wigdahl B, Guttentag SH, Floros J. Differences in N-linked glycosylation between human surfactant protein-B variants of the C or T allele at the single-nucleotide polymorphism at position 1580: implications for disease. Biochem J. 2003;369(Pt 1):179-184. [CrossRef]
 
Huusko J, Taponen S, Petäjä-Repo UE, et al. Allele-specific glycosylation of ILE131THR variant retards surfactant protein B processing and secretion: basis of predisposition to respiratory distress syndrome. Pediatr Res. 2011;70:656. [CrossRef]
 
Yang L, Johansson J, Ridsdale R, et al. Surfactant protein B propeptide contains a saposin-like protein domain with antimicrobial activity at low pH. J Immunol. 2010;184(2):975-983. [CrossRef]
 
Ryan MA, Akinbi HT, Serrano AG, et al. Antimicrobial activity of native and synthetic surfactant protein B peptides. J Immunol. 2006;176(1):416-425. [CrossRef]
 
Xia Q, Grant SF. The genetics of human obesity. Ann N Y Acad Sci. 2013;1281:178-190. [CrossRef]
 

Figures

Figure Jump LinkFigure 1. A, Single nucleotide polymorphisms (SNPs) in surfactant proteins. SNPs in the surfactant proteins examined in the first cohort of 84 patients. P values are results of comparison between the 42 severe and 42 mild cases. B, The rs1130866 genotype distribution in patients with pandemic 2009 influenza A(H1N1) infection (n = 380) and in the general Han Chinese population (n = 197). Data of the Beijing and Southern Han Chinese population were obtained from the 1000 Genomes Project.30 SFTPB = surfactant protein B gene; SFTPC = surfactant protein C gene; SFTPD = surfactant protein D gene; UTR = untranslated region.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Demographics and Underlying Risk Conditions of Patients With A(H1N1)pdm09 Infection in This Study

Data are given as No. (%) unless otherwise stated. A(H1N1)pdm09 = pandemic 2009 influenza A(H1N1); IQR = interquartile range; na = not applicable.

Table Graphic Jump Location
Table 2 —Distribution and Univariate Analysis of rs1130866 Genotypes of Patients With A(H1N1)pdm09 in This Study

See Table 1 legend for expansion of abbreviation.

a 

Fisher exact test.

Table Graphic Jump Location
Table 3 —Comparison of the rs1130866 Genotypes Between Patients With Laboratory-Confirmed A(H1N1)pdm09 Infection and General Han Chinese Population Obtained From the 1000 Genomes Project Database

See Table 1 legend for expansion of abbreviation.

a 

Fisher exact test.

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Mildenberger E, deMello DE, Lin Z, Kössel H, Hoehn T, Versmold HT. Focal congenital alveolar proteinosis associated with abnormal surfactant protein B messenger RNA. Chest. 2001;119(2):645-647. [CrossRef]
 
Ewis AA, Kondo K, Dang F, et al. Surfactant protein B gene variations and susceptibility to lung cancer in chromate workers. Am J Ind Med. 2006;49(5):367-373. [CrossRef]
 
Wang GR, Christensen ND, Wigdahl B, Guttentag SH, Floros J. Differences in N-linked glycosylation between human surfactant protein-B variants of the C or T allele at the single-nucleotide polymorphism at position 1580: implications for disease. Biochem J. 2003;369(Pt 1):179-184. [CrossRef]
 
Huusko J, Taponen S, Petäjä-Repo UE, et al. Allele-specific glycosylation of ILE131THR variant retards surfactant protein B processing and secretion: basis of predisposition to respiratory distress syndrome. Pediatr Res. 2011;70:656. [CrossRef]
 
Yang L, Johansson J, Ridsdale R, et al. Surfactant protein B propeptide contains a saposin-like protein domain with antimicrobial activity at low pH. J Immunol. 2010;184(2):975-983. [CrossRef]
 
Ryan MA, Akinbi HT, Serrano AG, et al. Antimicrobial activity of native and synthetic surfactant protein B peptides. J Immunol. 2006;176(1):416-425. [CrossRef]
 
Xia Q, Grant SF. The genetics of human obesity. Ann N Y Acad Sci. 2013;1281:178-190. [CrossRef]
 
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