PEDIATRICS Vol. 121 No. 3 March 2008, pp. 493-496 (doi:10.1542/peds.2007-1889)
ARTICLE |
Increased Concordance of Severe Respiratory Syncytial Virus Infection in Identical Twins
a Department of Respiratory Medicine, Bispebjerg Hospital, Copenhagen, Denmark
b Bandim Health Project, State Serum Institute, Copenhagen, Denmark
c Danish Pediatric Asthma Center, University Hospital of Copenhagen, Gentofte, Denmark
d Danish Twin Registry, University of Southern Denmark, Odense, Denmark
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. We estimated differences in the severity of respiratory syncytial virus infection attributable to genetic and environmental factors.
METHODS. Record linkage data on hospitalizations attributable to respiratory syncytial virus infection were gathered on all twins (12346 pairs) born in Denmark between 1994 and 2003. Latent-factor models of genetic and environmental effects were fitted to the observed data by using maximal likelihood methods.
RESULTS. Identical twins resembled each other significantly more than did fraternal twins for respiratory syncytial virus hospitalization (concordance rate: 0.66 vs 0.53), which suggests genetic influences on disease severity. Genetic factors accounted for 16%, family environment for 73%, and nonshared environment for 11% of the individual susceptibility to develop severe respiratory syncytial virus infection.
CONCLUSIONS. The severity of respiratory syncytial virus infection is determined partly by genetic factors. This result should stimulate the search for genetic markers of disease severity.
Key Words: respiratory syncytial virus • twin study • genetic
Abbreviations: DNPR—Danish National Patient Registry • RSV—respiratory syncytial virus • CI—confidence interval
Respiratory syncytial virus (RSV) affects most children at some point during the first 1 to 2 years of life.1 Clinical manifestations range from mild upper respiratory tract illness, acute otitis media, and pneumonia to severe bronchiolitis. The incidence of hospitalization for treatment of RSV bronchiolitis is reported to be 1% to 3% in westernized countries, and this is one of the most common causes of hospitalization in infancy and early childhood.1 It is not understood why only a small subset of infected patients develop severe disease requiring hospitalization, whereas the majority of patients have mild disease. Prematurity, immunodeficiencies, bronchopulmonary dysplasia, cystic fibrosis, and congenital heart disease are recognized risk factors.2 Even in subjects without preexisting disease, however, RSV severity is subject to individual variation. A genetic polymorphism in the promoter region of the interleukin-8 gene has been reported to be associated with RSV bronchiolitis in patients without other known risk factors.3 Furthermore, polymorphisms in the interleukin-4, interleukin-10, interleukin-13, chemokine receptor CX3CR1, and surfactant protein A and D genes have been implicated in susceptibility to severe disease.4–8 These observations indicate that immunogenetic factors play a role in determining differences in susceptibility to severe RSV infection. With the aim of studying the general contribution of genetic factors to disease severity, we analyzed record linkage data on RSV hospitalizations for all twins born in Denmark between 1994 and 2003.
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METHODS |
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Study Population
The study population comprised all live-born Danish twin pairs born between 1994 and 2003.9 In 2003, zygosity for twin pairs from the 1994 to 2000 birth cohorts was assessed as part of a multidisciplinary questionnaire survey, by using 4 questions on similarity and mistaken identity (response rate: 68%).9 Zygosity was assessed correctly for >96% of the twin pairs with these questions.10 In total, zygosity was determined for 69.3% of the population born in 1994 to 2003.
Information on RSV infection was gathered from the Danish National Patient Registry (DNPR)11 and the RSV database.12 The DNPR records all hospitalizations in Denmark from 1977 onward. A RSV case is defined as a child with 
1 of the following discharge diagnoses (based on the International Statistical Classification of Diseases and Related Health Problems, 10th Revision): J12.1, RSV pneumonia; J20.5, RSV bronchitis; J21.0, RSV bronchiolitis; B97.4, other disease caused by RSV. The RSV database recorded data on hospitalized children with verified RSV antigen, as tested with an enzyme-linked immunosorbent assay or immunofluorescence assay, from 1996 to 2003. Data on birth weight (in grams) and maternal smoking during pregnancy (yes/no) were collected from the DNPR.
Statistical Analyses
Classic twin studies are based on the assumption that identical twins share not only all of their genes but also their upbringing and early environment. In contrast, fraternal twins share only 50% of their genes (in addition to their upbringing and early environment). Therefore, if identical twins resemble each other more for a disease, compared with fraternal twins, then genetic factors are assumed to contribute to the development of that disease.
Probandwise concordance for RSV hospitalization was calculated for the different gender-zygosity groups. The probandwise concordance denotes the probability that one twin would be affected if the co-twin is affected. Because we had complete ascertainment of cases, the concordance could be estimated as 2 times the number of concordant affected pairs (both twins are affected) divided by 2 times the number of concordant affected pairs plus the number of discordant pairs (1 twin is affected).13
Age (in days) at the first hospitalization for treatment of RSV infection was modeled with a Cox proportional-hazards regression model. In this analysis, the time to hospitalization for a co-twin of an affected twin was the underlying time. Age at onset, gender, maternal smoking during pregnancy, and birth weight were covariates.
Tetrachoric correlations were estimated with a multifactorial threshold model.14 Tetrachoric correlations are measures of similarity for dichotomous variables that estimate what the correlation would be if the variables were measured on a continuous scale; therefore, they represent the correlation between RSV hospitalizations for twin 1 and twin 2 within a twin pair.14 Birth weight and maternal smoking during pregnancy were incorporated into the threshold model, which allowed them to affect the liability thresholds for RSV hospitalization.
Latent-factor models for genetic and environmental effects were fitted to the observed data.14 These models, which are standard in twin analyses, assumed that the individual susceptibility to RSV hospitalization was a linear function of additive genetic effects (loci contributing additively to disease risk, designated A), shared environmental effects (environmental factors that increase the resemblance between members of the same family, designated C), and nonshared environmental effects (influences unique to an individual, designated E).15 From biometrical genetic theory, the expected covariance is A + C for identical twin pairs, whereas it is 0.5A + C for fraternal twins. Nested submodels were subsequently fitted by successively fixing the different variance components to 0. The difference in log likelihood between the saturated and nested models provided an estimate of the significance of the contribution of the individual variance components to disease susceptibility. P values of <0.05 were considered to be statistically significant. The statistical package Mx was used for the analyses.16 The protocol was evaluated and approved by the scientific ethics committee.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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A total of 12346 twin pairs (24692 subjects) were identified and linked to information on hospitalizations attributable to RSV infection (referred to as severe RSV infection/severe disease), yielding 1417 cases. Of these, 302 subjects (21%) experienced
1 additional hospitalization attributable to RSV. The distribution of subjects with severe RSV infection is shown in Table 1. The sample ranged from 2 to 12 years of age when record linkage was performed. The overall cumulative (lifetime) prevalence of severe RSV infection was 5.7%, with boys being more affected than girls (6.2% vs 5.2%; odds ratio: 1.20; 95% confidence interval [CI]: 1.07–1.33; P = .001). The prevalence of severe RSV infection was the same in identical and fraternal twins (7.4% vs 6.2%; P = .15).
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We found significantly higher concordance rates and correlations in susceptibility to severe RSV infection in identical twin pairs, compared with fraternal twin pairs (P = .02), which indicates a genetic contribution to disease severity. The hazard ratio between identical and fraternal twins, as estimated in a time-to-event analysis, was 1.43 (95% CI: 1.03–2.00; P = .03), which suggests that the time to concordance for identical twins is shorter than that for fraternal twins. The 1-year probabilities of avoiding hospitalization were 50% for a co-twin of an affected identical twin and 65% for a co-twin of an affected fraternal twin. In twin pairs concordant for severe RSV infection, the diagnosis was made simultaneously (within 2 weeks) in 96% of the cases in identical twins and in 93% of the cases in fraternal twins (Fig 1).
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Results from variance-component analysis are shown in Table 2. A model that included effects of additive genetic factors and shared and nonshared environmental factors described individual susceptibility to severe RSV infection best. Variance structures were not significantly different for boys, compared with girls, with genes (heritability) accounting for 16%, shared environment for 73%, and nonshared environment for 11% of the individual susceptibility to develop severe RSV infection. Restricting the analysis to include only cohorts born between 1994 and 2000, for which zygosity determination was systematic, gave parameter estimates that were slightly more in favor of a genetic explanation (heritability: 19%). The change was statistically insignificant, however, which indicates that the analytic sample was representative of the entire population. An analysis confined to subjects in whom severe RSV infection was present if the case appeared in both the DNPR and the RSV database indicated even-tighter genetic control of disease severity (concordance rate for identical twins: 0.61; concordance rate for fraternal twins: 0.45; P = .01; heritability: 22%).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This study of a nationwide twin cohort showed that the severity of RSV infection is determined partially by genetic factors. Approximately 20% of the propensity to develop severe RSV infection was attributable to genetic differences. Our data indicated that household environment explained 73% of the variation in the severity of RSV infection, consistent with the infectious nature of the disease.
Our large sample size provided sufficient power to estimate this modest genetic influence. Furthermore, we were able to describe RSV infection in several dimensions, on the basis of both hospitalization and laboratory data. This increases the validity of our conclusions. Finally, our sample was drawn from nationwide registries, avoiding bias from recall and selection. However, the tendency for parents to admit both twins if only one was severely affected likely deflated our estimate of genetic effects. In this respect, a smoother (nonordinal) outcome measure might have strengthened our conclusion. Similarly, inclusion of additional confounding factors in the analysis might have provided us with additional reassurance. In particular, because identical twins could be suspected to share several prenatal and postnatal determinants of RSV infection to a greater extent than fraternal twins, additional information on, for example, prematurity would have made us more confident that we have not overestimated the influence of genetics.
Our findings suggest that host-related differences in genetic makeup cause some subjects to develop more-critical manifestations of RSV infection. This is in keeping with previous reports suggesting that certain cytokine gene polymorphisms are disadvantageous with respect to RSV infection.3–8 The concept of a genetic component reacting with RSV infection opens the possibility of genetic identification of subjects at risk. Eventually determining the genetic defect may lead to the discovery of the mechanisms involved in the deficient immune response, pointing the way to targeted treatments.17
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our study showed that the severity of RSV infection is determined partly by genetic factors. This result should stimulate research into the genetic determinants of disease severity. It is, however, important to realize that a small estimate of genetic variance is not the same as a small effect of individual genotypes. Although only approximately one fifth of the variance in our population was attributable to genetic variance, substantial effects of particular genotypes can still be expected in various populations. Similarly, it is important to note that prenatal and postnatal environmental and sociodemographic factors play equally important roles in determining the course of infection. In particular, a substantial role of genetic factors does not preclude the possibility that the development of the disease can be modified by environmental intervention.
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ACKNOWLEDGMENTS |
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Dr Thomsen is sponsored by a Danish Medical Research Council grant.
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FOOTNOTES |
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Accepted Aug 21, 2007.
Address correspondence to Simon Francis Thomsen, MD, PhD, Department of Respiratory Medicine, Bispebjerg Hospital, Bispebjerg Bakke 23, Building 60 DK-2400 Copenhagen NV, Denmark. E-mail: sft{at}city.dk
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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