PEDIATRICS Vol. 122 No. 3 September 2008, pp. 479-485 (doi:10.1542/peds.2007-2313)
ARTICLE |
Heritability of Bronchopulmonary Dysplasia, Defined According to the Consensus Statement of the National Institutes of Health
a Department of Pediatrics, Division of Neonatology
c Department of Psychiatry, University of British Columbia, Vancouver, Canada
b Neonatal Program, Children's and Women's Health Centre of British Columbia, Vancouver, Canada
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. The goal was to determine the magnitude of genetic effects on susceptibility and risk factors for bronchopulmonary dysplasia by using the clinically validated National Institutes of Health consensus definition as a demonstrated proxy for long-term respiratory and neurodevelopmental outcomes in extremely low birth weight infants.
METHODS. We analyzed clinical data from twin pairs born at 
30 completed weeks of gestation in British Columbia, Canada, between 1993 and 2006. Differences in correlations between monozygotic and dizygotic twin pairs and model-fitting approaches were used to quantify the relative contributions of genetic, shared environmental, and nonshared environmental effects.
RESULTS. Among 318 twins of known zygosity, monozygotic twin pair similarities were greater than those observed for dizygotic pairs, which suggests significant heritability for bronchopulmonary dysplasia. Model-fitting analyses confirmed that genetic effects accounted for 82% and 79% of the observed variance in bronchopulmonary dysplasia susceptibility, defined on the basis of the need for supplemental oxygen at 36 weeks or the National Institutes of Health consensus definition, respectively. Variations in rates of hemodynamically significant patent ductus arteriosus were largely accounted for by genetic effects, whereas the observed variability in susceptibility to blood-borne bacterial infections was largely attributable to environmental factors, both common and unique to each infant.
CONCLUSIONS. Susceptibility to bronchopulmonary dysplasia and persistence of patent ductus arteriosus are both significantly heritable. Our study strengthens the case for investigating genetic risk stratification markers useful for predicting the most significant long-term respiratory and neurodevelopmental consequences of bronchopulmonary dysplasia in premature neonates.
Key Words: bronchopulmonary dysplasia • infant • premature • twin study • heritability • patent ductus arteriosus
Abbreviations: RDS—respiratory distress syndrome • BPD—bronchopulmonary dysplasia • NICHD—National Institute of Child Health and Human Development • PMA—postmenstrual age • PDA—patent ductus arteriosus
Bronchopulmonary dysplasia (BPD) is a multifactorial disease characterized by impaired alveolar and vascular lung development. Environmental factors, such as high levels of oxygen exposure, mechanical ventilation, and repeated infections, play major roles in pathogenesis, although recent studies have suggested an important genetic predisposition.1 Infants with BPD are at increased risk of death, childhood respiratory complications, and long-term neurodevelopmental problems.2,3 The lack of sustained clinical benefits from late postnatal therapeutic interventions and the undesirable harmful effects of postnatal corticosteroid treatment have fueled interest in seeking early biological markers useful in targeting therapeutic interventions aimed at promoting long-term pulmonary and neurodevelopmental benefits.4,5
Two previous studies reported genetic influences in the pathogenesis of BPD. The first was a family study by Parker et al,6 which showed a higher concordance for BPD within pairs of affected siblings. That study indicated that BPD has a familial component, but it was unable to determine whether the increased concordance in siblings was attributable to susceptibility genes shared between siblings or was attributable to environmental factors to which both siblings were exposed. Twin studies are a powerful tool to separate genetic and environmental effects by comparing the rates of disease occurrence in monozygotic and dizygotic twin pairs. Greater monozygotic than dizygotic within-pair similarity implies the presence of genetic influences, because of the twofold greater genetic similarity in monozygotic twins, compared with dizygotic pairs. By using data combined from 4 neonatal centers in the United States, Bhandari et al1 reported that 53% of the observed variability in the incidence of BPD was directly attributable to genetic differences (termed h2, or heritability). For practical reasons, however, the investigators used an arbitrary definition of BPD (ie, the need for supplemental oxygen at 36 weeks) that is known to correlate relatively weakly with later neurodevelopmental outcomes, particularly in the at-risk extremely low birth weight population.7
To address this issue, we applied the National Institute of Child Health and Human Development (NICHD)/National Heart, Lung, and Blood Institute Workshop definition for BPD developed in 2000.8 The main advantage of this definition is that it recognizes different levels of disease severity and more accurately predicts the spectrum of risk for adverse neurodevelopmental outcomes in early infancy, compared with other definitions.7 The purpose of the present study was to determine the magnitude of genetic effects on susceptibility and risk factors for BPD, comparing clinically validated proxy definitions for long-term respiratory and neurodevelopmental outcomes.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Subjects and Database
The sample consisted of 478 twins who were born between November 15, 1993, and December 31, 2006, and were admitted to the Children's and Women's Health Centre of British Columbia (Vancouver, Canada) (Tables 1 and 2). This center has the primary, provincial, level III–IV NICU, admitting
600 neonates annually, including the majority of extremely low birth weight infants born in the province of British Columbia. Data were recorded prospectively for all infants, from admission to discharge or death, by using prestructured, objectively defined criteria. Information collected included demographic data, maternal prenatal and perinatal history, delivery room and neonatal course, and main neonatal outcomes. The accuracy of the information in the database records was confirmed to be >95% through secondary review of a majority of the medical charts for infants in this study. The study population included all infants born at 30 completed weeks of gestation. Patients who died within 28 days of life or before postmenstrual age (PMA) of 36 weeks were excluded from the BPD analyses at 28 days and 36 weeks, respectively (see definitions below). Zygosity was determined by using chorionicity derived from early fetal ultrasound scans or placental histologic examinations performed at the Children's and Women's Health Centre of British Columbia. Histologic confirmation of chorionicity took precedence over fetal ultrasound results except in 2 cases in which prenatal septostomy of the membranes had been performed. Dichorionic twins were considered dizygous only if they differed in blood group or gender and otherwise were excluded from the analysis. Monochorionic twins were considered monozygous by default, because there are only extremely rare occurrences of dizygozity in such cases.9 The study was approved by the University of British Columbia Clinical Research Ethics Board.
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Definitions
Three widely used, clinically validated definitions of BPD were included in the analysis, that is, (1) chronic supplemental oxygen needs for
28 days (28-day oxygen need-based BPD)10; (2) chronic supplemental oxygen needs at either PMA of 36 weeks or discharge from the hospital, whichever came first (36-week oxygen need-based BPD)11; and (3) BPD as categorically defined (mild, moderate or severe) on the basis of the NICHD consensus definition (NICHD-defined BPD).8 In accordance with the NICHD consensus definition, mild BPD was defined as the need for supplemental oxygen for 28 days. Moderate BPD was defined as the need for supplemental oxygen at PMA of 36 weeks without positive pressure support (eg, nasal continuous positive airway pressure therapy or mechanical ventilation). Severe BPD was defined as the need for positive pressure support (eg, nasal continuous positive airway pressure therapy or mechanical ventilation) because of chronic lung disease at PMA of 36 weeks. Information about the respiratory status of the infant up to the time of discharge from the hospital also was obtained for all infants who were transferred elsewhere before PMA of 36 weeks. Our institution did not use a physiologic test confirming the oxygen requirement at the time of assessment.12 Gestational age was determined on the basis of the first day of the last menstrual period if the cycle dates were considered to be accurate or through early ultrasound dating if not. Discordant intrauterine growth was defined as a >20% discrepancy in growth measurements between the fetuses. Respiratory distress syndrome (RDS) was defined according to clinical criteria of symptoms of respiratory distress in the first 24 hours of life and/or a need for surfactant administration. Patent ductus arteriosus (PDA) was defined on the basis of clinical signs, with echocardiographic confirmation. However, only patients with hemodynamically significant PDA requiring treatment with either indomethacin or surgical ligation were entered into the analysis.
Statistical Analyses
Heritability is estimated by comparing the intrapair similarity (eg, indexed with a correlation coefficient) between monozygotic and dizygotic pairs. Unlike previously published reports, the present study used structural equation models to produce estimates of the relative contributions of additive genetic, shared environmental, and nonshared environmental influences. Additive genetic influences reflect genetic effects passed directly from parents to their offspring. Shared environmental effects include any experiences that influence all infants within a family to the same degree (eg, socioeconomic status or institutional practices). Nonshared environmental effects include events that have different effects on individual family members (eg, intercurrent illness). Structural equation model fitting has become the standard method for estimating heritability, primarily because it permits statistical evaluation of the significance of genetic and environmental effects and computation of confidence intervals not possible with previous methods.13,14
Intrapair similarities for each of the definitions were estimated with PRELIS 2.3 statistical software (Scientific Software International, Mooresville, IN).15 This statistical program selects the appropriate correlation coefficient to take into account the level of measurement of each definition (eg, interval or categorical data).14 For 28-day oxygen need-based BPD, 36-week oxygen need-based BPD, RDS, PDA requiring indomethacin treatment, and PDA requiring surgical ligation (coded as 0 = absence or 1 = presence), canonical correlations were computed from contingency tables created between siblings for each zygosity. A Pearson product-moment correlation was calculated for NICHD-defined BPD (coded as 0 = absence, 1 = mild, 2 = moderate, or 3 = severe) and number of positive blood cultures. The introduction of date of birth as a covariate did not change the intrapair twin correlations significantly.
The study used a structural equation model-fitting approach that fit 4 separate models to the monozygotic and dizygotic intrapair correlations for each definition to estimate the magnitude and to test the statistical significance of the parameters of additive genetic influences, shared environmental influences, and nonshared environmental influences, with the method of weighted least-squares fitting, by using Mx statistical software (Virginia Commonwealth University, http://views.vcu.edu).14,16 The primary means of assessing the relative fit of each model involved comparing the magnitudes of 
2 likelihood ratios computed for each model against one another. Models with lower 2 values indicated a superior fit, compared with models with higher 2 values. Differences between models were tested against the 2 distribution (P < .05). Model 1 was the baseline model that estimated the magnitude of additive genetic, shared environmental, and nonshared environmental influences. Model 2 tested the statistical significance of shared family environment (eg, shared environmental influences) in comparison with the baseline model. The significance of shared environmental influences was tested by subtracting the 2 value for the baseline model (model 1) from the 2 value for model 2, with testing against a 2 distribution. An absence of significant changes in 2 between models indicated that the deleted parameter had no effect. Conversely, a significant change in 2 indicated that the parameter contributed significantly to the observed variability and must be retained. Model 3 tested the significance of genetic influences by specifying only shared and nonshared environmental influences, whereas model 4 (nonshared environmental influences only) tested whether events or circumstances unique to each individual alone could satisfactorily account for the data.
In addition to 2, model fit was assessed by using Akaike's information criterion (Akaike's information criterion = 2 – 2df).17 The Akaike's information criterion is used because it factors into the magnitude of the 2 likelihood ratio the principle of parsimony, in which models that can account for the data with fewer parameters are considered superior to models that specify more parameters. In summary, the most satisfactory model in the present study was one that did not increase 2 significantly, yielded the smallest value for Akaike's information criterion, and accounted for the variance with the fewest parameters. The estimates of the additive genetic, shared environmental, and nonshared environmental parameters from the best-fitting model were squared to yield the familiar standardized proportions of the variance attributable to each effect (h2A, c2, and e2, respectively).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Clinical characteristics were similar for the entire cohort of 478 neonates and the subset of 318 neonates of known zygosity used for the analysis (Table 1). Within the group of known zygosity, monozygotic and dizygotic neonates were similar with respect to potential confounding variables, with the exception that there was a higher incidence of RDS and a lower incidence of bacteremia in dizygotic twins (Table 2).
In the initial analyses, intrapair correlations within monozygotic and dizygotic twins were determined for the 3 definitions of BPD, that is, 28-day oxygen need-based BPD, 36-week oxygen need-based BPD, and NICHD-defined BPD. As shown in Table 3, correlation coefficients within monozygotic pairs were greater for 36-week oxygen need-based BPD and NICHD-defined BPD, which suggests the presence of a significant genetic influence on the need for supplemental oxygen at 36 weeks. Similarly, monozygotic correlations exceeded dizygotic correlations for PDA requiring either indomethacin or surgical treatment, which suggests the presence of a genetic liability for hemodynamically significant PDA. Little genetic influence was suggested for 28-day oxygen need-based BPD, RDS, or the number of positive blood cultures (Table 3).
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Structural equations fitted to the correlations coefficients confirmed the results suggested by the twin correlations. As shown in Table 4, for PDA requiring indomethacin treatment, 36-week oxygen need-based BPD, and NICHD-defined BPD, deletion of shared environmental effects in model 2 (compared with the baseline model) did not increase likelihood ratios significantly, which indicated that shared environmental effects were negligible. However, deletion of additive genetic effects in model 3 resulted in a significant increase in
2 for these variables, which indicated a significant genetic contribution. Model 4 (nonshared environmental influences only), which deleted both genetic and shared environmental effects, resulted in a significant increase in 2 for all definitions tested (data not shown). Therefore, model 2, which specified only additive genetic and nonshared environmental influences, provided the most satisfactory explanation for the observed variability in these outcomes. In contrast, the variability in 28-day oxygen need-based BPD and RDS could be explained entirely by shared and nonshared environmental effects. As shown in Table 4, shared environmental effects significantly increased 2, whereas deletion of additive genetic effects resulted in no significant change in 2. For the number of positive blood cultures, because the dizygotic twin correlation exceeded the monozygotic twin correlation, no additive genetic effects were suggested. This was confirmed by identical fits of the baseline model and model 3, which estimated only shared and nonshared environmental effects. Finally, for PDA requiring surgical ligation, deletion of both additive genetic and shared environmental parameters significantly increased 2, which indicated that additive genetic, shared environmental, and nonshared environmental effects significant affected variability in this outcome. The parameter estimates for additive genetic, shared environmental, and nonshared environmental effects were squared to yield the heritability estimates h2A, c2, and e2, respectively. For definitions with a significant heritable component, estimates of h2A were 78% for NICHD-defined BPD, 82% for 36-week oxygen need-based BPD, 48% for PDA requiring surgical ligation, and 93% for PDA requiring indomethacin treatment (Table 5).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The present study indicates that susceptibility to BPD is significantly heritable in neonates with gestational ages of
30 weeks, with the use of clinically validated definitions for long-term pulmonary and neurodevelopmental outcomes. We also report, for the first time, significant genetic effects on hemodynamically significant PDA, a risk factor for BPD. In contrast to previous studies, the methodologic approach used in our analysis allowed delineation of the roles of common environmental stressors and those unique to each infant (ie, nonshared environmental effects). This has particular importance in understanding the multifactorial pathogenesis of BPD. For 36-week oxygen need-based BPD and NICHD-defined BPD, heritability estimates were somewhat higher than reported previously, perhaps because of differences in the relative magnitude of environmental stressors, the inclusion of lower-gestational age neonates in our study, or differences in the methods used.1 It is of particular interest that the relative contributions of genetic and environmental effects seemed to vary depending on the severity of BPD. Variations in 28-day oxygen need-based BPD were attributable completely to environmental effects and predominantly to shared environmental effects. Dependence on supplemental oxygen at 28 days likely reflects an early phase in the disease process, one largely determined by factors common to both twins (such as gestational age), whereas the condition at 36 weeks seems to better reflect underlying biological susceptibility.8
Although this study indicates a significant genetic component in the susceptibility to BPD, it cannot address the molecular nature of this effect. In common with other complex diseases, environmental influences likely interact to alter genetic susceptibility. Positive pressure ventilation (inducing alveolar stretching) and oxygen treatment trigger systemic and local inflammatory responses that can be damaging to the lungs of immunologically immature preterm infants.18 Animals genetically engineered to have altered surfactant protein levels, excessive cytokine (eg, interleukin 6 or 13) production, or deficiency in Toll-like receptor 4, which is a critical receptor component for the lipopolysaccharide inflammatory response to Gram-negative bacteria, showed increased susceptibility to hyperoxia-induced lung injury.19–23 In humans, polymorphisms in surfactant protein B, tumor necrosis factor 
, angiotensin-converting enzyme, and gluthathione-S-transferase-P1 genes, with known altered biological functions, were linked in small studies to variations in the risk of BPD or its severity,24–27 although others failed to show similar associations in independent populations.28,29
PDA persistence was also largely heritable in our analysis, a finding that is consistent with a significant contribution of individuals' ethnic backgrounds to susceptibility.30 PDA closure depends mainly on circulating levels of endogenous prostaglandins, produced by cyclooxygenase, in addition to nitric oxide, which mediates ductal relaxation in highly immature neonates.31 To date, only 1 study has reported an association between an A1166C polymorphism in the angiotensin II type 1 receptor gene and PDA persistence, although the mechanism underlying this association is unclear.32 In humans, several cyclooxygenase genetic variants have been described, which may account for interindividual differences in pharmacologic responses to cyclooxygenase inhibitors.33
A limitation to all retrospective twin analyses, including ours, is the potential for disease misclassification. This can significantly affect heritability estimates (see ref 13 for review). This is best illustrated by our findings of strong shared environmental effects but no significant genetic effects on RDS, in sharp contrast to previous reports.34 The RDS definition used for our cohort did not specifically incorporate radiologic criteria, and disease classification might have been biased by our practice of routinely administering surfactant early to neonates weighing <1000 g, potentially impairing our ability to measure genetic effects. Nonetheless, this observation highlights the sizeable impact institutional variations in clinical practice and disease incidence, as well as issues of disease misclassification, can have on estimates of heritability. In relation to BPD, a somewhat arbitrarily defined disease, we think that our methods of rigorously verifying the accuracy of the clinical information and using validated long-term proxy measures maximized our ability to detect most clinically relevant genetic effects.
Advances in human genome mapping now open the exciting possibility that knowledge of genetic variants may be used to target therapy on the basis of risk stratification. Our results provide essential independent corroboration of a significant contribution of heritability in the pathogenesis and severity of BPD, as well as persistent PDA. In addition, we delineated the relative contribution of environmental effects, potentially amenable to changes in clinical practice. The use of the NICHD consensus definition greatly strengthens the rationale for identifying genetic markers useful for stratifying risk and targeting interventions to prevent BPD and its most undesirable, lifelong, neurodevelopmental consequences in prematurely born children.
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ACKNOWLEDGMENTS |
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Dr Lavoie was supported by a Canadian Child Health Clinician-Scientist Program Award from the Canadian Institute of Health Research. This work was funded by the BC Children's Hospital Foundation Telethon Award.
We are grateful to neonatologist colleagues for careful reading of and comments on the manuscript.
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FOOTNOTES |
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Accepted Dec 13, 2007.
Address correspondence to Pascal M. Lavoie, MD, PhD, FRCPC, Department of Pediatrics, Division of Neonatology, Children's and Women's Health Centre of British Columbia, Room 1R47, 4480 Oak St, Vancouver BC, Canada V6H 3V4. E-mail: plavoie{at}cw.bc.ca
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Environmental risk factors and familial influences contribute to BPD susceptibility.
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| What This Study Adds Significant heritability contributes to BPD, defined according to the NICHD consensus definition, which is a better proxy for long-term respiratory and neurodevelopmental outcomes in extremely low birth weight infants. Susceptibility to PDA persistence also is significantly heritable.
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