Abstract
Introduction:
The genetic contribution to the development of bronchopulmonary dysplasia (BPD) in prematurely born infants is substantial, but information related to the specific genes involved is lacking.
Results:
Genotype analysis revealed, after multiple comparisons correction, two significant single-nucleotide polymorphism (SNPs), rs3771150 (IL-18RAP) and rs3771171 (IL-18R1), in African Americans (AAs) with BPD (vs. AAs without BPD; q < 0.05). No associations with Caucasian (CA) BPD, AA or CA respiratory distress syndrome (RDS), or prematurity in either AAs or CAs were identified with these SNPs. Respective frequencies were 0.098 and 0.093 in infants without BPD and 0.38 for each SNP in infants with BPD. In the replication set (82 cases; 102 controls), the P values were 0.012 for rs3771150 and 0.07 for rs3771171. Combining P values using Fisher’s method, overall P values were 8.31 × 10−7 for rs3771150 and 6.33 × 10−6 for rs3771171.
Discussion:
We conclude that IL-18RAP and IL-18R1 SNPs identify AA infants at risk for BPD. These genes may contribute to AA BPD pathogenesis via inflammatory-mediated processes and require further study.
Methods:
We conducted a case–control SNP association study of candidate genes (n = 601) or 6,324 SNPs in 1,091 prematurely born infants with gestational age <35 weeks, with or without neonatal lung disease including BPD. BPD was defined as a need for oxygen at 28 days.
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References
Horbar JD, Badger GJ, Carpenter JH, et al.; Members of the Vermont Oxford Network. Trends in mortality and morbidity for very low birth weight infants, 1991-1999. Pediatrics 2002;110(1 Pt 1): 143–51.
Baraldi E, Filippone M . Chronic lung disease after premature birth. N Engl J Med 2007;357: 1946–55.
Short EJ, Kirchner HL, Asaad GR, et al. Developmental sequelae in preterm infants having a diagnosis of bronchopulmonary dysplasia: analysis using a severity-based classification system. Arch Pediatr Adolesc Med 2007;161: 1082–7.
Vrijlandt EJ, Boezen HM, Gerritsen J, Stremmelaar EF, Duiverman EJ . Respiratory health in prematurely born preschool children with and without bronchopulmonary dysplasia. J Pediatr 2007;150: 256–61.
Walter EC, Ehlenbach WJ, Hotchkin DL, Chien JW, Koepsell TD . Low birth weight and respiratory disease in adulthood: a population-based case-control study. Am J Respir Crit Care Med 2009;180: 176–80.
Greenough A . Does low birth weight confer a lifelong respiratory disadvantage? Am J Respir Crit Care Med 2009;180: 107–8.
Hallman M, Marttila R, Pertile R, Ojaniemi M, Haataja R . Genes and environment in common neonatal lung disease. Neonatology 2007;91: 298–302.
Lavoie PM, Pham C, Jang KL . Heritability of bronchopulmonary dysplasia, defined according to the consensus statement of the national institutes of health. Pediatrics 2008;122: 479–85.
Meng H, Gruen JR . Genetic approaches to complications of prematurity. Front Biosci 2007;12: 2344–51.
Pavlovic J, Papagaroufalis C, Xanthou M, et al. Genetic variants of surfactant proteins A, B, C, and D in bronchopulmonary dysplasia. Dis Markers 2006;22: 277–91.
Weber B, Borkhardt A, Stoll-Becker S, Reiss I, Gortner L . Polymorphisms of surfactant protein A genes and the risk of bronchopulmonary dysplasia in preterm infants. Turk J Pediatr 2000;42: 181–5.
Rova M, Haataja R, Marttila R, Ollikainen V, Tammela O, Hallman M . Data mining and multiparameter analysis of lung surfactant protein genes in bronchopulmonary dysplasia. Hum Mol Genet 2004;13: 1095–104.
Makri V, Hospes B, Stoll-Becker S, Borkhardt A, Gortner L . Polymorphisms of surfactant protein B encoding gene: modifiers of the course of neonatal respiratory distress syndrome? Eur J Pediatr 2002;161: 604–8.
Mikerov AN, Umstead TM, Gan X, et al. Impact of ozone exposure on the phagocytic activity of human surfactant protein A (SP-A) and SP-A variants. Am J Physiol Lung Cell Mol Physiol 2008;294: L121–30.
Wang G, Umstead TM, Phelps DS, Al-Mondhiry H, Floros J . The effect of ozone exposure on the ability of human surfactant protein A variants to stimulate cytokine production. Environ Health Perspect 2002;110: 79–84.
Huang W, Wang G, Phelps DS, Al-Mondhiry H, Floros J . Human SP-A genetic variants and bleomycin-induced cytokine production by THP-1 cells: effect of ozone-induced SP-A oxidation. Am J Physiol Lung Cell Mol Physiol 2004;286: L546–53.
Wang G, Taneva S, Keough KM, Floros J . Differential effects of human SP-A1 and SP-A2 variants on phospholipid monolayers containing surfactant protein B. Biochim Biophys Acta 2007;1768: 2060–9.
Wang G, Bates-Kenney SR, Tao JQ, Phelps DS, Floros J . Differences in biochemical properties and in biological function between human SP-A1 and SP-A2 variants, and the impact of ozone-induced oxidation. Biochemistry 2004;43: 4227–39.
Hilgendorff A, Heidinger K, Pfeiffer A, et al. Association of polymorphisms in the mannose-binding lectin gene and pulmonary morbidity in preterm infants. Genes Immun 2007;8: 671–7.
Hadchouel A, Decobert F, Franco-Montoya ML, et al. Matrix metalloproteinase gene polymorphisms and bronchopulmonary dysplasia: identification of MMP16 as a new player in lung development. PLoS ONE 2008;3: e3188.
Abman SH . Impaired vascular endothelial growth factor signaling in the pathogenesis of neonatal pulmonary vascular disease. Adv Exp Med Biol 2010;661: 323–35.
Concolino P, Capoluongo E, Santonocito C, et al. Genetic analysis of the dystroglycan gene in bronchopulmonary dysplasia affected premature newborns. Clin Chim Acta 2007;378: 164–7.
Kwinta P, Bik-Multanowski M, Mitkowska Z, Tomasik T, Legutko M, Pietrzyk JJ . Genetic risk factors of bronchopulmonary dysplasia. Pediatr Res 2008;64: 682–8.
Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003;100: 9440–5.
Kakkar R, Lee RT . The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov 2008;7: 827–40.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21: 263–5.
Gordon D, Finch SJ, Nothnagel M, Ott J . Power and sample size calculations for case-control genetic association tests when errors are present: application to single nucleotide polymorphisms. Hum Hered 2002;54: 22–33.
Gordon D, Levenstien MA, Finch SJ, Ott J . Errors and linkage disequilibrium interact multiplicatively when computing sample sizes for genetic case-control association studies. Pac Symp Biocomput 2003:490–501.
Coalson JJ . Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003;8: 73–81.
Bhandari A, Bhandari V . Pitfalls, problems, and progress in bronchopulmonary dysplasia. Pediatrics 2009;123: 1562–73.
Tsuji-Takayama K, Aizawa Y, Okamoto I, et al. Interleukin-18 induces interferon-gamma production through NF-kappaB and NFAT activation in murine T helper type 1 cells. Cell Immunol 1999;196: 41–50.
Bose CL, Dammann CE, Laughon MM . Bronchopulmonary dysplasia and inflammatory biomarkers in the premature neonate. Arch Dis Child Fetal Neonatal Ed 2008;93: F455–61.
Paananen R, Husa AK, Vuolteenaho R, Herva R, Kaukola T, Hallman M . Blood cytokines during the perinatal period in very preterm infants: relationship of inflammatory response and bronchopulmonary dysplasia. J Pediatr 2009;154: 39–43.e3.
Jobe AJ . The new BPD: an arrest of lung development. Pediatr Res 1999;46: 641–3.
Krueger M, Heinzmann A, Mailaparambil B, Härtel C, Göpel W . Polymorphisms of interleukin 18 in the genetics of preterm birth and bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed 2011;96: F299–300.
Banerjee SK, Young HW, Volmer JB, Blackburn MR . Gene expression profiling in inflammatory airway disease associated with elevated adenosine. Am J Physiol Lung Cell Mol Physiol 2002;282: L169–82.
Wagenaar GT, ter Horst SA, van Gastelen MA, et al. Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative stress. Free Radic Biol Med 2004;36: 782–801.
Seldin MF, Shigeta R, Villoslada P, et al. European population substructure: clustering of northern and southern populations. PLoS Genet 2006;2: e143.
Pritchard JK, Rosenberg NA . Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet 1999;65: 220–8.
Cochran WG . Some methods for strengthening the common chi-squared tests. Biometrics 1954;10: 417–51.
Armitage P . Tests for linear trends in proportions and frequencies. Biometrics 1955; 11: 375–86.
Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81: 559–75.
WELCH BL . The generalisation of student’s problems when several different population variances are involved. Biometrika 1947;34: 28–35.
Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I . Controlling the false discovery rate in behavior genetics research. Behav Brain Res 2001;125: 279–84.
Ott J . Analysis of Human Genetic Linkage. Baltimore, MD: Johns Hopkins University Press 1999.
Gabriel SB, Schaffner SF, Nguyen H, et al. The structure of haplotype blocks in the human genome. Science 2002;296: 2225–9.
Acknowledgements
The authors thank Rosanne Pogash and Mark Hansen for valuable input, Anamika Singh for help with DNA extraction, Julie Graham and Gina Marcucci for typing, and the Pennsylvania State University College of Medicine Macromolecular Core Facility for real-time PCR.
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Floros, J., Londono, D., Gordon, D. et al. IL-18R1 and IL-18RAP SNPs may be associated with bronchopulmonary dysplasia in African-American infants. Pediatr Res 71, 107–114 (2012). https://doi.org/10.1038/pr.2011.14
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DOI: https://doi.org/10.1038/pr.2011.14
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