Baas, Emma M.

Finken, M. J. J.

Romijn, Michelle

Rotteveel, Joost

van der Pal, Sylvia M.

Vrijlandt, E. J. L. E.

English

Proceedings - University of Groningen

   University of GroningenNo association between glucocorticoid receptor polymorphisms and long-term respiratoryoutcome after very preterm birthDutch POPS 19 Col; Baas, Emma M.; Romijn, Michelle; van der Pal, Sylvia M.; Vrijlandt, E. J.L. E.; Rotteveel, Joost; Finken, M. J. J.Published in:EndocrineDOI:10.1007/s12020-021-02672-7IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dutch POPS 19 Col, Baas, E. M., Romijn, M., van der Pal, S. M., Vrijlandt, E. J. L. E., Rotteveel, J., &Finken, M. J. J. (2021). No association between glucocorticoid receptor polymorphisms and long-termrespiratory outcome after very preterm birth. Endocrine, 73(1), 226-229. Advance online publication.https://doi.org/10.1007/s12020-021-02672-7CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Endocrine (2021) 73:226–229https://doi.org/10.1007/s12020-021-02672-7RESEARCH LETTERNo association between glucocorticoid receptor polymorphisms andlong-term respiratory outcome after very preterm birthEmma M. Baas1 ● Michelle Romijn 1 ● Sylvia M. van der Pal2 ● Elianne J. L. E. Vrijlandt3 ● Joost Rotteveel1 ●Martijn J. J. Finken1 ● Dutch POPS-19 Collaborative Study GroupReceived: 10 July 2020 / Accepted: 24 February 2021 / Published online: 20 March 2021© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021In preterm infants in their first weeks of life, thehypothalamic-pituitary-adrenal (HPA) axis is unable toproduce sufficient amounts of cortisol for the degree ofillness [1, 2]. The causes for this phenomenon are prolongedcentral suppression, immature adrenocortical enzymes and acortisol-cortisone shuttle that favors cortisone [1, 3]. Cor-tisol is known for its anti-inflammatory effect. It has beendemonstrated among preterm infants that low-cortisol levelsmay predispose to disrupted lung development, manifestedas bronchopulmonary dysplasia (BPD) in approximately20% of all infants born <32 weeks of gestation [4, 5].A factor that might contribute to lung development afterpreterm birth is sensitivity to glucocorticoids. In adults,single-nucleotide polymorphisms (SNPs) in the glucocorti-coid receptor (GR) gene have previously been associatedwith alterations in glucocorticoid sensitivity [6, 7]. TheR23K polymorphism has been associated with decreasedsensitivity to glucocorticoids [8], while the N363S poly-morphism has been associated with increased glucocorti-coid sensitivity [9].We hypothesized that GR polymorphisms, might influ-ence respiratory morbidity after preterm birth. Previousstudies among preterm infants showed that these GRpolymorphisms were not associated with the risk of devel-oping BPD [10, 11]. However, the consequences of GRpolymorphisms on long-term respiratory outcome after verypreterm birth remain to be explored. Therefore, we inves-tigated associations between the GR polymorphisms R23Kand N363S and long-term respiratory outcomes in a cohortof subjects born very preterm birth who were followed upuntil young adulthood.Materials and methodsStudy design and participantsFor this study, data from the Project On Preterm and Small-for-gestational-age infants (POPS) study were used. ThePOPS study is a birth cohort study that had included 94%(N= 1338) of all liveborn very preterm (i.e., gestationalage <32 weeks) and/or very-low-birth-weight (i.e., <1500grams) infants throughout the Netherlands in 1983. Variousperinatal and neonatal characteristics were collected frombirth onwards, including the presence of BPD. BPD wasdefined as clinical signs of respiratory distress in conjunc-tion with abnormal findings on a chest X-ray and supple-mental oxygen at 28 days of age [5]. At the age of 19 years,all alive subjects were approached to participate in a follow-up study (POPS-19 study), in which, among other data, GRpolymorphisms were collected. The study was approvedby the medical ethics committee of all participating centers.All subjects gave written informed consent for participationin this study [8].Data collectionRespiratory outcomes were determined by self-report usingthe European Community Respiratory Health Survey(ECRHS) questionnaire [12]. The ECRHS questionnaireThese authors contributed equally: Emma M. Baas, Michelle RomijnMembers of the Dutch POPS-19 Collaborative Study Group are listedbelow Author contributions.* Michelle Romijnm.romijn1@amsterdamumc.nl1 Emma Children’s Hospital, Amsterdam UMC, Vrije UniversiteitAmsterdam, Pediatric Endocrinology, Amsterdam, TheNetherlands2 TNO, Child Health, Leiden, The Netherlands3 Beatrix Children’s Hospital, University Medical CenterGroningen, University of Groningen, Department of PediatricPulmonology and Pediatric Allergy, Groningen, The Netherlands1234567890();,:1234567890();,:was developed from pre-existing questionnaires that hadalready been used in multinational studies [12–14], andcontains questions about the presence of respiratory pro-blems or symptoms. Symptoms on the ECRHS ques-tionnaire showed correlation with objective measures oflung function [15]. This questionnaire was sent to all sub-jects known to be alive. At the same time, subjects wereseen for blood sampling at one of the participating centers[8].Laboratory analysisGR SNPs were determined by performing polymerase chainreactions using 2.5 ng of genomic DNA and standardreagents. Subsequently, they were genotyped by massspectrometry using standard conditions [8]. The genotypedistribution for both the R23K and the N363S polymorph-ism was in agreement with the distribution predicted by theHardy–Weinberg equilibrium (P= 0.54 for the R23Kpolymorphism, and P= 0.66 for the N363S polymorph-ism), and are mutual exclusives.Statistical analysisStatistical analyses were performed with SPSS Statisticsversion 26. Patient characteristics were compared betweenR23K carriers and non-carriers, and between N363S carriersand non-carriers, using the Chi square-test for dichotomousdata and the independent samples t-test or their nonpara-metric equivalents for continuous data. Outcomes werecompared between R23K carriers and non-carriers, andbetween N363S carriers and non-carriers, using logisticregression analysis.ResultsOf the 1012 very preterm born infants 676 (67%) were stillalive at the age of 19. Of these, 498 (74%) consented toparticipate in the POPS-19 study. In 318 (64%) of themgenomic data and ECHRS symptoms were known. After theexclusion of subjects with any congenital malformation,294 were available for analysis, including 21 (7%) R23Kcarriers, 15 (5%) N363S carriers and 258 (88%) non-carriers.Perinatal characteristics did not differ between the groups(data not shown).Respiratory outcomes at age 19 are shown by GR gen-otype in Table 1. No differences in scores of asthma, chestwheezing or shortness of breath were found between R23Kcarriers and non-carriers, or between N363S carriers andnon-carriers. Eczema was positively associated with R23Kcarriage (OR 3.05, 95% CI 1.03, 9.05, p value 0.045).Table1Respiratoryoutcomesatage19andneonatalrespiratoryoutcomesbygenotypeGenotypeOR+95%CIPvalueR23KN=21N363SN=15Non-carriersN=258R23Kvsnon-carriersN363Svsnon-carriersR23Kvsnon-carriersN363Svsnon-carriersRespiratoryoutcomesatage19Eczema—n(%)5(23.8%)1(6.7%)24(9.3%)3.05(1.03,9.05)0.70(0.09,5.53)0.0450.73Hayfever—n(%)1(4.8%)3(20.0%)18(7.0%)0.67(0.09,5.26)3.33(0.86,12.89)0.700.08Asthma—n(%)1(4.8%)1(6.7%)19(7.4%)0.68(0.09,5.36)1.02(0.13,8.25)0.710.99Asthmaattacklast12months—n(%)1(4.8%)0(0.0%)5(1.9%)NANA1.001.00Chestwheezinglast12months—n(%)8(38.1%)3(20.0%)56(21.7%)2.19(0.86,5.54)0.89(0.24,3.29)0.100.86SOBduringexercise—n(%)4(19.0%)0(0.0%)34(13.2%)1.28(0.40,4.06)NA0.681.00SOBwhilewalkingwithpeoplesameage—n(%)1(4.8%)0(0.0%)12(4.7%)0.86(0.11,6.98)NA0.891.00Needtostopforbreathwhenwalkingatownpaceonlevelground—n(%)0(0.0%)0(0.0%)8(3.1%)NANA1.001.00NeonatalrespiratoryoutcomesBPD—n(%)1(4.8%)2(13.3%)20(7.8%)0.60(0.08,4.67)1.83(0.39,8.69)0.620.45CPAPorIPPV,days—median[IQR]3[0–11]1[0,6]2[0,8]1.03(0.98,1.07)1.02(0.97,1.07)0.230.40SOBshortnessofbreath,BPDbronchopulmonarydysplasia,CPAPcontinuouspositiveairwaypressure,IPPVIntermittentpositivepressureventilation,Nnumber,IQRinterquartilerangeEndocrine (2021) 73:226–229 227Furthermore, no differences in the duration of respiratorysupport with continuous positive airway pressure (CPAP),intermittent positive pressure ventilation (IPPV) or thenumbers developing BPD were seen between R23K carriersand non-carriers and N363S carriers and non-carriers.DiscussionIn this study we found no association between the GRpolymorphisms R23K and N363S and respiratory outcomes19 years after very preterm birth.Respiratory outcome after preterm birth is determined bya complex interplay of lung immaturity, need for andduration of assisted ventilation, oxygen supplies, andrecurrent or enduring infections [16], in addition to otherfactors that are not specifically related to prematurity, suchas socioeconomic status, (maternal) smoking, BMI, andphysical activity [17]. Furthermore, our sample was born inthe pre-surfactant era [18]. Increasing degrees of pre-maturity and BPD were associated with more airflowimpairment later in life [17], possibly due to the presence ofsmaller airways [19, 20]. Although GR SNPs might influ-ence some of these processes, due to the multitude of factorsthat determine respiratory outcome after preterm birth theiroverall contribution is probably negligible.We found that carriers of the R23K polymorphism had ahigher odds of eczema. Although this association mightreflect a biologically plausible mechanism, it could also be achance finding. However, contrary to expectation, we foundthat carriers of the N363S polymorphism had a higher oddsof hay fever. Clearly, our results should be balanced againstthe small numbers of variant allele carriers.We found GR polymorphisms to be unrelated to the oddsof BPD, consistent with findings by Schreiner et al. [10].The lack of association can be explained by the complexmultifactorial pathophysiology of BPD or by selectivesurvival of certain genotypes [21]. However, the genotypefrequencies in this study did not differ from the genotypefrequencies in the Dutch norm population, which arguesagainst a major survivor effect [8].Our study has several strengths, including a large samplesize and long-term follow-up. Our study also has its lim-itations. Even though this study had a relatively large samplesize, the number of variant allele carriers (n= 36) was small.Nonetheless, the genotype distribution for both polymorph-isms was in agreement with the distribution predicted by theHardy–Weinberg equilibrium. Second, the POPS-19 studywas not designed specifically for our research question. GRSNPs were determined at age 19. In the early 1980s, manyvery preterm infants did not survive, which inevitably maygive rise to selection bias. In addition, participants were notrepresentative for the current generation of very preterminfants, which are more immature. Insufficient cortisol pro-duction and BPD are more frequent at lower gestational ages[2]. Third, patient-reported respiratory data are not asobjective as data derived from spirometry. Since respiratoryproblems may develop many years after preterm birth, serialfollow-up of spirometry would allow to determine the courseof pulmonary development after very preterm birth. Fourth,our study lacked an assessment of adrenocortical output andinflammatory markers during the neonatal course.In summary, our study did not show associationsbetween the GR polymorphisms R23K and N363S andlong-term respiratory outcome 19 years after very pretermbirth. Future studies on this topic should include serialmeasurements of adrenocortical output along with inflam-matory markers during the neonatal course, and shouldinclude an objective assessment of lung function.Authors’ contributions E.M.B., M.R., S.M.P., E.J.L.E.V., J.R., M.J.J.F:made substantial contributions to the conception or design of the work;or the acquisition, analysis, or interpretation of data; or the creation ofnew software used in the work; drafted the work or revised it criticallyfor important intellectual content; approved the version to be published;agree to be accountable for all aspects of the work in ensuring thatquestions related to the accuracy or integrity of any part of the work areappropriately investigated and resolved.Dutch POPS-19 Collaborative Study Group E. T. M. Hille4, C. H. deGroot4, H. Kloosterboer-Boerrigter4, A. L. den Ouden4, A. Rijpstra4,S. P. Verloove-Vanhorick4, J. A. Vogelaar4, J. H. Kok5, A. Ilsen5, M.van der Lans5, W. J. C. Boelen-van der Loo5, T. Lundqvist5, H. S. A.Heymans5, E. J. Duiverman6, W. B. Geven6, M. L. Duiverman6, L. I.Geven6, E. J. L. E. Vrijlandt6, A. L. M. Mulder7, A. Gerver7, L. A. A.Kollée8, L. Reijmers8, R. Sonnemans8, J. M. Wit9, F. W. Dekker9,M. J. J. Finken9, N. Weisglas-Kuperus10, M. G. Keijzer-Veen10, A. J.van der Heijden10, J. B. van Goudoever10, M. M. van Weissenbruch11,A. Cranendonk11, H. A. Delemarre-van de Waal11, L. de Groot11, J. F.Samsom11, L. S. de Vries12, K. J. Rademaker12, E. Moerman12,M. Voogsgeerd12, M. J. K. de Kleine13, P. Andriessen13, C. C. M.Dielissen-van Helvoirt13, I. Mohamed13, H. L. M. van Straaten14,W. Baerts14, G. W. Veneklaas Slots-Kloosterboer14, E. M. J. Tuller-Pikkemaat14, M. H. Ens-Dokkum15, G. J. van Steenbrugge164TNO Quality of Life, Leiden, The Netherlands; 5Emma Children’sHospital AMC, Amsterdam, The Netherlands; 6University HospitalGroningen, Beatrix Children’s Hospital, Groningen, The Netherlands;7University Hospital Maastricht, Maastricht, The Netherlands; 8Uni-versity Medical Center St Radboud, Nijmegen, The Netherlands;9Leiden University Medical Center, Leiden, The Netherlands; 10Eras-mus MC – Sophia Children’s Hospital, University Medical CenterRotterdam, Rotterdam, The Netherlands; 11V.U. University MedicalCenter, Amsterdam, The Netherlands; 12Wilhelmina Children’s Hos-pital, UMC, Utrecht, The Netherlands; 13Máxima Medical Center,Veldhoven, The Netherlands; 14Isala Clinics, Zwolle, The Nether-lands; 15Royal Effatha Guyot Group, Zoetermeer, The Netherlands;16Dutch Association of Parents of Newborn Infants,Leidschendam, The Netherlands228 Endocrine (2021) 73:226–229Compliance with ethical standardsConflict of interest The authors declare no competing interests.Publisher’s note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.References1. M.J. Finken et al. Glucocorticoid programming in very pretermbirth. Horm. Res. Paediatr. 85(4), 221–231 (2016)2. K.L. Watterberg, S.M. Scott, Evidence of early adrenal insuffi-ciency in babies who develop bronchopulmonary dysplasia.Pediatrics 95(1), 120–125 (1995)3. M.J.J. Finken et al. Programming of the hypothalamus-pituitary-adrenal axis by very preterm birth. Ann. Nutr. Metab. 70(3),170–174 (2017)4. K.L. Watterberg et al. Links between early adrenal function andrespiratory outcome in preterm infants: airway inflammation andpatent ductus arteriosus. Pediatrics 105(2), 320–324 (2000)5. E. Bancalari et al. Bronchopulmonary dysplasia: clinical pre-sentation. J. Pediatr. 95(5 Pt 2), 819–823 (1979)6. K. Ogasawara et al. A polymorphism in the glucocorticoidreceptor gene is associated with refractory hypotension in pre-mature infants. Pediatr. Neonatol. 59(3), 251–257 (2018)7. D.M. Haas et al. The impact of glucocorticoid polymorphisms onmarkers of neonatal respiratory disease after antenatal beta-methasone administration. Am. J. Obstet. Gynecol. 208(3), 215e1–215216 (2013)8. M.J. Finken et al. The 23K variant of the R23K polymorphism inthe glucocorticoid receptor gene protects against postnatal growthfailure and insulin resistance after preterm birth. J. Clin. Endo-crinol. Metab. 92(12), 4777–4782 (2007)9. N.A. Huizenga et al. A polymorphism in the glucocorticoidreceptor gene may be associated with and increased sensitivity toglucocorticoids in vivo. J. Clin. Endocrinol. Metab. 83(1),144–151 (1998)10. C. Schreiner et al. Glucocorticoid receptor gene variants andneonatal outcome in very-low-birth-weight preterm infants. Neo-natology 111(1), 22–29 (2017)11. R. Bertalan et al. Association between birth weight in pretermneonates and the BclI polymorphism of the glucocorticoid receptorgene. J. Steroid Biochem. Mol. Biol. 111(1-2), 91–94 (2008)12. E.J. Vrijlandt et al. Gender differences in respiratory symptoms in19-year-old adults born preterm. Respir. Res. 6, 117 (2005)13. G. Biino et al. ECRHS screening questionnaire scoring: a meth-odological suggestion for asthma assessment. European Com-munity Health Survey. J. Outcome Meas. 4(4), 740–762 (2000)14. P.G. Burney et al. The European Community Respiratory HealthSurvey. Eur. Respir. J. 7(5), 954–960 (1994)15. H.M. Boezen et al. Relation between respiratory symptoms, pul-monary function and peak flow variability in adults. Thorax 50(2),121–126 (1995)16. E.J. Vrijlandt et al. Respiratory health in prematurely born pre-school children with and without bronchopulmonary dysplasia.J. Pediatr. 150(3), 256–261 (2007)17. P. Nasanen-Gilmore et al. Lung function in adults born preterm.PLoS ONE 13(10), e0205979 (2018)18. N. El-Gendy et al. Delivery and performance of surfactantreplacement therapies to treat pulmonary disorders. Ther Deliv 4(8), 951–980 (2013)19. J.C. Hogg, P.D. Pare, T.L. Hackett, The contribution of smallairway obstruction to the pathogenesis of chronic obstructivepulmonary disease. Physiol. Rev. 97(2), 529–552 (2017)20. J.W. Duke et al. Premature birth affects the degree of airwaydysanapsis and mechanical ventilatory constraints. Exp. Physiol.103(2), 261–275 (2018)21. A.H. Jobe, The new bronchopulmonary dysplasia. Curr. Opin.Pediatr. 23(2), 167–172 (2011)Endocrine (2021) 73:226–229 229

No association between glucocorticoid receptor polymorphisms and long-term respiratory outcome after very preterm birth

University of Groningen

   University of GroningenNo association between glucocorticoid receptor polymorphisms and long-term respiratoryoutcome after very preterm birthDutch POPS 19 Col; Baas, Emma M.; Romijn, Michelle; van der Pal, Sylvia M.; Vrijlandt, E. J.L. E.; Rotteveel, Joost; Finken, M. J. J.Published in:EndocrineDOI:10.1007/s12020-021-02672-7IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dutch POPS 19 Col, Baas, E. M., Romijn, M., van der Pal, S. M., Vrijlandt, E. J. L. E., Rotteveel, J., &Finken, M. J. J. (2021). No association between glucocorticoid receptor polymorphisms and long-termrespiratory outcome after very preterm birth. Endocrine, 73(1), 226-229. https://doi.org/10.1007/s12020-021-02672-7CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Endocrine (2021) 73:226–229https://doi.org/10.1007/s12020-021-02672-7RESEARCH LETTERNo association between glucocorticoid receptor polymorphisms andlong-term respiratory outcome after very preterm birthEmma M. Baas1 ● Michelle Romijn 1 ● Sylvia M. van der Pal2 ● Elianne J. L. E. Vrijlandt3 ● Joost Rotteveel1 ●Martijn J. J. Finken1 ● Dutch POPS-19 Collaborative Study GroupReceived: 10 July 2020 / Accepted: 24 February 2021 / Published online: 20 March 2021© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021In preterm infants in their first weeks of life, thehypothalamic-pituitary-adrenal (HPA) axis is unable toproduce sufficient amounts of cortisol for the degree ofillness [1, 2]. The causes for this phenomenon are prolongedcentral suppression, immature adrenocortical enzymes and acortisol-cortisone shuttle that favors cortisone [1, 3]. Cor-tisol is known for its anti-inflammatory effect. It has beendemonstrated among preterm infants that low-cortisol levelsmay predispose to disrupted lung development, manifestedas bronchopulmonary dysplasia (BPD) in approximately20% of all infants born <32 weeks of gestation [4, 5].A factor that might contribute to lung development afterpreterm birth is sensitivity to glucocorticoids. In adults,single-nucleotide polymorphisms (SNPs) in the glucocorti-coid receptor (GR) gene have previously been associatedwith alterations in glucocorticoid sensitivity [6, 7]. TheR23K polymorphism has been associated with decreasedsensitivity to glucocorticoids [8], while the N363S poly-morphism has been associated with increased glucocorti-coid sensitivity [9].We hypothesized that GR polymorphisms, might influ-ence respiratory morbidity after preterm birth. Previousstudies among preterm infants showed that these GRpolymorphisms were not associated with the risk of devel-oping BPD [10, 11]. However, the consequences of GRpolymorphisms on long-term respiratory outcome after verypreterm birth remain to be explored. Therefore, we inves-tigated associations between the GR polymorphisms R23Kand N363S and long-term respiratory outcomes in a cohortof subjects born very preterm birth who were followed upuntil young adulthood.Materials and methodsStudy design and participantsFor this study, data from the Project On Preterm and Small-for-gestational-age infants (POPS) study were used. ThePOPS study is a birth cohort study that had included 94%(N= 1338) of all liveborn very preterm (i.e., gestationalage <32 weeks) and/or very-low-birth-weight (i.e., <1500grams) infants throughout the Netherlands in 1983. Variousperinatal and neonatal characteristics were collected frombirth onwards, including the presence of BPD. BPD wasdefined as clinical signs of respiratory distress in conjunc-tion with abnormal findings on a chest X-ray and supple-mental oxygen at 28 days of age [5]. At the age of 19 years,all alive subjects were approached to participate in a follow-up study (POPS-19 study), in which, among other data, GRpolymorphisms were collected. The study was approvedby the medical ethics committee of all participating centers.All subjects gave written informed consent for participationin this study [8].Data collectionRespiratory outcomes were determined by self-report usingthe European Community Respiratory Health Survey(ECRHS) questionnaire [12]. The ECRHS questionnaireThese authors contributed equally: Emma M. Baas, Michelle RomijnMembers of the Dutch POPS-19 Collaborative Study Group are listedbelow Author contributions.* Michelle Romijnm.romijn1@amsterdamumc.nl1 Emma Children’s Hospital, Amsterdam UMC, Vrije UniversiteitAmsterdam, Pediatric Endocrinology, Amsterdam, TheNetherlands2 TNO, Child Health, Leiden, The Netherlands3 Beatrix Children’s Hospital, University Medical CenterGroningen, University of Groningen, Department of PediatricPulmonology and Pediatric Allergy, Groningen, The Netherlands1234567890();,:1234567890();,:was developed from pre-existing questionnaires that hadalready been used in multinational studies [12–14], andcontains questions about the presence of respiratory pro-blems or symptoms. Symptoms on the ECRHS ques-tionnaire showed correlation with objective measures oflung function [15]. This questionnaire was sent to all sub-jects known to be alive. At the same time, subjects wereseen for blood sampling at one of the participating centers[8].Laboratory analysisGR SNPs were determined by performing polymerase chainreactions using 2.5 ng of genomic DNA and standardreagents. Subsequently, they were genotyped by massspectrometry using standard conditions [8]. The genotypedistribution for both the R23K and the N363S polymorph-ism was in agreement with the distribution predicted by theHardy–Weinberg equilibrium (P= 0.54 for the R23Kpolymorphism, and P= 0.66 for the N363S polymorph-ism), and are mutual exclusives.Statistical analysisStatistical analyses were performed with SPSS Statisticsversion 26. Patient characteristics were compared betweenR23K carriers and non-carriers, and between N363S carriersand non-carriers, using the Chi square-test for dichotomousdata and the independent samples t-test or their nonpara-metric equivalents for continuous data. Outcomes werecompared between R23K carriers and non-carriers, andbetween N363S carriers and non-carriers, using logisticregression analysis.ResultsOf the 1012 very preterm born infants 676 (67%) were stillalive at the age of 19. Of these, 498 (74%) consented toparticipate in the POPS-19 study. In 318 (64%) of themgenomic data and ECHRS symptoms were known. After theexclusion of subjects with any congenital malformation,294 were available for analysis, including 21 (7%) R23Kcarriers, 15 (5%) N363S carriers and 258 (88%) non-carriers.Perinatal characteristics did not differ between the groups(data not shown).Respiratory outcomes at age 19 are shown by GR gen-otype in Table 1. No differences in scores of asthma, chestwheezing or shortness of breath were found between R23Kcarriers and non-carriers, or between N363S carriers andnon-carriers. Eczema was positively associated with R23Kcarriage (OR 3.05, 95% CI 1.03, 9.05, p value 0.045).Table1Respiratoryoutcomesatage19andneonatalrespiratoryoutcomesbygenotypeGenotypeOR+95%CIPvalueR23KN=21N363SN=15Non-carriersN=258R23Kvsnon-carriersN363Svsnon-carriersR23Kvsnon-carriersN363Svsnon-carriersRespiratoryoutcomesatage19Eczema—n(%)5(23.8%)1(6.7%)24(9.3%)3.05(1.03,9.05)0.70(0.09,5.53)0.0450.73Hayfever—n(%)1(4.8%)3(20.0%)18(7.0%)0.67(0.09,5.26)3.33(0.86,12.89)0.700.08Asthma—n(%)1(4.8%)1(6.7%)19(7.4%)0.68(0.09,5.36)1.02(0.13,8.25)0.710.99Asthmaattacklast12months—n(%)1(4.8%)0(0.0%)5(1.9%)NANA1.001.00Chestwheezinglast12months—n(%)8(38.1%)3(20.0%)56(21.7%)2.19(0.86,5.54)0.89(0.24,3.29)0.100.86SOBduringexercise—n(%)4(19.0%)0(0.0%)34(13.2%)1.28(0.40,4.06)NA0.681.00SOBwhilewalkingwithpeoplesameage—n(%)1(4.8%)0(0.0%)12(4.7%)0.86(0.11,6.98)NA0.891.00Needtostopforbreathwhenwalkingatownpaceonlevelground—n(%)0(0.0%)0(0.0%)8(3.1%)NANA1.001.00NeonatalrespiratoryoutcomesBPD—n(%)1(4.8%)2(13.3%)20(7.8%)0.60(0.08,4.67)1.83(0.39,8.69)0.620.45CPAPorIPPV,days—median[IQR]3[0–11]1[0,6]2[0,8]1.03(0.98,1.07)1.02(0.97,1.07)0.230.40SOBshortnessofbreath,BPDbronchopulmonarydysplasia,CPAPcontinuouspositiveairwaypressure,IPPVIntermittentpositivepressureventilation,Nnumber,IQRinterquartilerangeEndocrine (2021) 73:226–229 227Furthermore, no differences in the duration of respiratorysupport with continuous positive airway pressure (CPAP),intermittent positive pressure ventilation (IPPV) or thenumbers developing BPD were seen between R23K carriersand non-carriers and N363S carriers and non-carriers.DiscussionIn this study we found no association between the GRpolymorphisms R23K and N363S and respiratory outcomes19 years after very preterm birth.Respiratory outcome after preterm birth is determined bya complex interplay of lung immaturity, need for andduration of assisted ventilation, oxygen supplies, andrecurrent or enduring infections [16], in addition to otherfactors that are not specifically related to prematurity, suchas socioeconomic status, (maternal) smoking, BMI, andphysical activity [17]. Furthermore, our sample was born inthe pre-surfactant era [18]. Increasing degrees of pre-maturity and BPD were associated with more airflowimpairment later in life [17], possibly due to the presence ofsmaller airways [19, 20]. Although GR SNPs might influ-ence some of these processes, due to the multitude of factorsthat determine respiratory outcome after preterm birth theiroverall contribution is probably negligible.We found that carriers of the R23K polymorphism had ahigher odds of eczema. Although this association mightreflect a biologically plausible mechanism, it could also be achance finding. However, contrary to expectation, we foundthat carriers of the N363S polymorphism had a higher oddsof hay fever. Clearly, our results should be balanced againstthe small numbers of variant allele carriers.We found GR polymorphisms to be unrelated to the oddsof BPD, consistent with findings by Schreiner et al. [10].The lack of association can be explained by the complexmultifactorial pathophysiology of BPD or by selectivesurvival of certain genotypes [21]. However, the genotypefrequencies in this study did not differ from the genotypefrequencies in the Dutch norm population, which arguesagainst a major survivor effect [8].Our study has several strengths, including a large samplesize and long-term follow-up. Our study also has its lim-itations. Even though this study had a relatively large samplesize, the number of variant allele carriers (n= 36) was small.Nonetheless, the genotype distribution for both polymorph-isms was in agreement with the distribution predicted by theHardy–Weinberg equilibrium. Second, the POPS-19 studywas not designed specifically for our research question. GRSNPs were determined at age 19. In the early 1980s, manyvery preterm infants did not survive, which inevitably maygive rise to selection bias. In addition, participants were notrepresentative for the current generation of very preterminfants, which are more immature. Insufficient cortisol pro-duction and BPD are more frequent at lower gestational ages[2]. Third, patient-reported respiratory data are not asobjective as data derived from spirometry. Since respiratoryproblems may develop many years after preterm birth, serialfollow-up of spirometry would allow to determine the courseof pulmonary development after very preterm birth. Fourth,our study lacked an assessment of adrenocortical output andinflammatory markers during the neonatal course.In summary, our study did not show associationsbetween the GR polymorphisms R23K and N363S andlong-term respiratory outcome 19 years after very pretermbirth. Future studies on this topic should include serialmeasurements of adrenocortical output along with inflam-matory markers during the neonatal course, and shouldinclude an objective assessment of lung function.Authors’ contributions E.M.B., M.R., S.M.P., E.J.L.E.V., J.R., M.J.J.F:made substantial contributions to the conception or design of the work;or the acquisition, analysis, or interpretation of data; or the creation ofnew software used in the work; drafted the work or revised it criticallyfor important intellectual content; approved the version to be published;agree to be accountable for all aspects of the work in ensuring thatquestions related to the accuracy or integrity of any part of the work areappropriately investigated and resolved.Dutch POPS-19 Collaborative Study Group E. T. M. Hille4, C. H. deGroot4, H. Kloosterboer-Boerrigter4, A. L. den Ouden4, A. Rijpstra4,S. P. Verloove-Vanhorick4, J. A. Vogelaar4, J. H. Kok5, A. Ilsen5, M.van der Lans5, W. J. C. Boelen-van der Loo5, T. Lundqvist5, H. S. A.Heymans5, E. J. Duiverman6, W. B. Geven6, M. L. Duiverman6, L. I.Geven6, E. J. L. E. Vrijlandt6, A. L. M. Mulder7, A. Gerver7, L. A. A.Kollée8, L. Reijmers8, R. Sonnemans8, J. M. Wit9, F. W. Dekker9,M. J. J. Finken9, N. Weisglas-Kuperus10, M. G. Keijzer-Veen10, A. J.van der Heijden10, J. B. van Goudoever10, M. M. van Weissenbruch11,A. Cranendonk11, H. A. Delemarre-van de Waal11, L. de Groot11, J. F.Samsom11, L. S. de Vries12, K. J. Rademaker12, E. Moerman12,M. Voogsgeerd12, M. J. K. de Kleine13, P. Andriessen13, C. C. M.Dielissen-van Helvoirt13, I. Mohamed13, H. L. M. van Straaten14,W. Baerts14, G. W. Veneklaas Slots-Kloosterboer14, E. M. J. Tuller-Pikkemaat14, M. H. Ens-Dokkum15, G. J. van Steenbrugge164TNO Quality of Life, Leiden, The Netherlands; 5Emma Children’sHospital AMC, Amsterdam, The Netherlands; 6University HospitalGroningen, Beatrix Children’s Hospital, Groningen, The Netherlands;7University Hospital Maastricht, Maastricht, The Netherlands; 8Uni-versity Medical Center St Radboud, Nijmegen, The Netherlands;9Leiden University Medical Center, Leiden, The Netherlands; 10Eras-mus MC – Sophia Children’s Hospital, University Medical CenterRotterdam, Rotterdam, The Netherlands; 11V.U. University MedicalCenter, Amsterdam, The Netherlands; 12Wilhelmina Children’s Hos-pital, UMC, Utrecht, The Netherlands; 13Máxima Medical Center,Veldhoven, The Netherlands; 14Isala Clinics, Zwolle, The Nether-lands; 15Royal Effatha Guyot Group, Zoetermeer, The Netherlands;16Dutch Association of Parents of Newborn Infants,Leidschendam, The Netherlands228 Endocrine (2021) 73:226–229Compliance with ethical standardsConflict of interest The authors declare no competing interests.Publisher’s note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.References1. M.J. Finken et al. Glucocorticoid programming in very pretermbirth. Horm. Res. Paediatr. 85(4), 221–231 (2016)2. K.L. Watterberg, S.M. Scott, Evidence of early adrenal insuffi-ciency in babies who develop bronchopulmonary dysplasia.Pediatrics 95(1), 120–125 (1995)3. M.J.J. Finken et al. Programming of the hypothalamus-pituitary-adrenal axis by very preterm birth. Ann. Nutr. Metab. 70(3),170–174 (2017)4. K.L. Watterberg et al. Links between early adrenal function andrespiratory outcome in preterm infants: airway inflammation andpatent ductus arteriosus. Pediatrics 105(2), 320–324 (2000)5. E. Bancalari et al. Bronchopulmonary dysplasia: clinical pre-sentation. J. Pediatr. 95(5 Pt 2), 819–823 (1979)6. K. Ogasawara et al. A polymorphism in the glucocorticoidreceptor gene is associated with refractory hypotension in pre-mature infants. Pediatr. Neonatol. 59(3), 251–257 (2018)7. D.M. Haas et al. The impact of glucocorticoid polymorphisms onmarkers of neonatal respiratory disease after antenatal beta-methasone administration. Am. J. Obstet. Gynecol. 208(3), 215e1–215216 (2013)8. M.J. Finken et al. The 23K variant of the R23K polymorphism inthe glucocorticoid receptor gene protects against postnatal growthfailure and insulin resistance after preterm birth. J. Clin. Endo-crinol. Metab. 92(12), 4777–4782 (2007)9. N.A. Huizenga et al. A polymorphism in the glucocorticoidreceptor gene may be associated with and increased sensitivity toglucocorticoids in vivo. J. Clin. Endocrinol. Metab. 83(1),144–151 (1998)10. C. Schreiner et al. Glucocorticoid receptor gene variants andneonatal outcome in very-low-birth-weight preterm infants. Neo-natology 111(1), 22–29 (2017)11. R. Bertalan et al. Association between birth weight in pretermneonates and the BclI polymorphism of the glucocorticoid receptorgene. J. Steroid Biochem. Mol. Biol. 111(1-2), 91–94 (2008)12. E.J. Vrijlandt et al. Gender differences in respiratory symptoms in19-year-old adults born preterm. Respir. Res. 6, 117 (2005)13. G. Biino et al. ECRHS screening questionnaire scoring: a meth-odological suggestion for asthma assessment. European Com-munity Health Survey. J. Outcome Meas. 4(4), 740–762 (2000)14. P.G. Burney et al. The European Community Respiratory HealthSurvey. Eur. Respir. J. 7(5), 954–960 (1994)15. H.M. Boezen et al. Relation between respiratory symptoms, pul-monary function and peak flow variability in adults. Thorax 50(2),121–126 (1995)16. E.J. Vrijlandt et al. Respiratory health in prematurely born pre-school children with and without bronchopulmonary dysplasia.J. Pediatr. 150(3), 256–261 (2007)17. P. Nasanen-Gilmore et al. Lung function in adults born preterm.PLoS ONE 13(10), e0205979 (2018)18. N. El-Gendy et al. Delivery and performance of surfactantreplacement therapies to treat pulmonary disorders. Ther Deliv 4(8), 951–980 (2013)19. J.C. Hogg, P.D. Pare, T.L. Hackett, The contribution of smallairway obstruction to the pathogenesis of chronic obstructivepulmonary disease. Physiol. Rev. 97(2), 529–552 (2017)20. J.W. Duke et al. Premature birth affects the degree of airwaydysanapsis and mechanical ventilatory constraints. Exp. Physiol.103(2), 261–275 (2018)21. A.H. Jobe, The new bronchopulmonary dysplasia. Curr. Opin.Pediatr. 23(2), 167–172 (2011)Endocrine (2021) 73:226–229 229

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No association between glucocorticoid receptor polymorphisms and long-term respiratory outcome after very preterm birth

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