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      A study of genes encoding cytokines ( IL6, IL10, TNF), cytokine receptors ( IL6R, IL6ST), and glucocorticoid receptor ( NR3C1) and susceptibility to bronchopulmonary dysplasia

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          Abstract

          Background

          Bronchopulmonary dysplasia (BPD) is a common chronic lung disease associated with very preterm birth. The major risk factors include lung inflammation and lung immaturity. In addition, genetic factors play an important role in susceptibility to moderate-to-severe BPD. In this study, the aim was to investigate whether common polymorphisms of specific genes that are involved in inflammation or differentiation of the lung have influence on BPD susceptibility.

          Methods

          Genes encoding interleukin-6 ( IL6) and its receptors ( IL6R and IL6ST), IL-10 ( IL10), tumor necrosis factor ( TNF), and glucocorticoid receptor ( NR3C1) were assessed for associations with moderate-to-severe BPD susceptibility. Five IL6, nine IL6R, four IL6ST, one IL10, two TNF, and 23 NR3C1 single nucleotide polymorphisms (SNPs) were analyzed in very preterm infants born in northern Finland (56 cases and 197 controls) and Canada (58 cases and 68 controls). IL-6, TNF and gp130 contents in umbilical cord blood, collected from very preterm infants, were studied for associations with the polymorphisms. Epistasis (i.e., interactions between SNPs in BPD susceptibility) was also examined. SNPs showing suggestive associations were analyzed in additional replication populations from Finland (39 cases and 188 controls) and Hungary (29 cases and 40 controls).

          Results

          None of the studied SNPs were associated with BPD nor were the IL6, TNF or IL6ST SNPs associated with cord blood IL-6, TNF and gp130, respectively. However, epistasis analysis suggested that SNPs in IL6ST and IL10 were associated interactively with risk of BPD in the northern Finnish population; however, this finding did not remain significant after correction for multiple testing and the finding was not replicated in the other populations.

          Conclusions

          We conclude that the analyzed SNPs within IL6, IL6R, IL6ST, IL10, TNF, and NR3C1 were not associated with BPD. Furthermore, there was no evidence that the studied SNPs directly contribute to the cord blood protein contents.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12881-014-0120-7) contains supplementary material, which is available to authorized users.

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          Most cited references 29

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          Impact of a physiologic definition on bronchopulmonary dysplasia rates.

           Kathy Auten,  N Newman,   (2004)
          Bronchopulmonary dysplasia (BPD) is the endpoint of many intervention trials in neonatology, yet the outcome measure when based solely on oxygen administration may be confounded by differing criteria for oxygen administration between physicians. We previously reported a technique to standardize the definition of BPD between sites by using a timed room-air challenge in selected infants. We hypothesized that a physiologic definition of BPD would reduce the variation in observed rates of BPD among different neonatal centers. Methodology. A total of 1598 consecutive inborn premature infants (501-1249 g birth weight) who remained hospitalized at 36 weeks' postmenstrual age were prospectively assessed and assigned an outcome with both a clinical definition and physiologic definition of BPD. The clinical definition of BPD was oxygen supplementation at exactly 36 weeks' postmenstrual age. The physiologic definition of BPD was assigned at 36 +/- 1 weeks' postmenstrual age and included 2 distinct subpopulations. First, neonates on positive pressure support or receiving >30% supplemental oxygen with saturations between 90% and 96% were assigned the outcome BPD and not tested further. Second, those receiving 30% with saturations >96% underwent a room-air challenge with continuous observation and oxygen-saturation monitoring. Outcomes of the room-air challenge were "no BPD" (saturations > or =90% during weaning and in room air for 30 minutes) or "BPD" (saturation <90%). At the conclusion of the room-air challenge, all infants were returned to their baseline oxygen levels. Safety (apnea, bradycardia, increased oxygen use) and outcomes of the physiologic definition versus the clinical definition were assessed. A total of 560 (35.0%) neonates were diagnosed with BPD by the clinical definition of oxygen use at 36 weeks' postmenstrual age. The physiologic definition diagnosed BPD in 398 (25.0%) neonates in the cohort. All infants were safely studied. There were marked differences in the impact of the definition on BPD rates between centers (mean reduction: 10%; range: 0-44%). Sixteen centers had a decrease in their BPD rate, and 1 center had no change in their rate. The physiologic definition of BPD reduced the overall rate of BPD and reduced the variation among centers. Significant center differences in the impact of the physiologic definition were seen, and differences remained even with the use of this standardized definition. The magnitude of the change in BPD rate is comparable to the magnitude of treatment effects seen in some clinical trials in BPD. The physiologic definition of BPD facilitates the measurement of BPD as an outcome in clinical trials and the comparison between and within centers over time.
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            The human glucocorticoid receptor: molecular basis of biologic function.

            The characterization of the subfamily of steroid hormone receptors has enhanced our understanding of how a set of hormonally derived lipophilic ligands controls cellular and molecular functions to influence development and help achieve homeostasis. The glucocorticoid receptor (GR), the first member of this subfamily, is a ubiquitously expressed intracellular protein, which functions as a ligand-dependent transcription factor that regulates the expression of glucocorticoid-responsive genes. The effector domains of the GR mediate transcriptional activation by recruiting coregulatory multi-subunit complexes that remodel chromatin, target initiation sites, and stabilize the RNA-polymerase II machinery for repeated rounds of transcription of target genes. This review summarizes the basic aspects of the structure and actions of the human (h) GR, and the molecular basis of its biologic functions.
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              Familial and genetic susceptibility to major neonatal morbidities in preterm twins.

              Intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia remain significant causes of morbidity and mortality in preterm newborns. Our goal was to assess the familial and genetic susceptibility to intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia. Mixed-effects logistic-regression and latent variable probit model analysis were used to assess the contribution of several covariates in a multicenter retrospective study of 450 twin pairs born at or =1 affected member had both members affected versus 3.69 expected. After controlling for covariates, genetic factors accounted for 53% of the variance in liability for bronchopulmonary dysplasia. Twin analyses show that intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia are familial in origin. These data demonstrate, for the first time, the significant genetic susceptibility for bronchopulmonary dysplasia in preterm infants.
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                Author and article information

                Contributors
                johanna.huusko@oulu.fi
                minna.k.karjalainen@oulu.fi
                mari.mahlman@gmail.com
                ritva.saastamoinen@oulu.fi
                Anneli.Kari@hus.fi
                sture.andersson@hus.fi
                toldigergely@yahoo.com
                Outi.Tammela@uta.fi
                Mika.Ramet@uta.fi
                plavoie@cw.bc.ca
                mikko.hallman@oulu.fi
                Journal
                BMC Med Genet
                BMC Med. Genet
                BMC Medical Genetics
                BioMed Central (London )
                1471-2350
                1 November 2014
                1 November 2014
                2014
                : 15
                : 1
                Affiliations
                [ ]Department of Pediatrics, Institute of Clinical Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
                [ ]Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
                [ ]Biocenter Oulu, Oulu, Finland
                [ ]Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
                [ ]First Department of Pediatrics, Semmelweis University, Budapest, Hungary
                [ ]Department of Pediatrics, Tampere University Hospital, Tampere, Finland
                [ ]BioMediTech, University of Tampere, Tampere, Finland
                [ ]Child and Family Research Institute of British Columbia, Vancouver, Canada
                Article
                120
                10.1186/s12881-014-0120-7
                4258941
                25409741
                © Huusko et al.; licensee BioMed Central Ltd. 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                © The Author(s) 2014

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