Influence of Common Non-Synonymous Toll-like Receptor 4 Polymorphisms on Bronchopulmonary Dysplasia and Prematurity in Human Infants

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease and major risk factor for severe respiratory syncytial virus (RSV) infection among preterm infants. The Toll-like receptor 4 (TLR4) is involved in oxidative injury responses in the lungs. Two non-synonymous single nucleotide polymorphisms in the TLR4 gene have been associated with RSV infection in children. However, it is unclear to what extent this association is confounded by BPD or prematurity. In this study, we analyzed two population-based cohorts of preterm infants at risk for BPD as well as ethnicity-matched infants born at term, to test whether the TLR4 polymorphisms Asp299Gly (rs4986790) and Thr399Ile (rs4986791) are independently associated with BPD or premature birth. In a Canadian cohort (n = 269) composed of a majority of Caucasian preterm infants (BPD incidence of 38%), the TLR4-299 heterozygous genotype was significantly under-represented in infants without BPD (1.6% of infants versus 12% in infants with severe BPD) after adjusting for twins, ethnicity, gestational age, birth weight and gender (p = 0.014). This association was not replicated in a Finnish cohort (n = 434) of premature singletons or first-born siblings of Caucasian descent, although the incidence of BPD was substantially lower in this latter population (15%). We did not detect a significant association (>2-fold) between TLR4 genotypes and prematurity (p>0.05). We conclude that these TLR4 genotypes may have, at best, a modest influence on BPD severity in some populations of high-risk preterm infants. Further studies are warranted to clarify how clinical heterogeneity may impact genetic susceptibility to BPD

Expression of CPPED1 in human trophoblasts is associated with timing of term birth

Understanding of timing of human parturition is incomplete. Therefore, we carried out proteomic analyses of full-term placentas from uncomplicated pregnancies to identify protein signatures associated with the onset of spontaneous delivery. We found quantitative associations of 10 proteins with spontaneous term birth, evident either in the basal or in the chorionic plates or in both. Additional 18 proteins were associated according to the location within placenta indicating local variations in protein amounts. Calcineurin-like phosphoesterase domain-containing 1 (CPPED1), a phosphatase previously suggested dephosphorylating AKT1/PKB, was one of the identified proteins. qRT-PCR revealed the mRNA level of CPPED1 was higher in elective caesarean deliveries than in spontaneous births, while immunohistochemistry showed CPPED1 in cytotrophoblasts, syncytiotrophoblasts and extravillous trophoblasts. Noteworthy, phosphorylation status of AKT1 did not differ between placentas from elective caesarean and spontaneous deliveries. Additionally, analyses of samples from infants indicated that single-nucleotide polymorphisms rs11643593 and rs8048866 of CPPED1 were associated with duration of term pregnancy. Finally, post-transcriptional silencing of CPPED1 in cultured HTR8/SVneo cells by siRNAs affected gene expression in pathways associated with inflammation and blood vessel development. We postulate that functions regulated by CPPED1 in trophoblasts at choriodecidual interphase have a role in the induction of term labour, but it may be independent of AKT1

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

Peer reviewe

Genetic background and antenatal risk factors of bronchopulmonary dysplasia

Abstract Advances over the past few decades in ante- and neonatal care have led to the survival of a growing number of premature infants of extremely low gestational age. However, the occurrence of serious diseases, particularly those affecting the most immature infants, remains high. Bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants, is one such disease. Our current understanding of the molecular pathogenesis of BPD is incomplete; consequently, there are few preventive and therapeutic options for BPD. Moreover, it is challenging to predict the risk of BPD. Previous studies of BPD in twins revealed that the heritability of BPD is quite high. However, the individual genes that predispose premature infants to BPD are largely unknown. The aim of this study was to identify and study genes associated with BPD in order to investigate its pathogenesis. An additional aim was to add to knowledge of the risk of BPD in newborn premature infants, with an emphasis on twins. A candidate gene study found no consistent association between common polymorphisms of vascular endothelial growth factor receptor 2 and BPD. A second candidate gene study noted an association between the gene encoding Kit ligand and BPD. A genome-wide association study found a suggestive association between a locus close to the gene encoding C-reactive protein (CRP) and BPD, and in subsequent analyses, plasma levels of CRP during the first week of life predicted BPD. Finally, a nationwide register study found that the risk of BPD was lower in twins than in singletons. The results of this study add to what is known of the genetics and pathogenesis of BPD. They also provide new data on the risk of BPD, which may be used to improve early identification of infants for whom the risk of developing BPD is high.Tiivistelmä Ennenaikaisen syntymän ja keskoslasten hoidon kehittymisen myötä yhä useammat huomattavan epäkypsinä syntyneet lapset jäävät henkiin. Samalla erityisesti juuri näitä lapsia uhkaavien sairauksien esiintyvyys on pysynyt korkeana. Bronkopulmonaalinen dysplasia (BPD, keskosen krooninen keuhkosairaus) on yksi näistä sairauksista. BPD:n molekyylitasoinen tautimekanismi on vielä osin tuntematon, eikä BPD:tä tehokkaasti estävää tai siitä parantavaa hoitoa ole. Myös BPD riskin arvioiminen vastasyntyneen keskoslapsen kohdalla on vaikeaa. BPD on huomattavan perinnöllinen tauti. BPD:lle altistavista geeneistä on kuitenkin vasta vähän tietoa. Tämän tutkimuksen tavoitteena oli lisätä tietoa BPD:n tautimekanismista tutkimalla BPD:lle altistavia geenejä. Lisäksi tutkimuksessa tarkasteltiin BPD:n esiintyvyyttä ja syntymää edeltäviä riskitekijöitä erityisesti kaksosten osalta. Ehdokasgeenitutkimuksessa verisuonten endoteelikasvutekijää koodaava geeni ei assosioitunut toistuvasti BPD:hen. Kit ligandia koodaava geeni sen sijaan assosioitui. Koko genomin assosiaatiotutkimuksessa C-reaktiivista proteiinia (CRP) koodaavan geenin lähistöltä löydettiin BPD:hen mahdollisesti assosioituva alue. Lisäksi ensimmäisen viikon CRP-arvojen osoitettiin ennakoivan myöhemmin kehittyvää BPD:tä. BPD-riskin todettiin olevan matalampi kaksi- kuin yksisikiöisistä raskauksista syntyneillä lapsilla. Tutkimuksen tulokset lisäävät tietoa BPD:n perinnöllisyydestä ja sitä kautta BPD:n tautimekanismista. Tutkimus toi myös uutta tietoa BPD:n riskitekijöistä parantaen vastasyntyneen keskoslapsen BPD-riskin arviota

Association between <i>TLR4</i> genotypes and BPD in preterm cohort B.

<p>GA: Gestational age; BW: Birth weight;</p>*<p>Combining heterozygous/rare homozygous genotypes.</p>†<p>Chi-square or Fisher exact as indicated.</p

Ethnicity of infants in preterm cohort A and matched control term infants.

†<p>Differences considered statistically significant are underlined.</p>*<p>Combined heterogenous/rare homozygous genotype includes both preterm and infants born at term. NF  =  none found. The term “First Nations” refers to Canadian Indigenous Nations as defined by the Government of Canada.</p

Multiple regression analysis between clinical co-variables and <i>TLR4-299</i> genotype^* (dependent variable).

*<p>Results are shown for combined heterozygous/rare homozygous genotypes in binary regression. Significance was also comparable using all three genotypes (Asp/Asp, Asp/Gly and Gly/Gly) in regression models using BPD (p = 0.016) as the dependent variable.</p

Association between <i>TLR4</i> genotypes and BPD in preterm cohort A.

<p>GA: Gestational age; BW: Birth weight; 95%CI: 95% confidence interval.</p>*<p>Combining heterozygous/rare homozygous genotypes.</p>†<p>Statistically significant differences are underlined;</p>§<p>Comparing the Moderate/Severe with the No BPD group.</p

Clinical characteristics of infants in preterm cohort A.

&<p>Up to transfer to peripheral centre or discharge home.</p>*<p>Based on neonates alive at 36 weeks PMA.</p>†<p>Differences considered statistically significant are underlined.</p>£<p>Differences were not statistically significant (p>0.05) based on non-parametric Mann-Whitney U testing. NC = Not calculated.</p