Data mining and multiparameter analysis of lung surfactant protein genes in bronchopulmonary dysplasia

Abstract

Bronchopulmonary dysplasia (BPD), the most common chronic lung disease in infancy, is influenced by a number of antenatal and postnatal risk factors and is mostly preceded by respiratory distress syndrome (RDS) in the newborn. Surfactant protein (SP-A, -B, -C and -D) gene variations may play a role in both BPD and RDS. An association study between these candidate genes and BPD was performed. A total of 365 preterm Finnish infants in a high-risk population with gestational age <or=32 weeks were genotyped for all SP genes. A multiparameter analysis was performed using Agrawal's algorithm based data mining and conventional methods of statistical allelic association. In singletons and presenting multiples, the frequency of SP-B intron 4 deletion variant allele was increased in BPD versus controls (P=0.008, OR=2.0, 95%CI 1.2-3.4). The presence of the SP-B intron 4 deletion variant was a risk factor for BPD even when essential external confounding factors were included in the analyses. No other SP polymorphisms associated with BPD, and the SP-B intron 4 variation did not associate with RDS. Transcription Element Search Software predicted allele-specific differences at several putative transcription factor binding sites that may be important in SP-B regulation. The present multiparameter analysis demonstrates the presumable direct involvement of the SP-B intron 4 deletion variant allele as a genetic risk factor to BPD. We propose that two separate SP-B gene polymorphisms have a phenotypic significance via separate molecular mechanisms: the intron 4 length variation affecting transcriptional regulation, and the exonic Ile131Thr variation affecting post-translationally.

A Polymorphism in the Macrophage Migration Inhibitory Factor Promoter Is Associated With Bronchopulmonary Dysplasia

“…Some of the studies that reported gene polymorphisms associated with BPD did not evaluate the independency from O 2 exposure (10,13,14), making it rather difficult to evaluate the interaction of the associated polymorphisms with the main environmental causative factor of BPD. Interestingly, a recent report showed that a promoter polymorphism (Ϫ460 T/C) of the VEGF gene was associated with an increased risk of BPD, independently from the duration of O 2 exposure (12).…”

Heritability of Bronchopulmonary Dysplasia, Defined According to the Consensus Statement of the National Institutes of Health

“…interleukin-6 or 13), or deficiency in Toll-like receptor 4, which is a critical receptor component for gram-negative bacteria's lipopolysaccharide inflammatory response, show increased susceptibility to hyperoxia-induced lung injury. [19][20][21][22][23] In humans, polymorphisms in surfactant protein A & B, TNF-α, angiotensin-converting enzyme and gluthathione-S-transferase-P1 genes, genes, and having known altered biological functions, have been linked in small studies with variations in risk of BPD or its severity, [24][25][26][27] although others have 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 individual's ethnic background to susceptibility.…”

Association of polymorphisms in the mannose-binding lectin gene and pulmonary morbidity in preterm infants

“…Thus, the functional relationship of MBL and other humoral lectins as SP-D and SP-A in the pulmonary innate host defense may reveal new aspects in the pathogenesis of the disease that need to be focussed in further studies. 43,44 Furthermore, the results of this study need to be validated in further independent samples. The fact that no association between the development of early-onset or nosocomial infections and the MBL polymorphisms investigated was detected can be explained by the severe immaturity of the immune system in the preterm infants.…”