Human Molecular Genetics Advance Access originally published online on April 21, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 11 1095-1104
DOI: 10.1093/hmg/ddh132
Human Molecular Genetics, Vol. 13, No. 11 © Oxford University Press 2004; all rights reserved
Data mining and multiparameter analysis of lung surfactant protein genes in bronchopulmonary dysplasia
1Department of Paediatrics and Biocenter Oulu, University of Oulu, PO Box 5000, FIN-90014 Oulu, Finland, 2Seinäjoki Central Hospital, FIN-60220 Seinäjoki, Finland, 3CSC, The Finnish IT Centre for Science, PO Box 405, FIN-02101 Espoo, Finland and 4Tampere University Hospital, PO Box 2000, FIN-33521 Tampere, Finland
Received January 9, 2004; Revised March 12, 2004; Accepted April 1, 2004
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 
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.
* To whom correspondence should be addressed. Tel: +358 85376602; Fax: +358 85376600; Email: rhh{at}cc.oulu.fi
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