Surfactant Protein-C Promoter Variants Associated With Neonatal Respiratory Distress Syndrome Reduce Transcription

• Published in: Pediatric research Vol. 68; no. 3; pp. 216 - 220
• Main Authors: Wambach, Jennifer A, Yang, Ping, Wegner, Daniel J, An, Ping, Hackett, Brian P, Cole, F S, Hamvas, Aaron
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2010; Lippincott Williams & Wilkins
• Subjects: Animals; Base Sequence; Biological and medical sciences; Case-Control Studies; Cell Line, Tumor; European Continental Ancestry Group - genetics; General aspects; Genotype; Humans; Infant, Newborn; Linkage Disequilibrium; Logistic Models; Luciferases; Medical sciences; Medicine; Medicine & Public Health; Mice; Molecular Sequence Data; Pediatric Surgery; Pediatrics; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic - genetics; Pulmonary Surfactant-Associated Protein C - genetics; Pulmonary Surfactant-Associated Protein C - metabolism; Respiratory Distress Syndrome, Newborn - genetics; Sequence Analysis, DNA; Transcription, Genetic - genetics; translational-investigation; Untranslated Regions - genetics; Pediatrics; Genetic variability; Transcription; Genotype; Protein C; Neonatal distress; Genetic determinism; Promoter; Variant; Association; Pulmonary surfactant; Adult respiratory distress syndrome; Genetics; Collectin; Natural anticoagulant
• ISSN: 0031-3998; 1530-0447
• DOI: 10.1203/PDR.0b013e3181eb5d68

Dominant mutations in coding regions of the surfactant protein-C gene, SFTPC , cause respiratory distress syndrome (RDS) in infants. However, the contribution of variants in noncoding regions of SFTPC to pulmonary phenotypes is unknown. By using a case-control group of infants ≥34 weeks gestation ( n = 538), we used complete resequencing of SFTPC and its promoter, genotyping, and logistic regression to identify 80 single nucleotide polymorphisms (SNPs). Three promoter SNPs were statistically associated with neonatal RDS among European descent infants. To assess the transcriptional effects of these three promoter SNPs, we selectively mutated the SFTPC promoter and performed transient transfection using MLE-15 cells and a firefly luciferase reporter vector. Each promoter SNP decreased SFTPC transcription. The combination of two variants in high linkage dysequilibrium also decreased SFTPC transcription. In silico evaluation of transcription factor binding demonstrated that the rare allele at g.−1167 disrupts a SOX (SRY-related high mobility group box) consensus motif and introduces a GATA-1 site, at g.−2385 removes a MZF-1 (myeloid zinc finger) binding site, and at g.−1647 removes a potential methylation site. This combined statistical, in vitro , and in silico approach suggests that reduced SFTPC transcription contributes to the genetic risk for neonatal RDS in developmentally susceptible infants.