are associated with susceptibility to respiratory distress ... The main SP-A1 allele 6A22 (P = 0.030), genotype ... distress syndrome; surfactant protein A; twins.
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ORIGINAL
ARTICLE
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Surfactant protein A gene locus and respiratory distress syndrome in Finnish premature twin pairs Riitta Marttila1, Ritva Haataja2,3, Mika RaÈmet2,3, Marja-Leena Pokela2, Outi Tammela4 and Mikko Hallman2,3
BACKGROUND. Surfactant protein A (SP-A) polymorphisms are associated with susceptibility to respiratory distress syndrome (RDS). According to present hypothesis the association between SP-A polymorphisms and RDS may not be applicable to the entire population of premature infants. AIM. The present study was designed to evaluate the associations between SP-A allelic variants and RDS in a population consisting of 198 premature twin pairs. METHOD. Genotype analysis of the SP-A1 and SP-A2 genes and twin zygosity de®nition were carried out. RESULTS. The main SP-A1 allele 6A2 (P = 0.030), genotype 6A2/6A2 (P = 0.0042) and haplotype 6A2-1A0 (P = 0.016) were over-represented in healthy premature twin infants compared to RDS twins. The homozygous genotype 6A2/6A2 was over-represented in twin pairs of whom both were healthy compared to twins concordant for RDS (odds ratio 0.18, con®dence intervals 0.06±0.6, P = 0.0016) and born between 32 and 36 weeks. 6A2/6A2 was also overrepresented in healthy twin pairs with birth weight sum higher than the median (OR 0.15, CI 0.04±0.6, P = 0.0025). CONCLUSIONS. In twins, the association between SP-A polymorphism and RDS is different from that seen in premature singleton infants. The factor associated with SPA genotype-speci®c susceptibility to RDS appears to be related to the size of uterus and the length of gestation at birth. Keywords: genetics; intrauterine growth; newborn; prematurity; respiratory distress syndrome; surfactant protein A; twins
Ann Med 2003; 35: 344±352
From the 1Central Hospital of Southern Ostrobothnia, SeinaÈjoki, Finland, 2Department of Pediatrics, University of Oulu, Finland, 3Biocenter Oulu, University of Oulu, Finland, 4Department of Pediatrics, University of Tampere, Tampere, Finland. Correspondence: Mikko Hallman, MD, Department of Pediatrics and Biocenter Oulu, FIN-90014 University of Oulu, PO Box 5000, Finland. Fax: +358-8-4315 5559: E-mail: mikko. hallman@oulu.® Received: 17 January 2003; revision accepted 27 March 2003. # 2003 Taylor & Francis. ISSN 0785-3890 DOI 10.1080/07853890310006389
Introduction
Neonatal respiratory distress syndrome (RDS) of premature infants manifests as progressive respiratory failure shortly after birth. The susceptibility to RDS is due to a de®ciency of surfactant required for alveolar stability (1). Along with phospholipids, surfactant proteins play critical roles in surfactant function. The synthesis and secretion of the surfactant complex are developmentally regulated by hormones and growth factors (2). Glucocorticoids given antenatally accelerate lung maturity, thus preventing RDS (3). Several environmental and genetic factors contribute to the risk of RDS (4±10). The speci®c genes underlying the susceptibility to RDS are incompletely known. The most abundant surfactant protein, surfactant protein A (SP-A), is a hydrophilic collagen-type lectin that binds to the surfactant complex improving surface activity, and serves as a component of the innate host defense system in the lung (11, 12). The human SP-A locus in chromosome 10q22-q23 consists of two functional genes, SP-A1 and SP-A2 (13, 14). The coding sequences of both genes have several single-nucleotide polymorphisms (SNPs) (15, 16). Some of the SNPs result in amino acid substitution that potentially in¯uences the function of the SPA protein complex, whereas the others are silent changes. The major SP-A1 allele 6A2 contains an insertion of 11 base pairs in the 3'untranslated region of the gene, which is absent in the other SP-A1 alleles. There is evidence of allele-speci®c differences in the SP-A mRNA levels (17) in response to cytokines (18) and glucocorticoids (19). Allelic association studies have shown evidence of SP-A having a role in the etiology of RDS (20). The association between SP-A alleles and RDS is dependent on the gestational age of the premature infant (21). Recent family-based transmission disequilibrium tests further support the role of speci®c SP-A alleles and haplotypes as genetic susceptibility or protection factors for RDS (10, 22). Annals of Medicine 35
SP-A
ALLELES AND RISK OF
Abbreviations and acronyms RDS SP-A SNP CI OR HOR MZ DZ EDTA PCR cRFLP TNF
respiratory distress syndrome surfactant protein A single nucleotide polymorphism con®dence interval odds ratio homogeneity of the odds ratio monozygotic dizygotic ethylenediaminetetraacetate polymerase chain reaction converted restriction fragment length polymorphism tumor necrosis factor
According to present hypothesis the association between SP-A polymorphisms and RDS may not be applicable to the entire population of premature infants (21, 2). There also seems to be variation in the SP-A allele distribution between different ethnic populations (20, 21). The present twin study was undertaken to de®ne the role of the SP-A gene polymorphism and gene-environmental interactions in the incidence of RDS in infants of Caucasian origin.
Subjects and methods Study design
The study population consisted of Finnish premature (