Pulmonary surfactant, a lipoprotein complex, is essential for normal lung function. Deficiency of surfactant can result in Respiratory Distress Syndrome (RDS) in the prematurely born infant. In certain families there is recurrence of RDS and some studies have suggested a genetic etiology of RDS. Prematurity, race, and gender also contribute to the etiology of RDS. It is unknown whether a single gene defect, different single gene defects in different families, or multiple gene defects in the same family contribute(s) to the pathogenesis of RDS. Thus, it is hypothesized that the etiology of RDS is multigenic/multifactorial. Our published work indicates that genetic alterations in the SP-B locus, comprising at least two classes of alleles that appear to be race-dependent are associated with RDS. Because not all infants with RDS carried the described alterations, additional genetic alterations associated with RDS must exist. Based on these findings, we hypothesize that the SP-B locus is likely to contain genes that either affect individual predisposition to RDS, or identify individual risk factors of RDS, or are linked to genes that have an impact on RDS. Because of the importance of SP-B in the function of surfactant and our findings we will use the candidate gene approach to study the genetic contribution of the SP-B locus to RDS. In specific, we propose to 1) characterize polymorphic markers in the SP-B locus with regards to meiotic stability and informativeness: 2) study associations between these markers and RDS. First we will study how each allele of marker locus is associated with the alleles of another marker locus to determine haplotypes. Then we will study associations between alleles/haplotypes and well-defined RDS and control subgroups. These studies will determine whether a single or multiple alleles/haplotypes associate with RDS pointing to genetic homogeneity or heterogeneity, respectively. 3) Study the relative contribution of genetic and nongenetic factors to RDS by studying concordance of RDS in twins. Significant concordance of RDS in monozygotic twins will suggest a significant genetic contribution. Concordance within twin pairs of an allele/haplotype and RDS will suggest a significant contribution by the loci studied. 4) Study families with recurrence of RDS to determine the strength of any association made in the previous Aims and assess the genetic heterogeneity of the disease. It is hoped that the proposed studies will establish a strong association between a marker and RDS, a prerequisite for subsequent studies, i.e. identify the disease gene(s) itself. This association may allow us to gain insight into the etiology of different RDS disease entities. It may also point to alternate treatment strategies for specific RDS subgroups (e.g. individuals who do not respond to antenatal steroid therapy).