Abstract Derangement in pulmonary surfactant or its components and alveolar collapse are common findings in idiopathic pulmonary fibrosis (IPF). Surfactant proteins play important roles in innate host defense and normal function of the lung. We examined associations between IPF and genetic polymorphic variants of surfactant pro- teins, SP-A1, SP-A2, SP-B, SP-C, and SP-D. One SP-A1 (6A 4 ) allele and single nucleotide polymorphisms (SNPs) that characterize the 6A 4 allele, and one SP-B (B1580_C) were found with higher frequency (P≤0.01) in nonsmoker and smoker IPF (n=84) subgroups, respectively, compared with healthy controls (n=194). To explore whether a tryp- tophan (present in 6A 4 ) or an arginine (present in other SP-A1 alleles and in all SP-A2 alleles) at amino acid 219 alters protein behavior, two truncated proteins that varied only at amino acid 219 were oxidized by exposure to ozone. Differences in the absorption spectra (310–350 nm) be- tween the two truncated recombinant SP-A proteins were observed both before and after protein oxidation, suggest- ing allele-specific aggregation differences attributable to amino acid 219. The SP-B SNP B1580_C (odds ratio:7.63; confidence interval:1.64–35.4; P≤0.01), to be a risk factor for IPF smokers, has also been shown to be a risk factor for other pulmonary diseases. The SP-C and SP-D SNPs and SP-B-linked microsatellite markers studied did not associate with IPF. These findings indicate that surfactant protein variants may serve as markers to identify subgroups of patients at risk, and we speculate that these contribute to IPF pathogenesis. Introduction Pulmonary surfactant and surfactant proteins in general have been shown to play important roles in surfactant-re- lated functions, such as the lowering of surface tension in the alveoli at low lung volumes (Floros and Phelps 1997), and in host-defense functions including the regulation of proinflammatory cytokine production, chemotaxis, and tis- sue repair (Floros and Phelps 2002; Phelps 2001). There- fore, derangement in composition, structure, or function of surfactant proteins (SP-A, SP-B, SP-C, SP-D) may contribute to the development of many pulmonary dis- eases. The surfactant protein genes have all been character- ized and found to have a number of genetic polymor- phisms and/or mutations. These surfactant protein poly- morphisms, although not lethal, may, under certain condi- tions, compromise health and contribute to a disease patho- genesis of complex etiology in subjects who carry specific polymorphic markers. Therefore, the physiological rele- vance of the surfactant proteins to lung health and their natural genetic variation, which can serve as “tags” to iden- tify disease subgroups, make surfactant proteins good mod- els in the study of pulmonary diseases. Moises Selman · Hung-Mo Lin · Martha Montaño · Audrey L. Jenkins · Andrea Estrada · Zhenwu Lin · Guirong Wang · Susan L. DiAngelo · Xiaoxuan Guo · Todd M. Umstead · C. Max Lang · Annie Pardo · David S. Phelps · Joanna Floros Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis Hum Genet (2003) 113 : 542–550 DOI 10.1007/s00439-003-1015-4 Received: 2 June 2003 / Accepted: 1 August 2003 / Published online: 6 September 2003 ORIGINAL INVESTIGATION M. Selman · M. Montaño · A. Estrada Instituto Nacional de Enfermedades Respiratorias, México DF, México H.-M. Lin Department of Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA Z. Lin · G. Wang · S. L. DiAngelo · X. Guo · J. Floros (✉) Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA Tel.: +1-717-5316972, Fax: +1-717-5317667, e-mail: jfloros@psu.edu T. M. Umstead · D. S. Phelps · J. Floros Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA A. L. Jenkins · C. M. Lang Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA J. Floros Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA A. Pardo Facultad de Ciencias UNAM, México DF, México © Springer-Verlag 2003