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Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis

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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 proteins, SP-A1, SP-A2, SP-B, SP-C, and SP-D. One SP-A1 (6A4) allele and single nucleotide polymorphisms (SNPs) that characterize the 6A4 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 tryptophan (present in 6A4) 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) between the two truncated recombinant SP-A proteins were observed both before and after protein oxidation, suggesting 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.

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Acknowledgements

The authors thank Dr. Makhatadze for the gift of pGIa vector and advice on protein purification, and Sue Myers for typing. This work was supported by NIH R37 HL34788, NIH R01 ES09882, NIH 5T 32RR07066–04 (A.J.), by Philip Morris Incorporated, and by the General Clinical Research Center at the Penn State University, College of Medicine.

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Selman, M., Lin, HM., Montaño, M. et al. Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis. Hum Genet 113, 542–550 (2003). https://doi.org/10.1007/s00439-003-1015-4

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