A common polymorphism in the SFTPD gene influences assembly, function, and concentration of surfactant protein D

Surfactant protein D (SP-D) plays important roles in the host defense against infectious microorganisms and in regulating the innate immune response to a variety of pathogen-associated molecular pattern. SP-D is mainly expressed by type II cells of the lung, but SP-D is generally found on epithelial surfaces and in serum. Genotyping for three single-nucleotide variations altering amino acids in the mature protein in codon 11 (Met¹¹Thr), 160 (Ala ¹⁶⁰Thr), and 270 (Ser²⁷⁰Thr) of the SP-D gene was performed and related to the SP-D levels in serum. Individuals with the Thr/Thr¹¹-encoding genotype had significantly lower SP-D serum levels than individuals with the Met/Met¹¹ genotype. Gel filtration chromatography revealed two distinct m.w. peaks with SP-D immunoreactivity in serum from Met/Met¹¹-encoding genotypes. In contrast, Thr/Thr ¹¹ genotypes lacked the highest m.w. form. A similar SP-D size distribution was found for recombinant Met¹¹ and Thr¹¹ expressed in human embryonic kidney cells. Atomic force microscopy of purified SP-D showed that components eluting in the position of the high m.w. peak consist of multimers, dodecamers, and monomers of subunits, whereas the second peak exclusively contains monomers. SP-D from both peaks bound to mannan-coated ELISA plates. SP-D from the high m.w. peak bound preferentially to intact influenza A virus and Gram-positive and Gram-negative bacteria, whereas the monomeric species preferentially bound to isolated LPS. Our data strongly suggest that polymorphic variation in the N-terminal domain of the SP-D molecule influences oligomerization, function, and the concentration of the molecule in serum.