Abstract
The dominant pathogenesis underlying the combined pulmonary fibrosis and emphysema (CPFE) remains unresolved. The receptor for advanced glycation end-products (RAGE) is highly expressed in lung tissues and interacts with distinct multiple ligands, implicating it in certain lung diseases. To elucidate the pathogenesis of CPFE, we genotyped three single nucleotide polymorphisms (SNPs: rs2070600, rs1800625, and rs2853807) of the gene encoding RAGE (AGER) in 111 CPFE patients and 337 chronic obstructive pulmonary disease (COPD) patients of Japanese by using StepOne Real-Time PCR System for SNP genotyping assay. Serum levels of soluble RAGE (sRAGE) were measured by ELISA. We found that the allele frequency of rs2070600 was significantly different between the two groups [corrected P (Pc) = 0.015]. In addition, the minor allele was associated with CPFE patients relative to COPD patients in a dominant effect model (Odds Ratio = 1.93; Pc = 0.018). Moreover, the serum sRAGE level was significantly lower in the CPFE group than the COPD group (P = 0.014). The rs2070600 minor allele was significantly associated with reduced sRAGE level in CPFE patients and independently affected sRAGE level reduction in this group (P = 0.020). We concluded that the AGER rs2070600 minor allele (Gly82Ser mutation) is associated with the pathogenesis of pulmonary fibrosis in CPFE in Japanese patients.
Highlights
Some patients with chronic obstructive pulmonary disease (COPD) have concomitant pulmonary fibrosis in addition to emphysema, which is known as combined pulmonary fibrosis and emphysema (CPFE)[1]
The CPFE patients presented with reductions in the predicted percentage of diffusing capacity of lung for carbon monoxide (%DLco)
The remarkable finding of the present study was that the rs2070600 single nucleotide polymorphism (SNP) of AGER was significantly associated with susceptibility to CPFE relative to COPD
Summary
Some patients with chronic obstructive pulmonary disease (COPD) have concomitant pulmonary fibrosis in addition to emphysema, which is known as combined pulmonary fibrosis and emphysema (CPFE)[1]. The single nucleotide polymorphism (SNP) rs2070600 (Gly82Ser) on exon 3 is located at the ligand-binding site and works at the N-linked glycosylation site of the p rotein[11,12] This SNP has been demonstrated to be significantly associated with sRAGE level[13], lung function14,15, COPD16,17, and idiopathic pulmonary fibrosis (IPF)[18]. The SNP rs1800625 is located at the gene promoter and functions to increase RAGE expression and sRAGE levels[12] This SNP is involved in the pathogenesis of inflammatory diseases and the severity of cystic fibrosis[19]. SNP rs2853807 is located in intron 8 of AGER and has been evaluated for an association with IPF in Japanese patients[18] We hypothesized that these SNPs in AGER could be involved in the pathogenetic differences between CPFE and COPD. We assessed associations of the three SNPs with serum sRAGE levels in these patients
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