The Gly82Ser mutation in AGER contributes to pathogenesis of pulmonary fibrosis in combined pulmonary fibrosis and emphysema (CPFE) in Japanese patients

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. 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. CPFE is characterized by upper-lobe emphysema and lower-lobe fibrosis on high-resolution computed tomography (HRCT) of the chest and preserved lung volume with serious diminished gas exchange capacity in pulmonary function tests. Because of frequent complications with pulmonary hypertension, acute lung injury, and lung cancer, the prognosis of CPFE is significantly poor relative to that of patients with emphysema only 1,2. To date, the pathogenesis of CPFE remains to be elucidated in terms of how the two conditions co-occur when they are considered to have different physiological and radiological characteristics. Our previous study demonstrated that enrichment of gene expression in fibrotic tissue differs from that in emphysematous lesions in lung tissues from patients with CPFE 3. Genetic factors have been suggested to be involved in CPFE pathogenesis. The receptor for advanced glycation end-products (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules 4. It interacts with distinct multiple ligands in ways that implicate it in homeostasis, development, inflammation, and certain lung diseases through modulation of multiple intracellular signaling pathways 4. RAGE is constitutively highly expressed in the lung 5 , where decreased expression is associated with pulmonary fibrosis 6 and lung cancer 7 and upregulated expression has been observed in COPD 8. The soluble form of RAGE (sRAGE) in the circulation is produced thro...

Chronic Obstructive Pulmonary Disease Combined with Interstitial Lung Disease

“…The ATP-binding cassette subfamily A member 3 (ABCA3) and surfactant protein-C (SFTPC) genes have important roles in the maintenance of lung surfactant homeostasis, and a few case reports have implied associations between CPFE and mutations in those genes [ 34 , 35 ]. A recent study by Kinjo et al [ 36 ] investigated the Gly82Ser mutation in the advanced glycosylation end-product specific receptor ( AGER ) gene in 111 patients with CPFE and 337 patients with COPD in Japanese patients. It revealed that the AGER gene mutation leads to receptor for advanced glycation end products pathway inhibition, which may be associated with lung fibrosis in patients with CPFE.…”

The role of HMGB1/RAGE/TLR4 signaling pathways in cigarette smoke‐induced inflammation in chronic obstructive pulmonary disease

“…Single nucleotide polymorphisms (SNPs) of the AGER gene have been correlated with the release of sRAGE, 80 resulting in the formation of airway inflammation. The related and common mutation sites are RS2071288, RS2070600, RS1800625, RS1800624, and rs184003 78,81‐83 . In addition, RAGE mediates the PTM of functional genes, and is also involved in COPD onset.…”

“…The related and common mutation sites are RS2071288, RS2070600, RS1800625, RS1800624, and rs184003. 78,[81][82][83] In addition, RAGE mediates the PTM of functional genes, and is also involved in COPD onset. Li et al 84 found that the chemokine CXCL1, TLR6, and oncostatin M were hypomethylated in the promoter regions with less severe airway inflammation caused by CS exposure after the RAGE gene was knocked out.…”

Chronic obstructive pulmonary disease combined with interstitial lung disease

“…The ATP-binding cassette subfamily A member 3 (ABCA3) and surfactant protein-C (SFTPC) genes have important roles in the maintenance of lung surfactant homeostasis, and a few case reports have implied associations between CPFE and mutations in those genes 34,35 . A recent study by Kinjo et al investigated the Gly82Ser mutation in the advanced glycosylation end-product specific receptor (AGER) gene in 111 patients with CPFE and 337 patients with COPD in Japanese patients 36 . It revealed that the AGER gene mutation leads to RAGE pathway inhibition, which may be associated with lung fibrosis in patients with CPFE.…”