Specific Gene Mutation Linked to PF and Emphysema in Japanese Patients, Study Suggests

Japanese people diagnosed with both pulmonary fibrosis (PF) and emphysema appear to carry a single genetic mutation that contributes to the development of both conditions, a study reports. 

This mutation was linked to lower levels of the anti-inflammatory protein esRAGE in the blood of patients. 

The study, “The Gly82Ser mutation in AGER contributes to pathogenesis of pulmonary fibrosis in combined pulmonary fibrosis and emphysema (CPFE) in Japanese patients,” was published in the journal Nature Scientific Reports. 

Some patients with PF also have the lung condition emphysema — characterized by damage to the tiny sacs in the lungs called alveoli. Emphysema is a type of chronic obstructive pulmonary disease (COPD). 

People with combined PF and emphysema, or CPFE, have fibrosis in the lower lung and emphysema in the upper lung. However, how these two different conditions develop simultaneously is not clearly understood, with some studies suggesting genetic factors playing a role.

The receptor for advanced glycation end products, known as RAGE, is a protein located in cell membranes and is a central mediator in chronic inflammatory and immune responses. Normally, RAGE is produced at high levels in the lungs, but it is found at low levels in the lungs of people with PF. 

An alternate form of RAGE, known as endogenous secretory RAGE (esRAGE), which circulates in the blood, has been shown to have anti-inflammatory properties and is also produced at low levels in the lungs of PF patients. 

Three single mutations — called rs2070600, rs1800625, and rs2853807 — in the gene that carries the instructions for the production of RAGE and esRAGE proteins, known as AGER, have been associated with lung function in COPD and PF. 

Now, researchers at the Shinshu University School of Medicine in Japan have conducted a genetic analysis of these mutations in Japanese patients with CPFE and compared the results with those found in COPD patients to identify disease-related differences between them. 

The study included 108 men and three women with CPFE and 324 men and 13 women with COPD. The average age in both groups was about 72 years, and there were no differences in smoking history. CT scans to assess the extent of emphysema in both groups found no significant differences.

The genetic analysis, conducted on DNA extracted from blood samples, showed significant differences between CPFE and COPD patients regarding the rs2070600 mutation — the mutation was more frequent in CPFE patients. There was no difference in frequency between the two groups in regards to the other two mutations, rs1800625 and rs2853807. 

Levels of esRAGE in the blood, measured in 81 men with CPFE and 116 men with COPD, were significantly lower in CPFE patients than in COPD patients — 598.6 vs. 754.9 picograms (pg)/mL in COPD patients.

Furthermore, significantly lower esRAGE concentrations were found in CPFE patients with the rs2070600 mutation (503.8 pg/mL) than in COPD patients with this mutation (743.4 pg/mL). No difference was seen in CPFE and COPD patients without this mutation.

A significant difference in esRAGE levels was found between CPFE patients with and without the rs2070600 mutation — 503.8 pg/mL with vs. 651.5 pg/mL without the mutation. 

In contrast, esRAGE levels did not differ between COPD patients with and without the rs2070600 mutation. The rs2070600 mutation leads to a change from glycine amino acid (a building block of proteins) to serine at position 82 in the protein sequence, which is vital for RAGE function. 

“Taking the evidence together, rs2070600 seems to alter RAGE function, leading to reduced serum sRAGE in CPFE, confirming a genetic role in the pathogenesis of pulmonary fibrosis in CPFE,” the researchers wrote. 

A statistical analysis showed an independent correlation between the rs2070600 mutation and the reduced sRAGE levels in CPFE patients. This correlation was not found in COPD patients. The other two mutations showed no significant associations with serum RAGE levels in either patient group.

Lung cancer is a frequent complication of CPFE, and was present in 73.9% of CPFE patients and 43.3% of COPD patients included in this study. Of note, the frequencies of the three mutations were not significantly different between patients with lung cancer and those without. 

“In conclusion, the AGER rs2070600 SNP (Gly82Ser mutation) was associated with the pathogenesis of pulmonary fibrosis in CPFE in Japanese patients,” the researchers wrote.