A set of rare, disease-causing variants in genes that help control both the body’s immune response and cell adhesion — the process by which cells form connections with other cells or their environment — were found to be more common in China in patients with idiopathic pulmonary fibrosis (IPF) than in healthy people.
According to investigators, the discovery of these gene variants may help explain the reason why some signaling cascades involved in the control of the body’s immune system are altered in IPF patients. Yet, the team also noted that additional studies are needed to confirm these findings.
The data were reported in the study, “Whole-exome sequencing identifies susceptibility genes and pathways for idiopathic pulmonary fibrosis in the Chinese population,” published in the journal Nature Scientific Reports.
Although the exact causes that lead to the onset of IPF are unknown, several gene variants have been reported to help increase a person’s susceptibility to developing the disease. This is the case with one of the alleles of rs35705950, a single nucleotide polymorphism (SNP) found in the promoter region of the MUC5B gene.
Alleles are different forms of the same gene, while SNPs are variations in a single nucleotide — the DNA building blocks — in the DNA sequence of a gene. A promoter, meanwhile, is the DNA sequence within a gene that controls its activity.
While rs35705950 has been linked to IPF, the contribution of other rare genetic variants for the disease’s onset — particularly among the Chinese population — has not been thoroughly explored.
Now, investigators in China reported the findings of a study that sought to identify genes containing a high number of rare disease-causing variants that could be important genetic risk factors for IPF in a population of Chinese patients.
“We aimed to identify genes and biological pathways enriched with rare deleterious [disease-causing] variants, which would guide the future genetic and functional studies to elucidate the role of rare variants in the pathogenesis [development] of IPF,” the team wrote.
The scientists used whole-exome sequencing (WES), a technique that analyzes the DNA sequence of all genes that encode proteins (exome). WES was used to identify candidate genes in 110 IPF patients and 60 healthy individuals (controls) who were matched by age, gender, and smoking status to the IPF patients.
Genes that were found more often (enriched) in the IPF patients were subjected to additional analyses based on gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) to determine their biological function.
After performing these analyses, the investigators identified a total of 226 genes that contained a high number of rare disease-causing variants in the subgroup of IPF patients analyzed. From these, 36 genes were confirmed by GO and KEGG to be enriched in IPF patient samples.
When the investigators looked at each of these genes in more detail, they discovered that many of them were involved in signaling pathways that played a role in regulating the body’s immune system and the process of cell adhesion.
“These findings suggested that mutated genes involved in the immunity pathway or the cell adhesion pathway might play a role in the risk or susceptibility of IPF,” the researchers wrote.
A possible association between these identified genes and the known MUC5B risk allele also was investigated.
“Since IPF patients who do not carry the MUC5B risk allele have shorter survival from the time of diagnosis than those carrying the risk allele, we also assessed whether immune-related genes with rare deleterious variants were enriched in MUC5B non-carriers,” the team wrote.
The results showed no significant association between variants in these immune-related genes in patients with or without the MUC5B risk allele. Those findings, according to the team, “suggest that multiple genetic factors and mechanisms might play roles in IPF progression.”
Overall, based on the findings, the researchers believe that the variants found in specific genes might “partially explain changes in gene expression [activity] involved in the immunity/inflammatory pathways in IPF patients.”
However, more work needs to be done to confirm these results and to determine exactly how the newly discovered gene variants work in IPF.
“Further validation studies with larger statistical power are needed to verify these findings and identify the underlying functional mechanisms,” the team concluded.
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