Genetic variations that lower the expression levels of a gene called RNF5 may explain why some people with cystic fibrosis (CF) are at lesser risk of developing lung infections, a study reports.
The study, “Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease,” was published in the journal eLIFE.
Lung infections are a common problem for CF patients, and a main cause of life-threatening complications. Most lung infections in these people are caused by Staphylococcus aureus and Pseudomonas aeruginosa bacteria.
However, some patients develop fewer infections — or milder infections at later stages — than others, for reasons that remain unknown.
Researchers at the University of California San Diego are studying the variability of a large set of genes — the human leukocyte antigens or HLA system that encodes for the MHC major histocompatibility complex proteins.
MHC protein complexes are responsible for presenting antigens (proteins that can trigger an immune reaction) to the immune cells. For instance, when a cell is infected, small peptides of the microorganism (antigens) are presented by the MHC complex to immune cells, so that they can detect and destroy the infected cell.
The HLA complex is extremely diverse in human populations, and genetic variations in these genes are long associated with the development of autoimmune diseases.
To investigate the relation between HLA types and disease features, the researchers analyzed data from the genome of induced pluripotent stem cells (iPSCs; cells that are able to generate almost any type of cell) from 419 individuals.
Data included a total of 180 MHC variants that were compared to over 4,000 disease traits.
Results showed that an HLA haplotype (a set of DNA variations, or polymorphisms, that tend to be inherited together) was strongly associated with a lower expression of the RNF5 gene, which is involved in the degradation of mutated CFTR proteins. (CFTR is the defective protein in CF; gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.)
Researchers argued that a lower expression of RNF5 allows for abnormal CFTR proteins to be stabilized, partly rescuing their function as ion channels at the cell surface.
This means that in patients carrying this HLA haplotype, the activity of RNF5 is lower, which results in less mucus secretion. This, in turn, makes these patients less prone to infections by bacteria like S. aureus and P. aeruginosa.
“We’ve known there’s an association between MHC genes and bacterial colonization in patients with cystic fibrosis, but no one knew why,” Kelly A. Frazer, PhD, a professor of pediatrics, director of the Institute for Genomic Medicine at UC San Diego School of Medicine, and the study’s lead author, said in a university news story.
“We assumed it was due to MHC’s involvement in the immune system. But now we know that’s likely not the only mechanism — different expression levels of RNF5 may also play an important role,” Frazer added.
Added Matteo D’Antonio, PhD, a scientist in Frazer’s lab and the study’s first author: “This study uncovered a new aspect of cystic fibrosis — one that could lead to new drug design and development, and allow clinicians to better tailor treatments.”
The researchers suggest further exploration of their findings “to identify causal mechanisms underlying disease associations in the MHC region, and potentially novel drug targets,” they wrote.
“The cystic fibrosis field is trying to figure out what are the modifiers across the genome that increase or decrease the probability that an individual patient will respond to” treatment, Frazer said, and her team now believes that “RNF5 may be one of these modifier genes.”