Gene Variations May Explain Resistance to Lung Infections in Some CF Patients, Study Says

Gene Variations May Explain Resistance to Lung Infections in Some CF Patients, Study Says
0
(0)

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.”

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Department of Microbiology & Immunology, Columbia University, New York.
Total Posts: 336

Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

×
Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Department of Microbiology & Immunology, Columbia University, New York.
Latest Posts
  • hemoptysis risk
  • ContraFect research
  • bacteria and lung infections
  • Trikafta

How useful was this post?

Click on a star to rate it!

Average rating 0 / 5. Vote count: 0

No votes so far! Be the first to rate this post.

As you found this post useful...

Follow us on social media!

We are sorry that this post was not useful for you!

Let us improve this post!

Tell us how we can improve this post?