Differences in CF by patient’s sex appear to be due to gene activity

Greater inflammation seen in females tied to X chromosome and RNA it codes

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Variations in levels of certain regulatory RNA molecules in immune cells may help to explain why women and girls with cystic fibrosis (CF) tend to have a higher inflammatory response than do men and boys with the disease.

“We and others have reported sex-differences in the course of CF, with females experiencing more severe inflammation and exhibiting poorer prognosis [outcomes] compared to males,” the study’s researchers wrote. “This sex disparity in CF exists despite the progress made in the early [disease] diagnosis and in the close therapeutic monitoring over the last years.”

Their study, “Sex-biased expression of selected chromosome x-linked microRNAs with potent regulatory effect on the inflammatory response in children with cystic fibrosis: A preliminary pilot investigation,” was published in the journal Frontiers in Immunology.

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#NACFC2022 – CF Exacerbations Differ Based on Patient’s Sex: Study

Sex differences in CF traced to differing levels of select microRNAs

Girls or women with CF tend to be more prone to infections and pulmonary exacerbations than their male counterparts, but the reasons for this difference are unclear.

Biological sex is determined by the X and Y chromosomes: people born with two X chromosomes are female, while those born with one X and one Y chromosome are male (other combinations also are possible, though rare).

Researchers in Belgium investigated whether this chromosomal difference might influence the activity of immune cells in CF patients according to their sex, helping to explain the difference in infection risk. Immune cells are important for fighting off infections.

Specifically, the researchers noted that the X chromosome contains instructions for making several micro-RNAs (miRNAs) — small RNA molecules that regulate the activity of specific genes in the cell. They tested whether immune-regulating miRNAs show differences in activity in cells from male or female CF patients.

“The X chromosome codes for a large number of microRNAs (miRNAs) that play a crucial role in the … regulation of several genes involved in various biological processes, including inflammation. However, their level of expression in CF males and females has not been sufficiently explored,” the researchers wrote.

They analyzed immune cells collected from blood samples of 29 children with CF (15 male, 14 female; median age of 7.87), as well as 20 children without the disease (10 male, 10 female; median age of 6.75) as a control group. Patients in the study had relatively stable disease, with low levels of inflammation markers and mild-to-moderate limitations in lung function.

Levels of three miRNAs — known as miR-223-3p, miR-106a-5p, and miR-221-3p — were higher in CF patients compared with the other children for both sexes. Another miRNA, called miR-502-5p, was at increased levels in male CF patients, but not in female patients, compared with control children of the respective sex, results showed.

Further analyses found that levels of miR-502-5p were comparable across sexes among the CF patients. However, levels of miR-221-3p were significantly higher in cells from female CF patients than male patients. Females with CF also tended to have lower expression of the proteins SOCS1 and PDLIM2, which are known to be regulated by this miRNA.

Higher miR-221-3p levels can be associated with higher activity of the gene coding for the pro-inflammatory signaling molecule interleukin-1-beta (IL-1b), the researchers noted.

Similar results were found when analysis was limited to children younger than 8 years old. This suggests that sex hormones like testosterone and estrogen are unlikely to play a role in these differences, the researchers said.

CF treatments, newborn screening help stabilize disease across sexes

Despite the differences evident by sex, all the CF children in this study had “a relatively stable clinical state,” the scientists noted and attributed to advances in disease treatments and to newborn screening for CF, allowing for an early start to treatment.

“While gender difference still exists in CF, significant advances in timely treatment and patient follow-up, have largely contributed to reduce the difference observed … between boys and girls,” they wrote. This holds even though “substantial differences between males and females could be detected at the transcript level,” meaning the process through which a gene’s DNA sequence is copied into an RNA molecule. It’s first step in gene expression.

The researchers stressed that this study is too small to draw firm conclusions, and further research is needed to validate and expand on its findings.