Potential sex-specific AS genetic markers seen, may aid treatment
Study into differing gene activity during programmed cell death, a key process
Genetic analyses found altered activity in several genes related to programmed cell death in ankylosing spondylitis (AS) patients that was not evident in healthy individuals, a study reported.
Significantly distinct genetic differences between men and women with AS also were identified, which researchers suggest may serve as new sex-specific disease biomarkers.
Programmed cell death, also known as apoptosis, is a process the body uses to eliminate unneeded or abnormal cells, and it is thought to be dysfunctional in some autoimmune diseases.
The study, “Identification of sex-specific biomarkers related to programmed cell death and analysis of immune cells in ankylosing spondylitis,” was published in the journal Scientific Reports.
Problems with programmed cell death can promote inflammation
An autoimmune condition, ankylosing spondylitis is marked by inflammation that mainly affects the joints of the spine. A hallmark AS symptom is inflammation of the sacroiliac joints, where the base of the spine meets the pelvis.
Problems with programmed cell death is thought to be involved in some autoimmune diseases. For example, pyroptosis is a highly inflammatory form of apoptosis, characterized by the rupture of cell membranes and the release of pro-inflammatory signaling proteins.
Researchers in China set out to understand the processes of apoptosis in AS by assessing differences in gene activity, called differentially expressed genes, in AS patients and their healthy counterparts (a control group). They also investigated differences between men and women with AS.
Although early studies suggested that the incidence of AS is higher among men than women, a recent study of more than 700,000 U.S. military personnel indicated a similar incidence by sex. Still, men and women typically experience differences in disease symptoms, progression, processes for disease diagnosis, and AS treatment outcomes.
Specifically, the researchers focused on differentially expressed genes in various types of programmed cell death: Those related to pyroptosis, as well as those related to ferroptosis (iron-related apoptosis), cuproptosis (copper-related apoptosis), anoikis (programmed cell death when cells detach from other cells), and autophagy, the cell’s recycling process.
Across all AS patients, analysis revealed 82 differentially expressed genes related to ferroptosis, 29 related to cuproptosis, 54 to autophagy, 21 to anoikis, and 74 related to pyroptosis. There were also notable differences between male and female patients, including 36 differentially expressed genes related to ferroptosis, 14 to cuproptosis, 19 to autophagy, 10 to anoikis, and 36 to pyroptosis.
Applying machine learning techniques, six genes related to programmed cell death stood out, including CLIC4, BIRC2, MATK, PKN2, SLC25A5, and EDEM1. The accuracy in distinguishing AS patients from healthy controls ranged from 78.3% to 81.9% for MATK, PKN2, and SLC25A5. The predictive accuracy of CLIC4, BIRC2, and EDEM1 ranged from 72.2% to 75.5%.
Differing activity seen in several genes between men, women with AS
For men with AS, genes with activities differing from controls were EDEM1, MAP3K11, and TRIM21, while for women, these genes were COX7B, PEX2, and RHEB. Moreover, a set of three genes also distinguished male from female patients: DDX3X, CAPNS1, and TMSB4Y.
Changes in EDEM1, MAP3K11, and TRIM21 activity showed a “high accuracy” in distinguishing male AS patients from controls, ranging from 89.5% to 95%. For female patients, COX7B, PEX2, and RHEB also showed accuracies that ranged between 82.2% and 91.4%.
Regarding genes with differing activity between men and women with AS, TMSB4Y has an accuracy of 93.6%, CAPNS1 of 92%, and DDX3X of 84.1%.
“By identifying DEGs [differentially expressed genes] associated with diverse cell death modalities, this study proffers invaluable insights into potential clinical targets for AS patients, taking cognizance of gender-specific nuances,” the researchers wrote.
They also assessed sex-related differences in the relative proportions of 22 types of immune cells in AS patients compared to control samples.
Overall, women with AS showed heightened immune cell activity than did men, and higher immune cell proportions compared with healthy controls. Immune correlation analysis detected relationships between identified DEGs and various immune cell types, showing both positive and negative correlations.
For example, lower EDEM1 gene activity correlated with immune neutrophils and unactivated immune B-cells, while lower MAP3K11 activity correlated with activated memory T-cells and antibody-producing plasma cells.
Higher COX7B activity significantly correlated with immune eosinophils. Also, higher RHEB activity correlated with anti-inflammatory regulatory T-cells and memory B-cells. Still, lower activity in this gene was related to macrophages and resting natural killer cells.
“The identification of gender-specific biological targets lays the groundwork for the development of tailored diagnostic and therapeutic strategies, heralding a pivotal step toward personalized care for AS patients,” the researchers wrote.
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