Two cell-death genes linked to disease development in AS
Findings suggest 'potential new targets' for treatment strategies: Study
Changes in the activity of two genes related to a type of programmed cell death called necroptosis — also implicated in other autoimmune diseases — were linked to the development of ankylosing spondylitis (AS), a new study revealed.
Those genes, FASLG and TARDBP, were “pinpointed” with the aid of three machine learning algorithms, according to the researchers.
Blood tests on people with or without AS confirmed the study’s findings, which provide “new insights into the molecular mechanisms of AS and suggest potential new targets for therapeutic strategies,” the team wrote.
The study, “Identification of necroptosis-related genes in ankylosing spondylitis by bioinformatics and experimental validation,” was published in the Journal of Cellular and Molecular Medicine.
Programmed cell death already linked to other autoimmune diseases
AS is an autoimmune disease that affects the joints of the spine, leading to back pain, spinal stiffness, and deformity. Inflammation of the sacroiliac joints — where the bottom of the spine meets the pelvis — is a hallmark sign of AS.
Necroptosis is a form of programmed cell death implicated in various inflammatory conditions, including rheumatoid arthritis. It normally functions as a defense mechanism, and is characterized by cell swelling and rupture.
However, “an investigation of its relationship with AS has not been reported,” the researchers wrote.
To address this gap, a team at Xi’an Jiaotong University in China compared the expression, or activity, of necroptosis-related genes between AS patients and healthy individuals, who served as controls.
Using data from the Gene Expression Omnibus (GEO) database, the team identified 18 genes expressed differently between people with and without AS. A computer-based analysis then focused on two genes that stood out from the rest: FASLG and TARDBP.
FASLG carries instructions for a protein that regulates the immune system, induces programmed cell death in certain immune cells, and has been linked with the autoimmune condition lupus. The TARDBP gene encodes the TDP-43 protein and is involved in protein production. It’s associated with several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Parkinson’s disease.
An examination of additional GEO datasets validated these findings — that FASLG was expressed at significantly lower levels in AS patients than controls, while TARDBP expression was increased.
A statistical analysis then demonstrated the ability of these genes’ activity to accurately distinguish between people with and without AS, which exceeded 75%, “indicating their potential as reliable biomarkers,” the team wrote.
Genes may contribute to disease development via cellular mechanisms
To confirm these findings, the team collected blood samples from 18 AS patients and 17 healthy individuals who were matched by age and sex. All of the patients tested positive for HLA-B27, a genetic marker associated with AS. They also had elevated blood levels of C-reactive protein, a biomarker for systemic, or bodywide, inflammation.
Blood tests aligned with the GEO data, showing high TARDBP and low FASLG activity levels in AS patients versus controls.
TARDBP and FASLG expression changes were then linked with the infiltration of certain immune cells, including T-cells (CD4-plus and CD8-plus), natural killer cells, and neutrophils. These results suggested that the “altered immune microenvironment in AS patients may be closely related to the expression level of FASLG and TARDBP,” the researchers noted.
Finally, drug prediction software detected 30 medicines with the potential target TARDBP and one for FASLG. They also identified several gene-regulating long non-coding RNAs that control the expression of FASLG, TARDBP, or both.
“FASLG and TARDBP may contribute to AS [development] by regulating the immune microenvironment and immune-related [signaling] pathways,” the researchers wrote.
More work is needed, however, to substantiate the link between these genes and disease development in AS, the researchers stressed.
“To validate the findings of this investigation, additional prospective basic research is required in future studies,” the team wrote.
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