ACE2 in Multiple Sclerosis: New Evidence for a Circulating Biomarker and Genetic Susceptibility Factor
Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disorder of the central nervous system characterized by marked clinical and biological heterogeneity, creating an urgent need for biomarkers that can improve diagnosis, stratification, and therapeutic monitoring. In this article, the authors examine angiotensin-converting enzyme 2 (ACE2), a key regulator of the renin–angiotensin system (RAS), as a candidate molecule in MS. The study is grounded in the idea that the classical RAS axis tends to promote inflammatory signaling, whereas the ACE2-associated protective axis may counterbalance inflammation, oxidative stress, apoptosis, and blood–brain barrier disruption. Because prior work had mainly focused on cerebrospinal fluid rather than serum, and because ACE2 genetic variation had not been well studied in MS in Jordanian patients, this investigation aimed to address both biochemical and genetic dimensions of ACE2 biology in relation to MS susceptibility.
Study Design and Analytical Strategy
The authors conducted a case–control study in Jordan, recruiting patients from major hospitals and selecting controls without autoimmune, neurological, or major chronic diseases. Serum ACE2 levels were measured by ELISA in 88 patients with MS and 87 healthy controls, while genotyping for two ACE2 polymorphisms, rs2074192 and rs2285666, was performed in a much larger cohort of 498 patients and 504 controls using Illumina HiSeq xTen sequencing. Importantly, the statistical framework accounted for the fact that ACE2 is located on the X chromosome, which required sex-stratified genetic modeling and Hardy–Weinberg equilibrium testing only in females. The study also incorporated multivariable regression, ROC analysis, and haplotype analysis, reflecting a methodologically careful attempt to link circulating protein levels, inherited variation, and clinical phenotype.
Elevated Serum ACE2 in Multiple Sclerosis
A central finding of the paper is that serum ACE2 concentrations were significantly higher in patients with MS than in healthy controls. The median ACE2 level was 1884.85 pg/ml in the MS group compared with 1059.72 pg/ml in controls, and this difference remained statistically significant in the primary adjusted analysis. The authors further evaluated the discriminatory capacity of serum ACE2 and found an area under the ROC curve of 0.783, which they interpret as indicating fair diagnostic performance. Using an optimal cut-point of 1459.03 pg/ml, ACE2 showed positive and negative predictive values of 76.7% and 77.6%, respectively. Taken together, these results suggest that circulating ACE2 is not merely altered in MS, but may have practical value as a blood-based biomarker, although not yet at a level sufficient for standalone diagnosis.
Biological Interpretation of the ACE2 Signal
The elevation of serum ACE2 in MS is particularly interesting because earlier work cited by the authors had reported reduced ACE2 levels in cerebrospinal fluid, implying that central and peripheral ACE2 biology may diverge. The paper proposes that higher serum ACE2 may reflect activation of the protective ACE2/Ang-(1–7)/Mas axis as a compensatory response to inflammatory injury, especially in a cohort dominated by relapsing-remitting MS. This interpretation is biologically plausible: ACE2 and its downstream peptides are associated with neuroprotection, maintenance of blood–brain barrier integrity, and attenuation of inflammatory damage. The authors also note that about 65% of patients were receiving disease-modifying therapy, raising the possibility that treatment status may influence circulating ACE2, especially since there was a near-significant trend toward lower ACE2 levels among treated patients.
Genetic Associations with MS Susceptibility
Beyond protein quantification, the study identifies statistically significant associations between ACE2 polymorphisms and MS susceptibility. For rs2074192, the TT genotype and T allele were enriched in patients with MS, supporting an association between this locus and disease risk. For rs2285666, the CC genotype and C allele were associated with MS cases. Haplotype analysis further strengthened the genetic signal: the T/C haplotype was more frequent in patients, whereas the C/C haplotype was more common in controls, suggesting that combinations of ACE2 variants may influence risk more meaningfully than single markers alone. The authors also found linkage disequilibrium between the two SNPs, indicating that these variants do not segregate independently and may be capturing shared underlying genetic architecture relevant to MS susceptibility.
Clinical Correlates and Sex-Specific Patterns
The study also explored whether ACE2-related measures mapped onto clinical characteristics. Serum ACE2 levels showed significant sex-related differences: women with MS had higher serum ACE2 than men with MS, whereas in controls the opposite pattern was observed. Genetically, rs2074192 was associated with EDSS disability level, and rs2285666 was associated with current disease-modifying therapy use, indicating that ACE2 variation may relate not only to disease presence but also to aspects of severity and treatment context. At the same time, serum ACE2 levels were not directly associated with genotype in either patients or controls, implying that the protein and genetic findings may represent partially independent biological layers. This nuance is important, because it argues against an overly simple one-variant/one-protein explanation and instead points toward a more complex regulatory network involving sex, immune state, and disease stage.
Significance, Limitations, and Future Directions
Overall, this article makes a meaningful contribution by proposing ACE2 as both a serum biomarker candidate and a susceptibility gene in MS within a Jordanian population. Its principal strength lies in combining biochemical and genetic evidence in the same study framework. Nevertheless, the authors are appropriately cautious: the serum protein analysis was performed in a relatively small subset, longitudinal samples were unavailable, and only two ACE2 SNPs were examined, limiting broader haplotypic interpretation. These constraints mean that the work should be viewed as a strong hypothesis-generating study rather than definitive proof of clinical utility. Future research should test these findings in larger and ethnically diverse cohorts, include more progressive MS cases, and use longitudinal sampling to determine whether ACE2 predicts relapse activity, disability progression, or therapeutic response. In that sense, the study opens an important line of investigation at the intersection of neuroimmunology, cardiovascular signaling biology, and precision medicine in MS.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Al-Keilani, M.S., Abdelrazeq, H.M., Hendi, N.N. et al. Association of angiotensin converting enzyme type 2 serum level and gene polymorphisms with multiple sclerosis. Sci Rep 16, 10690 (2026). https://doi.org/10.1038/s41598-026-46187-5
