Circulating microRNA miR-425-5p Associated with Brain White Matter Lesions and Inflammatory Processes
Abstract
:1. Introduction
2. Results
2.1. Clinical Impact of WML
2.2. hsa-miR-425-5p Is Associated with WMLs
2.2.1. Association of Target miRNAs with Structural AD-Related MRI Phenotypes
2.2.2. The Role of hsa-miR-425-5p in Inflammation
2.2.3. Target Genes of hsa-miR-425-5p in WMLs GWAS
2.3. Influence of Moderating Factors
- Moderation by sex: In sex interaction models, 19 and 18 nominally significant miRNAs were identified for total WML volume and number of WMLs, respectively (Table S5, Figure S14). Only for the number of WMLs, two miRNAs, hsa-miR-126-3p and hsa-miR-374a-5p, survived multiple tests (Table 2). In both cases, lower values of miRNA abundance (reflected in higher ΔCt values) were associated with a higher WML burden in females but with a reduced burden in males (Figure S16). Both miRNAs are expressed in the brain (Figure S15A,B) and the EGFL7 (EGF-like domain multiple 7) gene harboring MIR126 on chromosome 9 has been associated with AD as well as white matter growth (Table S4).
- Moderation by APOE ε4: In interaction analyses with the APOE ε4 carrier status, 13 and 19 nominally significant miRNAs were identified for total WML volume and number of WMLs, respectively (Table S6, Figure S14). None of them survived multiple testing corrections. The lowest p-value was observed for hsa-miR-140-5p on the number of WMLs (p = 0.0011). Carriers of the APOE ε4 allele had a beneficial outcome for WML burden in the case of high levels of hsa-miR-140-5p, whereas in the case of lower levels, the WML burden increased (Figure S17). Hsa-miR-140-5p is only slightly expressed in the brain (Figure S18) and its harboring gene WWP2 (WW domain containing E3 ubiquitin protein ligase 2) has been associated with addictive behavior and cognitive traits (Table S4).
- Moderation by smoking status: Interaction with smoking status revealed 13 and 15 nominal significant miRNAs for total WML volume and number of WMLs, respectively (Table S7, Figure S14). Three miRNAs reached BH-corrected significance in the latter model (hsa-miR-885-5p, hsa-miR-199a-5p, hsa-miR-194-5p; Table 3, Figure S19) with hsa-miR-199a-5p reaching significance in both WML models. Interestingly, only hsa-miR-885-5p shows a substantial expression in brain tissues (Figure S20A–C) and the strongest link towards neurodegenerative endpoints concerning its harboring gene ATP2B2 (ATPase plasma membrane Ca2+ transporting 2) (Table S4).
2.4. Significant Plasma-Circulating miRNAs Are Enriched in Neurodegeneration
3. Discussion
miRNA | Previous Results Regarding AD and/or Cognition from Pubmed |
---|---|
hsa-miR-425-5p | Regulation of AD pathogenic genes [23] Interacting with BACE1 [35] Upregulated in AD [24,25] Association with memory and learning disorders [36] Promotes formation of Aβ plaques [37] |
hsa-miR-126-3p | Overexpression could reduce Aβ plaque area and neuroinflammation in the hippocampus [38] Associated with inflammation in the pathogenesis of AD [39] Involved in neurogenesis [40] Upregulated in plasma of AD patients [41] Altered regulation in brain of AD male rats [42] Involved in neuronal accumulation of AD [43] Decreased in plasma of AD subjects [44] Part of a nine-miRNA signature as potential biomarker for AD [45] Dysregulated in plasma of AMD rats [46] Associated with stroke recovery [47] Negative correlation with cognitive function [48] Dysregulated in AD NMV [49] Cardiovascular events (including stroke) [50] Regulation of BDNF synthesis [51] |
hsa-miR-374a-5p | Part of plasma signature of obstructive sleep apnea in AD [52] Cardiovascular events (including stroke) [50] Overexpression reduces cell apoptosis [53] |
hsa-miR-885-5p | Regulating neuronal cell injury [54] Serum biomarker for AD [55] Upregulated in AD [56] Associated with higher metabolic risk profile in older subjects [57] |
hsa-miR-199a-5p | Involved in AD development [58] Related to cognitive impairment [59] Link between AD and diabetes [60] Protects cognitive function in ischemic stroke [61] |
hsa-miR-194-5p | Association with WML and cognitive impairment [16] Associated with higher metabolic risk profile in older subjects [57] Downregulated in blood of AD patients [62] Inhibit apoptosis of hippocampal neurons [63] |
hsa-miR-140-5p | Risk factor for memory impairment induced by Aβ [64] Associated with neurodegenerative diseases in general [65] Associated with vascular cognitive impairment [66] Associated with cognitive performance in healthy older adults [67] Associated with AD risk gene ADAM10 [68] Neuroprotective effects [69] |
4. Materials and Methods
4.1. SHIP Sample
4.2. Verbal Memory Scores
4.3. Brain Imaging Data
4.4. Plasma-Circulating miRNAs
4.5. Immunological Markers
4.6. Additional Variables
4.7. Statistical Analyses
- Clinical impact of WMLs: The following generalized linear models (GLM) were calculated with WMLs as predictors and verbal memory scores as outcomes.
+ hypertension + ICV
- 2.
- Impact of miRNAs on WMLs: GLMs were calculated with miRNA levels as predictors and WMLs (structural MRI markers) as outcome.
ICV + batch
- 3.
- Impact of target miRNAs and inflammatory markers: In GLMs, the association between circulating inflammatory markers (CRP, fibrinogen) and significant miRNAs was investigated and corrected for age, sex, miRNA batch, smoking, BMI, education, HCT, and PLT. CRP was log-transformed prior to analyses.
- 4.
- Moderation effect of sex, APOE ε4, smoking: Similar models as in 2. were performed, additionally including an interaction term between miRNA levels and sex, APOE ε4, or ever smoking.
4.8. Post Hoc In Silico Analysis
- Using GTExPortal (https://www.gtexportal.org/home/, accessed on 6 June 2023), miRNA TissueAtlas [79], Human Protein Atlas [80], and CNS microRNA Profiles database for mice [81], we investigated the expression of miRNAs and genes in different brain tissues of human and mouse samples.
- We used the over-representation analysis implemented in the miRNA Enrichment Analysis and Annotation Tool (miEAA 2.0) [85] to search for significant associations between sets of target miRNAs and disease outcomes, incorporating data from large miRNA, tissue, and pathway databases.
- Comparison with GWAS results: results for SNPs within target genes of significant miRNAs were looked up in publicly available GWAS summary statistics on white matter hyperintensity burden (dbGaP: phs002227.v1.p1 [11]).
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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TREND-0 miRNA/MRI Sample * (n = 648) | TREND-0 MRI Sample (n = 1854) | |
---|---|---|
Sex | ||
Males | 328 (50.6%) | 890 (48%) |
Females | 320 (49.4%) | 964 (52%) |
Age in years | 50.3 (13.7), [21–79] | 51.0 (13.9), [21–81] |
BMI | 27.2 (4.2), [17.7–48.0] | 27.5 (4.4), [17.7–48.0] |
Systolic blood pressure (mmHg) | 124.9 (16.3), [88–196] | 126.2 (17.2), [84–196] |
diastolic blood pressure (mmHg) | 76.5 (9.6), [51–115] | 77.1 (9.9), [47–118] |
Hypertension | 251 (38.8%) | 790 (42.7%) |
Current depressive symptoms (PHQ-9) | 12.7 (3.4), [9–35] | 12.8 (3.5), [9–35] |
Education | ||
<10 years | 68 (10.5%) | 273 (14.7%) |
=10 years | 369 (57%) | 1011 (54.5%) |
>10 years | 211 (32.5%) | 570 (30.8%) |
Smoking | ||
Never | 267 (41.2%) | 732 (39.5%) |
Former | 247 (38.1%) | 684 (36.9%) |
Current | 134 (20.7%) | 438 (23.6%) |
Verbal memory immediate recall | 5.4 (1.2), [0–8] | 5.4 (1.3), [0–8] |
Verbal memory delayed recall | 5.7 (1.6), [−3–8] | 5.8 (1.7), [−3–8] |
APOE ε4 carrier | 155 (24.0%) | 448 (24.2%) |
ICV in cm3 | 1563 (148), [1016–2040] | 1560 (145), [1016–2040] |
WMLV in cm3 | 0.56 (2.1), [0–27] | 0.68 (2.4), [0–43.8] |
Number of WMLs | 3.0 (4.2), [0–37] | 3.2 (4.4), [0–37] |
Presence of lesions | 454 (70.1%) | 1320 (71.2%) |
miRNA | WML Volume | Number of WMLs | Presence of WMLs | n |
---|---|---|---|---|
Direct effects | ||||
hsa-miR-425-5p | Pos, 0.46, 0.94 | Pos, 0.005, 0.63 | Pos, 5.9 × 10−5, 0.01 | 638 |
Interaction with sex | ||||
hsa-miR-126-3p | Neg, 1.7 × 10−3, 0.13 | Neg, 2.6 × 10−4, 0.044 | - | 641 |
hsa-miR-374a-5p | Neg, 0.03, 0.39 | Neg, 9.4 × 10−4, 0.08 | - | 410 |
Interaction with APOE ε4 carrier status | ||||
hsa-miR-140-5p * | Neg, 0.024, 0.58 | Neg, 0.001, 0.12 | - | 497 |
Interaction with smoking status | ||||
hsa-miR-199a-5p | Neg, 1.0 × 10−4, 0.018 | Neg, 2.6 × 10−4, 0.022 | - | 516 |
hsa-miR-885-5p | Pos, 9.6 × 10−4, 0.083 | Pos, 1.2 × 10−4, 0.022 | - | 544 |
hsa-miR-194-5p | Pos, 0.011, 0.32 | Pos, 7.8 × 10−4, 0.045 | - | 619 |
miR-425-5p | miR-126-3p | miR-374a-5p | miR-199a-5p | miR-885-5p | miR-194-5p | FDR Corrected p-Value | |
---|---|---|---|---|---|---|---|
Neurodegenerative diseases | x | x | x | x | x | x | 0.005 |
Niemann-pick disease | x | x | x | x | - | - | 3.5 × 10−4 |
Alzheimer’s disease | x | x | x | x | x | x | 0.008 |
Multiple sclerosis | x | x | x | x | - | x | 0.003 |
Amyotrophic lateral sclerosis | x | x | - | x | x | x | 0.006 |
Intellectual disability | x | x | - | x | x | x | 0.004 |
Vascular disease | x | - | x | x | x | x | 0.018 |
Brain disease | x | x | - | x | x | x | 0.012 |
Huntington’s disease | - | x | - | x | x | x | 0.009 |
Stroke | - | x | x | x | - | x | 0.011 |
Schizophrenia | - | x | - | x | x | - | 0.011 |
Hypertension | x | x | - | x | - | - | 0.023 |
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Van der Auwera, S.; Ameling, S.; Wittfeld, K.; Frenzel, S.; Bülow, R.; Nauck, M.; Völzke, H.; Völker, U.; Grabe, H.J. Circulating microRNA miR-425-5p Associated with Brain White Matter Lesions and Inflammatory Processes. Int. J. Mol. Sci. 2024, 25, 887. https://doi.org/10.3390/ijms25020887
Van der Auwera S, Ameling S, Wittfeld K, Frenzel S, Bülow R, Nauck M, Völzke H, Völker U, Grabe HJ. Circulating microRNA miR-425-5p Associated with Brain White Matter Lesions and Inflammatory Processes. International Journal of Molecular Sciences. 2024; 25(2):887. https://doi.org/10.3390/ijms25020887
Chicago/Turabian StyleVan der Auwera, Sandra, Sabine Ameling, Katharina Wittfeld, Stefan Frenzel, Robin Bülow, Matthias Nauck, Henry Völzke, Uwe Völker, and Hans J. Grabe. 2024. "Circulating microRNA miR-425-5p Associated with Brain White Matter Lesions and Inflammatory Processes" International Journal of Molecular Sciences 25, no. 2: 887. https://doi.org/10.3390/ijms25020887