Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation.

BACKGROUND: The plasma metabolome reflects the physiological state of various biological processes and can serve as a proxy for disease risk. Plasma metabolite variation, influenced by genetic and epigenetic mechanisms, can also affect the cellular microenvironment and blood cell epigenetics. The interplay between the plasma metabolome and the blood cell epigenome remains elusive. In this study, we performed an epigenome-wide association study (EWAS) of 1183 plasma metabolites in 693 participants from the LifeLines-DEEP cohort and investigated the causal relationships in DNA methylation-metabolite associations using bidirectional Mendelian randomization and mediation analysis. RESULTS: After rigorously adjusting for potential confounders, including genetics, we identified five robust associations between two plasma metabolites (L-serine and glycine) and three CpG sites located in two independent genomic regions (cg14476101 and cg16246545 in PHGDH and cg02711608 in SLC1A5) at a false discovery rate of less than 0.05. Further analysis revealed a complex bidirectional relationship between plasma glycine/serine levels and DNA methylation. Moreover, we observed a strong mediating role of DNA methylation in the effect of glycine/serine on the expression of their metabolism/transport genes, with the proportion of the mediated effect ranging from 11.8 to 54.3%. This result was also replicated in an independent population-based cohort, the Rotterdam Study. To validate our findings, we conducted in vitro cell studies which confirmed the mediating role of DNA methylation in the regulation of PHGDH gene expression. CONCLUSIONS: Our findings reveal a potential feedback mechanism in which glycine and serine regulate gene expression through DNA methylation.

Dysregulation of plasma circulating microRNAs in all-cause and cause-specific cancers: the Rotterdam Study.

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional regulation of gene expression. Mounting evidence underscores the dysregulation of miRNAs to be associated with cancer development and progression by acting as tumour suppressors and oncogenes. However, their potential as biomarkers for early diagnosis of different cancers remains incompletely unraveled. We explored the relationship between plasma circulatory miRNAs and cancer risk within the population-based Rotterdam Study cohort. Plasma samples were collected at baseline (between 2002 and 2005) and miRNA levels were measured in 1,999 participants, including 169 prevalent cancer cases. The occurrence of cancer was assessed by continuous monitoring of medical records in 1,830 cancer-free participants until January 1, 2015. We assessed the association between incidence of five common cancers (blood, lung, breast, prostate, and colorectal) and 591 miRNAs well-expressed in plasma, using adjusted Cox proportional-hazards regression models. Our longitudinal analysis identified 13 miRNAs significantly associated with incident hematologic tumors surpassing the Bonferroni-corrected P < 8.46 × 10- 5, 12 of them (miR-6124, miR-6778-5p, miR-5196, miR-654-5p, miR-4478, miR-4430, miR-4534, miR-1915-3p, miR-4644, miR-4292, miR-7111-5p, and miR-6870-5p) were also associated with prevalent hematologic tumors in the cross-sectional analysis at the baseline. In-silico analyses of the putative target genes of 13 identified miRNAs highlighted relevant genes and pathways linked to hematologic tumors. While no significant miRNA association was found for other four studied cancers, two miRNAs (miR-3157-5p and miR-3912-5p) showed nominal association with incident of three different cancer types. Overall, this study indicates that plasma levels of several miRNAs are dysregulated in hematologic tumors, highlighting their potential as biomarkers for early diagnosis as well as being involved in the pathogenesis of blood cancers.

Unraveling interindividual variation of trimethylamine N-oxide and its precursors at the population level.

Trimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO-to-precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in-depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome-wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO-to-precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish-TMAO, meat-carnitine, and plant-based food-betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.

Plasma Extracellular MicroRNAs Associated With Cardiovascular Disease Risk Factors in Middle-Aged and Older Adults.

BACKGROUND: Extracellular microRNAs (miRNAs) are a class of noncoding RNAs that remain stable in the extracellular milieu, where they contribute to various physiological and pathological processes by facilitating intercellular signaling. Previous studies have reported associations between miRNAs and cardiovascular diseases (CVDs); however, the plasma miRNA signatures of CVD and its risk factors have not been fully elucidated at the population level. METHODS AND RESULTS: Plasma miRNA levels were measured in 4440 FHS (Framingham Heart Study) participants. Linear regression analyses were conducted to test the cross-sectional associations of each miRNA with 8 CVD risk factors. Prospective analyses of the associations of miRNAs with new-onset obesity, hypertension, type 2 diabetes, CVD, and all-cause mortality were conducted using proportional hazards regression. Replication was carried out in 1999 RS (Rotterdam Study) participants. Pathway enrichment analyses were conducted and target genes were predicted for miRNAs associated with ≥5 risk factors in the FHS. In the FHS, 6 miRNAs (miR-193b-3p, miR-122-5p, miR-365a-3p, miR-194-5p, miR-192-5p, and miR-193a-5p) were associated with ≥5 risk factors. This miRNA signature was enriched for pathways associated with CVD and several genes annotated to these pathways were predicted targets of the identified miRNAs. Furthermore, miR-193b-3p, miR-194-5p, and miR-193a-5p were each associated with ≥2 risk factors in the RS. Prospective analysis revealed 8 miRNAs associated with all-cause mortality in the FHS. CONCLUSIONS: These findings highlight associations between miRNAs and CVD risk factors that may provide valuable insights into the underlying pathogenesis of CVD.

Plasma trimethylamine N-oxide (TMAO): associations with cognition, neuroimaging, and dementia.

BACKGROUND: The gut-derived metabolite Trimethylamine N-oxide (TMAO) and its precursors - betaine, carnitine, choline, and deoxycarnitine - have been associated with an increased risk of cardiovascular disease, but their relation to cognition, neuroimaging markers, and dementia remains uncertain. METHODS: In the population-based Rotterdam Study, we used multivariable regression models to study the associations between plasma TMAO, its precursors, and cognition in 3,143 participants. Subsequently, we examined their link to structural brain MRI markers in 2,047 participants, with a partial validation in the Leiden Longevity Study (n = 318). Among 2,517 participants, we assessed the risk of incident dementia using multivariable Cox proportional hazard models. Following this, we stratified the longitudinal associations by medication use and sex, after which we conducted a sensitivity analysis for individuals with impaired renal function. RESULTS: Overall, plasma TMAO was not associated with cognition, neuroimaging markers or incident dementia. Instead, higher plasma choline was significantly associated with poor cognition (adjusted mean difference: -0.170 [95% confidence interval (CI) -0.297;-0.043]), brain atrophy and more markers of cerebral small vessel disease, such as white matter hyperintensity volume (0.237 [95% CI: 0.076;0.397]). By contrast, higher carnitine concurred with lower white matter hyperintensity volume (-0.177 [95% CI: -0.343;-0.010]). Only among individuals with impaired renal function, TMAO appeared to increase risk of dementia (hazard ratio (HR): 1.73 [95% CI: 1.16;2.60]). No notable differences were observed in stratified analyses. CONCLUSIONS: Plasma choline, as opposed to TMAO, was found to be associated with cognitive decline, brain atrophy, and markers of cerebral small vessel disease. These findings illustrate the complexity of relationships between TMAO and its precursors, and emphasize the need for concurrent study to elucidate gut-brain mechanisms.

Association analysis between an epigenetic risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day (p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 (p = 0.002) and 0.50 (p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

Sex-differences in the association of social health and marital status with blood-based immune and neurodegeneration markers in a cohort of community-dwelling older adults.

BACKGROUND: The immune system has been proposed to play a role in the link between social health and all-cause dementia risk. We explored cross-sectional and longitudinal associations between social health, immune system balance and plasma neurodegeneration markers in community-dwelling older adults, and explored whether the balance between innate and adaptive immunity mediates associations between social health and both cognition and total brain volume. METHODS: Social health markers (social support, marital status, loneliness) were measured in the Rotterdam Study between 2002-2008. Immune system cell counts and balance were assessed repeatedly from 2002 to 2016 using white blood-cell-based indices and individual counts (granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)). Plasma neurodegeneration biomarkers (amyloid-ß40, amyloid-ß42, total tau and neurofilament light chain) were measured once from blood samples collected between 2002-2008. Global cognitive function and total brain volume (MRI) were measured at the follow-up visit between 2009-2014. We used linear mixed models to study longitudinal associations and performed causal mediation analyses. RESULTS: In 8374 adults (mean age 65.7, 57 % female), never married participants (n = 394) had higher GLR, PLR and SII compared to married peers at baseline and during follow-up, indicating imbalance towards innate immunity. Being never married was associated with higher plasma amyloid-ß40, and being widowed or divorced with higher plasma total tau levels at baseline. Widowed or divorced males, but not females, had higher GLR, PLR and SII at baseline. Higher social support was associated with lower PLR in females, but higher PLR in males. Loneliness was not associated with any of the immune system balance ratios. Never married males had higher levels of all plasma neurodegeneration markers at baseline. Immune system balance did not mediate associations between social health and cognition or total brain volume, but does interact with marital status. CONCLUSION: This study indicates that marital status is associated with blood-based immune system markers toward innate immunity and higher levels of plasma neurodegeneration markers. This is particularly evident for never married or previously married male older adults compared to married or female peers.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Association analysis between an epigenetic alcohol risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day (p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 (p = 0.002) and 0.50 (p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

The Rotterdam Study. Design update and major findings between 2020 and 2024.

The Rotterdam Study is a population-based cohort study, started in 1990 in the district of Ommoord in the city of Rotterdam, the Netherlands, with the aim to describe the prevalence and incidence, unravel the etiology, and identify targets for prediction, prevention or intervention of multifactorial diseases in mid-life and elderly. The study currently includes 17,931 participants (overall response rate 65%), aged 40 years and over, who are examined in-person every 3 to 5 years in a dedicated research facility, and who are followed-up continuously through automated linkage with health care providers, both regionally and nationally. Research within the Rotterdam Study is carried out along two axes. First, research lines are oriented around diseases and clinical conditions, which are reflective of medical specializations. Second, cross-cutting research lines transverse these clinical demarcations allowing for inter- and multidisciplinary research. These research lines generally reflect subdomains within epidemiology. This paper describes recent methodological updates and main findings from each of these research lines. Also, future perspective for coming years highlighted.

A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.

ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

Circulating metabolites associated with kidney function decline and incident CKD: a multi-platform population-based study.

Background: Investigation of circulating metabolites associated with kidney function and chronic kidney disease (CKD) risk could enhance our understanding of underlying pathways and identify new biomarkers for kidney function. Methods: We selected participants from the population-based Rotterdam Study with data on circulating metabolites and estimated glomerular filtration rate based on serum creatinine (eGFRcreat) available at the same time point. Data on eGFR based on serum cystatin C (eGFRcys) and urine albumin-to-creatinine ratio (ACR) were also included. CKD was defined as eGFRcreat <60 ml/min per 1.73 m2. Data on circulating metabolites (ntotal = 1381) was obtained from the Nightingale and Metabolon platform. Linear regression, linear mixed, and Cox proportional-hazards regression analyses were conducted to study the associations between metabolites and kidney function. We performed bidirectional two-sample Mendelian randomization analyses to investigate causality of the identified associations. Results: We included 3337 and 1540 participants with data from Nightingale and Metabolon, respectively. A total of 1381 metabolites (243 from Nightingale and 1138 from Metabolon) were included in the analyses. A large number of metabolites were significantly associated with eGFRcreat, eGFRcys, ACR, and CKD, including 16 metabolites that were associated with all four outcomes. Among these, C-glycosyltryptophan (HR 1.50, 95%CI 1.31;1.71) and X-12026 (HR 1.46, 95%CI 1.26;1.68) were most strongly associated with CKD risk. We revealed sex differences in the associations of 11-ketoetiocholanolone glucuronide and 11-beta-glucuronide with the kidney function assessments. No causal associations between the identified metabolites and kidney function were observed. Conclusion: Our study indicates that several circulating metabolites are associated with kidney function which are likely to have potential as biomarkers, rather than as molecules involved in the pathophysiology of kidney function decline.

Body composition and plasma total-tau, neurofilament light chain, and amyloid-ß: A population-based study.

A higher body mass at older age has been linked to a lower risk of dementia. This unexpected trend may be explained by age-related lean mass depletion, or methodological issues such as the long preclinical phase of dementia or competing risks. Focusing on preclinical markers of dementia may overcome these issues. Between 2002 and 2005, body composition and plasma total-tau, neurofilament light chain (NfL), amyloid-ß40, and amyloid-ß42 were measured in 3408 dementia-free participants from the population-based Rotterdam Study. The cross-sectional associations between body composition and plasma markers were determined using linear regression models. Whole body and fat mass, but not lean mass, were positively associated with total-tau, while all these measures were inversely associated with NfL. Apart from an inverse association between lean mass and amyloid-ß40, body composition measures were not associated with plasma amyloid-ß. Our findings suggest distinct effects of body composition on neurodegeneration.

Plasma neurofilament light chain in association to late-life depression in the general population.

AIM: Investigating what is underlying late-life depression is becoming increasingly important with the rapidly growing elderly population. Yet, the associations between plasma biomarkers of neuroaxonal damage and late-life depression remain largely unclear. Therefore, we determined cross-sectional and longitudinal associations of neurofilament light chain (NfL) with depression in middle-aged and elderly individuals, and total tau, ß-amyloid 40 and 42 for comparison. METHODS: We included 3,895 participants (71.78 years [SD = 7.37], 53.4% women) from the population-based Rotterdam Study. Between 2002 and 2005, NfL, total tau, ß-amyloid 40 and ß-amyloid 42 were determined in blood and depressive symptoms were measured with the Center for Epidemiologic Studies Depression scale (CES-D). Incident depressive events (clinically relevant depressive symptoms, depressive syndromes, major depressive disorders) were measured prospectively with the Center for Epidemiologic Studies Depression, a clinical interview and follow-up of medical records over a median follow-up of 7.0 years (interquartile range 1.80). We used linear and Cox proportional hazard regression models. RESULTS: Each log2 pg./mL increase in NfL was cross-sectionally associated with more depressive symptoms (adjusted mean difference: 0.32, 95% CI 0.05-0.58), as well as with an increased risk of any incident depressive event over time (hazard ratio: 1.22, 95% CI 1.01-1.47). Further, more amyloid-ß 40 was cross-sectionally associated with more depressive symptoms (adjusted mean difference: 0.70, 95% CI 0.15-1.25). CONCLUSION: Higher levels of NfL are cross-sectionally associated with more depressive symptoms and a higher risk of incident depressive events longitudinally. The association was stronger for NfL compared to other plasma biomarkers, suggesting a potential role of neuroaxonal damage in developing late-life depression.

Plasma circulating microRNAs associated with blood-based immune markers: a population-based study.

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression and different immune-related pathways. There is a great interest in identifying miRNAs involved in immune cell development and function to elucidate the biological mechanisms underlying the immune system, its regulation, and disease. In this study, we aimed to investigate the association of circulating miRNAs with blood cell compositions and blood-based immune markers. Circulating levels of 2083 miRNAs were measured by RNA-sequencing in plasma samples of 1999 participants from the population-based Rotterdam Study collected between 2002 and 2005. Full blood count measurements were performed for absolute granulocyte, platelet, lymphocyte, monocyte, white, and red blood cell counts. Multivariate analyses were performed to test the association of miRNAs with blood cell compositions and immune markers. We evaluated the overlap between predicted target genes of candidate miRNAs associated with immune markers and genes determining the blood immune response markers. First, principal component regression analysis showed that plasma levels of circulating miRNAs were significantly associated with red blood cell, granulocyte, and lymphocyte counts. Second, the cross-sectional analysis identified 210 miRNAs significantly associated (P < 2.82 × 10-5) with neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index. Further genetic look-ups showed that target genes of seven identified miRNAs (miR-1233-3p, miR-149-3p, miR-150-5p, miR-342-3p, miR-34b-3p, miR-4644, and miR-7106-5p) were also previously linked to NLR and PLR markers. Collectively, our study suggests several circulating miRNAs that regulate the innate and adaptive immune systems, providing insight into the pathogenesis of miRNAs in immune-related diseases and paving the way for future clinical applications.

Plasma neurofilament light chain in relation to 10-year change in cognition and neuroimaging markers: a population-based study.

Neurofilament light chain (NfL) is a promising biomarker for risk stratification and disease monitoring of dementia, but its utility in the preclinical disease stage remains uncertain. We determined the association of plasma NfL with (change in) neuroimaging markers and cognition in the population-based Rotterdam Study, using linear and logistic regression and mixed-effects models. Plasma NfL levels were measured using the Simoa NF-light™ assay in 4705 dementia-free participants (mean age 71.9 years, 57% women), who underwent cognitive assessment and brain MRI with repeated assessments over a 10-year follow-up period. Higher plasma NfL was associated with worse cognitive performance at baseline (g-factor: ß = - 0.12 (- 0.15; - 0.09), p < 0.001), and accelerated cognitive decline during follow-up on the Stroop color naming task (ß = 0.04 (0.02; 0.06), p < 0.001), with a smaller trend for decline in global cognition (g-factor ß = - 0.02 (- 0.04; 0.00), p = 0.044). In the subset of 975 participants with brain MRI, higher NfL was associated with poorer baseline white matter integrity (e.g., global mean diffusivity: ß = 0.12 (0.06; 0.19), p < 0.001), with similar trends for volume of white matter hyperintensities (ß = 0.09 (0.02; 0.16), p = 0.011) and presence of lacunes (OR = 1.55 (1.13; 2.14), p = 0.007). Plasma NfL was not associated with volumes or thickness of the total gray matter, hippocampus, or Alzheimer signature regions. In conclusion, higher plasma NfL levels are associated with cognitive decline and larger burden of primarily white matter pathology in the general population.

Gastric cancer and mesenchymal stem cell-derived exosomes: from pro-tumorigenic effects to anti-cancer vehicles.

Gastric cancer (GC) is one of the most prevalent malignancies in the world, with a high mortality rate in both women and men. Conventional treatments, like chemotherapy, radiotherapy and surgery, are facing some drawbacks like acquired drug resistance and various side effects, leading to cancer recurrence and increased morbidity; thus, development of novel approaches in targeted therapy would be very beneficial. Exosomes, extracellular vesicles with a size distribution of sub-150 nm, interplay in physiological and pathophysiological cell-cell communications and can pave the way for targeted cancer therapy. Accumulating pieces of evidence have indicated that exosomes derived from mesenchymal stem cells (MSC-EXs) can act as a double-edged sword in some cancers. The purpose of this review is to assess the differences between stem cell therapy and exosome therapy. Moreover, our aim is to demonstrate how naïve MSCs transform into GC-MSCs in the tumor microenvironment. Additionally, the tumorigenic and anti-proliferation effects of MSC-EXs derived from different origins were investigated. Finally, we suggest potential modifications and combination options that involve utilizing MSC-EXs from the foreskin and umbilical cord as promising sources to enhance the efficacy of gastric cancer treatment. This approach is presented in contrast to bone marrow cells, which are more heterogeneous, age-related, and are also easily affected by the patient's circulation system.

Phenome-wide association study on miRNA-related sequence variants: the UK Biobank.

BACKGROUND: Genetic variants in the coding region could directly affect the structure and expression levels of genes and proteins. However, the importance of variants in the non-coding region, such as microRNAs (miRNAs), remain to be elucidated. Genetic variants in miRNA-related sequences could affect their biogenesis or functionality and ultimately affect disease risk. Yet, their implications and pleiotropic effects on many clinical conditions remain unknown. METHODS: Here, we utilised genotyping and hospital records data in the UK Biobank (N = 423,419) to investigate associations between 346 genetic variants in miRNA-related sequences and a wide range of clinical diagnoses through phenome-wide association studies. Further, we tested whether changes in blood miRNA expression levels could affect disease risk through colocalisation and Mendelian randomisation analysis. RESULTS: We identified 122 associations for six variants in the seed region of miRNAs, nine variants in the mature region of miRNAs, and 27 variants in the precursor miRNAs. These included associations with hypertension, dyslipidaemia, immune-related disorders, and others. Nineteen miRNAs were associated with multiple diagnoses, with six of them associated with multiple disease categories. The strongest association was reported between rs4285314 in the precursor of miR-3135b and celiac disease risk (odds ratio (OR) per effect allele increase = 0.37, P = 1.8 × 10-162). Colocalisation and Mendelian randomisation analysis highlighted potential causal role of miR-6891-3p in dyslipidaemia. CONCLUSIONS: Our study demonstrates the pleiotropic effect of miRNAs and offers insights to their possible clinical importance.