MiR-139-5p is a causal biomarker for type 2 diabetes; Results from genome-wide microRNA profiling and Mendelian randomization analysis in a population-based study

Mens, Michelle M. J.; Mustafa, Rima; Ahmadizar, Fariba; Ma, Ikram; Evangelou, Marina; Kavousi, Maryam; Dehghan, Abbas; Ghanbari, Mohsen

doi:10.1101/2021.05.13.21257090

Cited by 3 publications

(4 citation statements)

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“…This miRNA has been reported by our group recently to be implicated in fatty liver disease [40]. At the same time, in the most recent publication with the Rotterdam Study data, we found the link between miR-193a-5p and incident of T2D [41]. These findings may indicate a potential role of miR-193a-5p in adiposity and metabolic pathways that warrant further experimental validation studies.…”

Section: Discussionsupporting

confidence: 78%

“…In our search in previous studies on the association between the obesity-related miRNAs and cardiovascular and metabolic diseases, we found evidence for five miRNAs. Particularly, the top obesity-associated miRNA (miR-193a-5p), which has been shown by our group and others to be associated with hepatic steatosis and T2D [40,41]. In addition, the high expression of miR-145-5p has been a risk factor for essential hypertension [57].…”

Section: Discussionmentioning

confidence: 95%

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Plasma circulating microRNAs associated with obesity, body fat distribution, and fat mass: the Rotterdam Study

et al. 2022

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BACKGROUND: MicroRNAs (miRNAs) represent a class of small non-coding RNAs that regulate gene expression posttranscriptionally and are implicated in the pathogenesis of different diseases. Limited studies have investigated the association of circulating miRNAs with obesity and body fat distribution and their link to obesity-related diseases using population-based data. METHODS: We conducted a genome-wide profile of circulating miRNAs in plasma, collected between 2002 and 2005, in 1208 participants from the population-based Rotterdam Study cohort. Obesity and body fat distribution were measured as body mass index (BMI), waist-to-hip ratio (WHR), android-fat to gynoid-fat ratio (AGR), and fat mass index (FMI) measured by anthropometrics and Dual X-ray Absorptiometry. Multivariable linear regression models were used to assess the association of 591 miRNAs wellexpressed in plasma with these traits adjusted for potential covariates. We further sought for the association of identified miRNAs with cardiovascular and metabolic diseases in the Rotterdam study and previous publications. RESULTS: Plasma levels of 65 miRNAs were associated with BMI, 40 miRNAs with WHR, 65 miRNAs with FMI, and 15 miRNAs with AGR surpassing the Bonferroni-corrected P < 8.46 × 10 −5 . Of these, 12 miRNAs were significantly associated with all traits, while four miRNAs were associated only with WHR, three miRNAs only with FMI, and miR-378i was associated only with AGR. The most significant association among the overlapping miRNAs was with miR-193a-5p, which was shown to be associated with type 2 diabetes and hepatic steatosis in the Rotterdam Study. Moreover, five of the obesity-associated miRNAs and two of the body fat distribution miRNAs have been correlated previously to cardiovascular disease. CONCLUSIONS: This study indicates that plasma levels of several miRNAs are associated with obesity and body fat distribution which could help to better understand the underlying mechanisms and may have the biomarker potential for obesity-related diseases.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 95%

Plasma circulating microRNAs associated with obesity, body fat distribution, and fat mass: the Rotterdam Study

et al. 2022

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“…Previous studies have identified miR‐193a‐5p to be positively correlated to BMI and to be upregulated in patients with obesity, diabetes, and nonalcoholic fatty liver disease. 89 , 90 , 91 Additionally, serum levels of miR‐193a‐5p have been shown to decrease in obese subjects following diet‐induced weight loss. 92 , 93 As miR‐193a‐5p is associated with insulin resistance parameters, the reduction of miR‐193a‐5p levels may serve to improve glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

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

Karlin,

Sooda,

Larson

et al. 2024

JAHA

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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.

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“…Similarly, reverse causation can be avoided because genetic variants are assigned before the development of the disease (Davey Smith and Hemani, 2014). MR has been widely used to explore the causality between miRNAs and diseases, such as COVID-19 (Li et al, 2021), schizophrenia (Mu et al, 2023), lung cancer , incident acute coronary syndrome (Shen et al, 2021), and type 2 diabetes (Mens et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Systematic genome-wide Mendelian randomization reveals the causal links between miRNAs and Parkinson’s disease

Shi,

Wu,

et al. 2024

Front. Neurosci.

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BackgroundMicroRNAs (miRNAs) have pivotal roles in gene regulation. Circulating miRNAs have been developed as novel candidate non-invasive biomarkers for diagnosis, prognosis, and treatment response for diseases. However, miRNAs that have causal effects on Parkinson’s Disease (PD) remain largely unknown. To investigate the causal relationships between miRNAs and PD, here we conduct a Mendelian randomization (MR) study.MethodsThis study utilized the summary-level data of respective genome-wide association studies (GWAS) for 2083 miRNAs and seven PD-related outcomes to comprehensively reveal the causal associations between the circulating miRNAs and PD. Two-sample MR design was deployed and the causal effects were estimated with inverse variance weighted, MR-Egger, and weighted median. Comprehensively sensitive analyses were followed, including Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis, to validate the robustness of our results. Finally, we investigated the potential role of the MR significant miRNAs by predicting their target genes and functional enrichment analysis.ResultsInverse variance weighted estimates suggested that two miRNAs, miR-205-5p (β = −0.46, 95%CI: −0.690 to −0.229, p = 9.3 × 10−5) and miR-6800-5p (β = −0.389, 95%CI: −0.575 to −0.202, p = 4.32 × 10−5), significantly decreased the rate of cognitive decline among PD patients. In addition, eight miRNAs were nominally associated with more than three PD-related outcomes each. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. Gene Ontology (GO) analysis showed that the targets of these causal miRNAs were significantly enriched in cell cycle, apoptotic, and aging pathways.ConclusionThis MR study identified two miRNAs whose genetically regulated expression might have a causal role in the development of PD dementia. Our findings provided potential miRNA biomarkers to make better and early diagnoses and risk assessments of PD.

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MiR-139-5p is a causal biomarker for type 2 diabetes; Results from genome-wide microRNA profiling and Mendelian randomization analysis in a population-based study

Cited by 3 publications

References 34 publications

Plasma circulating microRNAs associated with obesity, body fat distribution, and fat mass: the Rotterdam Study

Plasma circulating microRNAs associated with obesity, body fat distribution, and fat mass: the Rotterdam Study

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

Systematic genome-wide Mendelian randomization reveals the causal links between miRNAs and Parkinson’s disease

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