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Genetics and Epigenetics

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

Abstract

Background

MicroRNAs (miRNAs) represent a class of small non-coding RNAs that regulate gene expression post-transcriptionally 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 well-expressed 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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Fig. 1: Flowchart of the study participants.
Fig. 2: UpSet plots showing the intersections of miRNAs associated with four obesity-related traits.
Fig. 3: Comparison between plasma levels of 12 identified miRNAs in three BMI groups.
Fig. 4: Volcano plots showing the association of miRNAs with AGR (A) and FMI (B) after adjusting for BMI.

Data availability

The data that support the findings of this study are available in the supplementary material of this article. Correspondence and additional data requests should be addressed to MG.

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Acknowledgements

We gratefully acknowledge the contribution of participants, staff, general practitioners, and pharmacists in the Rotterdam Study. This manuscript is part of the Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy (SOPHIA) project. SOPHIA has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 875534. This Joint Undertaking support from the European Union’s Horizon 2020 research and innovation program and EFPIA and T1D Exchange, JDRF, and Obesity Action Coalition.

Funding

The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. MiRNA expression analyses by HTG EdgeSeq WTA was funded by Johnson & Johnson. The project was partly supported by the Erasmus MC Fellowship (EMCF20213) grant of MG. The mentioned funders had no role in the design and conduct of the study, nor in the decision to submit the manuscript for publication.

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MG and MAI were responsible for designing the research; YA conducted the analysis; XZ and MM helped in the miRNAs analysis; MG, FA, TV, ML, MK, and FR provided consultation regarding the T2D, lifestyle factors and obesity-related traits data in the Rotterdam study; All authors have critically reviewed and approved the final manuscript.

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Correspondence to Mohsen Ghanbari.

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Abozaid, Y.J., Zhang, X., Mens, M.M.J. et al. Plasma circulating microRNAs associated with obesity, body fat distribution, and fat mass: the Rotterdam Study. Int J Obes 46, 2137–2144 (2022). https://doi.org/10.1038/s41366-022-01227-8

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