Associations of circulating plasma microRNAs with age, body mass index and sex in a population-based study

BMC Medical Genomics, Oct 2015

Background Non-cellular blood circulating microRNAs (plasma miRNAs) represent a promising source for the development of prognostic and diagnostic tools owing to their minimally invasive sampling, high stability, and simple quantification by standard techniques such as RT-qPCR. So far, the majority of association studies involving plasma miRNAs were disease-specific case-control analyses. In contrast, in the present study, plasma miRNAs were analysed in a sample of 372 individuals from a population-based cohort study, the Study of Health in Pomerania (SHIP). Methods Quantification of miRNA levels was performed by RT-qPCR using the Exiqon Serum/Plasma Focus microRNA PCR Panel V3.M covering 179 different miRNAs. Of these, 155 were included in our analyses after quality-control. Associations between plasma miRNAs and the phenotypes age, body mass index (BMI), and sex were assessed via a two-step linear regression approach per miRNA. The first step regressed out the technical parameters and the second step determined the remaining associations between the respective plasma miRNA and the phenotypes of interest. Results After regressing out technical parameters and adjusting for the respective other two phenotypes, 7, 15, and 35 plasma miRNAs were significantly (q < 0.05) associated with age, BMI, and sex, respectively. Additional adjustment for the blood cell parameters identified 12 and 19 miRNAs to be significantly associated with age and BMI, respectively. Most of the BMI-associated miRNAs likely originate from liver. Sex-associated differences in miRNA levels were largely determined by differences in blood cell parameters. Thus, only 7 as compared to originally 35 sex-associated miRNAs displayed sex-specific differences after adjustment for blood cell parameters. Conclusions These findings emphasize that circulating miRNAs are strongly impacted by age, BMI, and sex. Hence, these parameters should be considered as covariates in association studies based on plasma miRNA levels. The established experimental and computational workflow can now be used in future screening studies to determine associations of plasma miRNAs with defined disease phenotypes.

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Associations of circulating plasma microRNAs with age, body mass index and sex in a population-based study

Ameling et al. BMC Medical Genomics Associations of circulating plasma microRNAs with age, body mass index and sex in a population-based study Sabine Ameling 0 1 2 Tim Kacprowski 0 1 Ravi Kumar Chilukoti 0 1 Carolin Malsch 1 Volkmar Liebscher 4 Karsten Suhre 3 6 Maik Pietzner 5 Nele Friedrich 2 5 Georg Homuth 1 Elke Hammer 1 2 Uwe Völker 1 2 0 Equal contributors 1 Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, , Friedrich-Ludwig-Jahn-Str. 15A, D-17475 Greifswald , Germany 2 DZHK (German Centre for Cardiovascular Research) , partner site Greifswald, Greifswald , Germany 3 Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar , Education City, PO Box 24144, Doha , Qatar 4 Institute of Mathematics and Informatics, Ernst-Moritz-Arndt-University , Greifswald 5 Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald , Greifswald , Germany 6 Helmholtz Zentrum München, Germany, Research Centre for Environmental Health , Neuherberg , Germany Background: Non-cellular blood circulating microRNAs (plasma miRNAs) represent a promising source for the development of prognostic and diagnostic tools owing to their minimally invasive sampling, high stability, and simple quantification by standard techniques such as RT-qPCR. So far, the majority of association studies involving plasma miRNAs were disease-specific case-control analyses. In contrast, in the present study, plasma miRNAs were analysed in a sample of 372 individuals from a population-based cohort study, the Study of Health in Pomerania (SHIP). Methods: Quantification of miRNA levels was performed by RT-qPCR using the Exiqon Serum/Plasma Focus microRNA PCR Panel V3.M covering 179 different miRNAs. Of these, 155 were included in our analyses after quality-control. Associations between plasma miRNAs and the phenotypes age, body mass index (BMI), and sex were assessed via a two-step linear regression approach per miRNA. The first step regressed out the technical parameters and the second step determined the remaining associations between the respective plasma miRNA and the phenotypes of interest. Results: After regressing out technical parameters and adjusting for the respective other two phenotypes, 7, 15, and 35 plasma miRNAs were significantly (q < 0.05) associated with age, BMI, and sex, respectively. Additional adjustment for the blood cell parameters identified 12 and 19 miRNAs to be significantly associated with age and BMI, respectively. Most of the BMI-associated miRNAs likely originate from liver. Sex-associated differences in miRNA levels were largely determined by differences in blood cell parameters. Thus, only 7 as compared to originally 35 sex-associated miRNAs displayed sex-specific differences after adjustment for blood cell parameters. Conclusions: These findings emphasize that circulating miRNAs are strongly impacted by age, BMI, and sex. Hence, these parameters should be considered as covariates in association studies based on plasma miRNA levels. The established experimental and computational workflow can now be used in future screening studies to determine associations of plasma miRNAs with defined disease phenotypes. BMI; Age; Sex; Circulating microRNA; miRNA; Association studies; Plasma; Blood - Background MicroRNAs (miRNAs) are small ~22 nt long noncoding RNAs which play important regulatory roles by targeting mRNAs for degradation or mediating translational repression. Thus, they affect a wide range of physiological and pathophysiological processes including cell differentiation, proliferation, apoptosis, angiogenesis or inflammation [1, 2]. Besides their common intracellular localization, miRNAs are present in different body fluids, particularly in blood. The factors that determine the levels of extracellular miRNAs, e.g. in plasma, such as active secretion or passive release due to cell lysis as well as the functional roles of these plasma miRNAs are still under investigation. Non-cellular blood circulating microRNAs (in the remainder of this paper referred to as plasma miRNAs) are highly ribonuclease-resistant because they are either enclosed in membranous vesicles as apoptotic bodies and exosomes or localized in complexes with RNA-binding proteins (Ago2), high-density lipoproteins or nucleophosmin [3–5]. Recent studies have proposed a hormone-like role for circulating miRNAs in intercellular communication [3, 4]. The putative value of plasma miRNAs as predictive and diagnostic biomarkers motivated the recent large-scale profiling of these molecules in the context of many diseases, such as cancer, diabetes, multiple sclerosis, coronary artery disease or myocardial infarction [6–8]. A selection of 19 potentially informative plasma miRNAs was investigated by Zampetaki et al. [8] in a prospective, populationbased study on cardiovascular disease. The study revealed associations between several miRNAs (...truncated)


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Sabine Ameling, Tim Kacprowski, Ravi Chilukoti, Carolin Malsch, Volkmar Liebscher, Karsten Suhre, Maik Pietzner, Nele Friedrich, Georg Homuth, Elke Hammer, Uwe Völker. Associations of circulating plasma microRNAs with age, body mass index and sex in a population-based study, BMC Medical Genomics, 2015, pp. 61, 8, DOI: 10.1186/s12920-015-0136-7