Population differences in microRNA expression and biological implications

Huang, R. Stephanie; Gamazon, Eric R.; Ziliak, Dana; Wen, Yujia; Im, Hae Kyung; Zhang, Wei; Wing, Claudia; Duan, Shiwei; Bleibel, Wasim K.; Cox, Nancy J.; Dolan, M. Eileen

doi:10.4161/rna.8.4.16029

Cited by 144 publications

(127 citation statements)

References 62 publications

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“…There is growing evidence indicating that there is strong variation in miRNA expression in human populations, within a given cellular state, cell type, or tissue (Wang et al 2009;Huang et al 2011;Lu and Clark 2012;Lappalainen et al 2013). The extent to which this variation is under genetic control (i.e., miRNA expression quantitative trait loci, miR-eQTLs) has recently begun to be investigated (Borel et al 2011;Rantalainen et al 2011;Gamazon et al 2012;Parts et al 2012;Civelek et al 2013;Gamazon et al 2013;Lappalainen et al 2013).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

A genomic portrait of the genetic architecture and regulatory impact of microRNA expression in response to infection

et al. 2014

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MicroRNAs (miRNAs) are critical regulators of gene expression, and their role in a wide variety of biological processes, including host antimicrobial defense, is increasingly well described. Consistent with their diverse functional effects, miRNA expression is highly context dependent and shows marked changes upon cellular activation. However, the genetic control of miRNA expression in response to external stimuli and the impact of such perturbations on miRNA-mediated regulatory networks at the population level remain to be determined. Here we assessed changes in miRNA expression upon Mycobacterium tuberculosis infection and mapped expression quantitative trait loci (eQTL) in dendritic cells from a panel of healthy individuals. Genome-wide expression profiling revealed that ∼40% of miRNAs are differentially expressed upon infection. We find that the expression of 3% of miRNAs is controlled by proximate genetic factors, which are enriched in a promoter-specific histone modification associated with active transcription. Notably, we identify two infection-specific response eQTLs, for miR-326 and miR-1260, providing an initial assessment of the impact of genotype-environment interactions on miRNA molecular phenotypes. Furthermore, we show that infection coincides with a marked remodeling of the genome-wide relationships between miRNA and mRNA expression levels. This observation, supplemented by experimental data using the model of miR-29a, sheds light on the role of a set of miRNAs in cellular responses to infection. Collectively, this study increases our understanding of the genetic architecture of miRNA expression in response to infection, and highlights the wide-reaching impact of altering miRNA expression on the transcriptional landscape of a cell.

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confidence: 99%

A genomic portrait of the genetic architecture and regulatory impact of microRNA expression in response to infection

et al. 2014

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“…Furthermore, previous work from our group and others has demonstrated that common genetic variants and microRNAs contributed to the variation in gene expression between LCLs derived from individuals of Yoruba people from Ibadan, Nigeria (YRI) and Caucasian residents of European ancestry from Utah (CEU) (Stranger et al 2007;Zhang et al 2008a;Huang et al 2011). Due to tissue-specific DNA methylation patterns (Rakyan et al 2008), studies in LCLs have the distinct advantage of being a pure population of B cells, as primary samples from humans can include more than one cell type, which may confound downstream analyses.…”

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confidence: 99%

Genome-Wide Variation of Cytosine Modifications Between European and African Populations and the Implications for Complex Traits

et al. 2013

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Elucidating cytosine modification differences between human populations can enhance our understanding of ethnic specificity in complex traits. In this study, cytosine modification levels in 133 HapMap lymphoblastoid cell lines derived from individuals of European or African ancestry were profiled using the Illumina HumanMethylation450 BeadChip. Approximately 13% of the analyzed CpG sites showed differential modification between the two populations at a false discovery rate of 1%. The CpG sites with greater modification levels in European descent were enriched in the proximal regulatory regions, while those greater in African descent were biased toward gene bodies. More than half of the detected population-specific cytosine modifications could be explained primarily by local genetic variation. In addition, a substantial proportion of local modification quantitative trait loci exhibited population-specific effects, suggesting that genetic epistasis and/or genotype · environment interactions could be common. Distinct correlations were observed between gene expression levels and cytosine modifications in proximal regions and gene bodies, suggesting epigenetic regulation of interindividual expression variation. Furthermore, quantitative trait loci associated with population-specific modifications can be colocalized with expression quantitative trait loci and single nucleotide polymorphisms previously identified for complex traits with known racial disparities. Our findings revealed abundant population-specific cytosine modifications and the underlying genetic basis, as well as the relatively independent contribution of genetic and epigenetic variations to population differences in gene expression. DNA methylation is a covalent cytosine modification that occurs at the C-5 position of cytosines at CpG dinucleotides and is dispersed unevenly over the genome (Bird 2002). Interindividual variation in cytosine modifications can be affected by both the stable underlying genetic sequence and dynamic environmental influences (Flanagan et al. 2006;Bock et al. 2008). Cytosine modifications are known to play an important role in the regulation of gene expression, with promoter methylation acting to silence gene expression (Grewal and Moazed 2003). Previous studies of human variation in gene expression have shown that differential gene expression can influence a variety of complex traits, including susceptibilities to common diseases and variation in drug response (Schadt et al. 2005;Emilsson et al. 2008;Cookson et al. 2009).The lymphoblastoid cell lines (LCLs) from the International HapMap Project (HapMap 2003;HapMap 2005) have been used recently for investigating within-and betweenpopulation differences in promoter methylation (Bell et al. 2011;Fraser et al. 2012). Furthermore, previous work from our group and others has demonstrated that common genetic variants and microRNAs contributed to the variation in gene expression between LCLs derived from individuals of We reasoned that an evaluation of the natural variation ...

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“…Although some miRNA genes were found to be evolutionarily conserved, it was demonstrated that the genetic background of a population, epigenetic factors, as well as the polymorphisms present in individuals, can influence their expression (13). Therefore, it is of importance to strengthen and expand previous findings by exploring miR expression in other populations as well.…”

Section: Plasma Levels Of Mir208b (A) and Mir499 (B) Were Significantmentioning

confidence: 96%

“…Consequently, better validation through larger studies is required for the establishment of miRs as biomarkers in clinical practice. Based on the elegant study of Huang et al (13) who showed that miRNA expression levels exhibit population differences, and the recorded dysregulation of two specific myocardialderived miRNAs in AMI patients (14,15), we decided to further investigate their expression in a Caucasian population. Specifically, the purpose of this study was to examine the expression of miR-208b and miR-499 in the plasma of Greek AMI patients, to determine their potential diagnostic value and to compare our results with those obtained from populations of diverse genetic backgrounds.…”

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confidence: 99%

Expression of miR-208b and miR-499 in Greek Patients with Acute Myocardial Infarction

Αγιαννιτόπουλος

Pavlopoulou

Tsamis

et al. 2018

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Abstract. Background/Aim: Certain microRNAs (miRs) present in human plasma are candidate biomarkers for cardiovascular diseases, including acute myocardial infarction (AMI). We examined the expression of two cardiac-specific miRs (miR-208b and miR-499) MicroRNAs (miRs) are evolutionary small endogenous, noncoding, single-stranded RNAs involved in the regulation of gene expression at the post-transcriptional level (1). They possess an important role in multiple biological processes by binding to their target mRNAs and altering the protein expression of their candidate targets (2). Circulating miRs detected in serum or plasma, are actively secreted in macrovesicles or exosomes from different cell types (3), including cardiomyocytes. Elevated mRNA expression levels have been involved in numerous human pathologies including cardiovascular diseases (4).Acute myocardial infarction (AMI) is the acute necrosis of myocardial tissue due to persistent and severe ischemia, and remains a leading cause of morbidity and mortality worldwide (5). Accurate and rapid diagnosis is crucial for the clinical management and prognosis of AMI (6). Thus, exploration of new potential biomarkers that will contribute in this direction is particularly important. Although the circulating levels of cardiac troponin proteins are currently regarded as the most prominent biomarkers for the diagnosis of AMI, measurable amounts of troponins are not usually released from damaged myocardium earlier than 4-8 h after the onset of symptoms (6, 7). In contrast, the levels of circulating plasma miRs can be measured rapidly using realtime PCR, offering two main advantages over standard antibody-based assays: increased sensitivity and specificity. Several studies have already considered circulating cardiacspecific or -enriched miRs as new biomarkers for the early diagnosis of .In fact, the vast majority of these studies have been performed in Asian populations, while limited studies from European populations are also available (12). Consequently, better validation through larger studies is required for the establishment of miRs as biomarkers in clinical practice. Based on the elegant study of Huang et al. (13) who showed that miRNA expression levels exhibit population differences, and the recorded dysregulation of two specific myocardialderived miRNAs in AMI patients (14, 15), we decided to further investigate their expression in a Caucasian population. Specifically, the purpose of this study was to 313

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Population differences in microRNA expression and biological implications

Cited by 144 publications

References 62 publications

A genomic portrait of the genetic architecture and regulatory impact of microRNA expression in response to infection

A genomic portrait of the genetic architecture and regulatory impact of microRNA expression in response to infection

Genome-Wide Variation of Cytosine Modifications Between European and African Populations and the Implications for Complex Traits

Expression of miR-208b and miR-499 in Greek Patients with Acute Myocardial Infarction

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