A Genetic Variant in the Seed Region of miR-4513 Shows Pleiotropic Effects on Lipid and Glucose Homeostasis, Blood Pressure, and Coronary Artery Disease

被引：40

作者：

Ghanbari, Mohsen ^{[1
,2
]}

de Vries, Paul S. ^{[1
]}

de Looper, Hans ^{[3
]}

Peters, Marjolein J. ^{[4
,5
]}

Schurmann, Claudia ^{[6
,7
]}

Yaghootkar, Hanieh ^{[8
]}

Doerr, Marcus ^{[9
,10
]}

Frayling, Timothy M. ^{[8
]}

Uitterlinden, Andre G. ^{[1
,4
,5
]}

Hofman, Albert ^{[1
]}

van Meurs, Joyce B. J. ^{[4
,5
]}

Erkeland, Stefan J. ^{[3
]}

Franco, Oscar H. ^{[1
]}

Dehghan, Abbas ^{[1
]}

机构：

[1] Erasmus Univ, Dept Epidemiol, Med Ctr, NL-3000 CA Rotterdam, Netherlands

[2] Mashhad Univ Med Sci, Sch Med, Dept Genet, Mashhad, Iran

[3] Erasmus Univ, Med Ctr, Inst Canc, Dept Hematol, NL-3000 CA Rotterdam, Netherlands

[4] Erasmus Univ, Dept Internal Med, Med Ctr, NL-3000 CA Rotterdam, Netherlands

[5] NGI, NCHA, Leiden, Netherlands

[6] Univ Med, Interfac Inst Genet & Funct Genom, Greifswald, Germany

[7] Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany

[8] Univ Exeter, Sch Med, Exeter, Devon, England

[9] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany

[10] DZHK German Ctr Cardiovasc Res, Greifswald, Germany

来源：

HUMAN MUTATION | 2014年 / 35卷 / 12期

关键词：

miRNA seed region; miRNA polymorphism; cardiometabolic phenotypes; GENOME-WIDE ASSOCIATION; MICRORNA TARGET SITES; GLYCEMIC TRAITS; LOCI; IDENTIFICATION; POLYMORPHISMS; DATABASE; MIRNAS; SNPS; RNAS;

D O I：

10.1002/humu.22706

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

MicroRNAs (miRNA) play a crucial role in the regulation of diverse biological processes by post-transcriptional modulation of gene expression. Genetic polymorphisms in miRNA-related genes can potentially contribute to a wide range of phenotypes. The effect of such variants on cardiometabolic diseases has not yet been defined. We systematically investigated the association of genetic variants in the seed region of miRNAs with cardiometabolic phenotypes, using the thus far largest genome-wide association studies on 17 cardiometabolic traits/diseases. We found that rs2168518:G>A, a seed region variant of miR-4513, associates with fasting glucose, low-density lipoprotein-cholesterol, total cholesterol, systolic and diastolic blood pressure, and risk of coronary artery disease. We experimentally showed that miR-4513 expression is significantly reduced in the presence of the rs2168518 mutant allele. We sought to identify miR-4513 target genes that may mediate these associations and revealed five genes (PCSK1, BNC2, MTMR3, ANK3, and GOSR2) through which these effects might be taking place. Using luciferase reporter assays, we validated GOSR2 as a target of miR-4513 and further demonstrated that the miRNA-mediated regulation of this gene is changed by rs2168518. Our findings indicate a pleiotropic effect of miR-4513 on cardiometabolic phenotypes and may improve our understanding of the pathophysiology of cardiometabolic diseases.

引用

页码：1524 / 1531

页数：8

共 69 条

[21] Genome-Wide Identification of SNPs in MicroRNA Genes and the SNP Effects on MicroRNA Target Binding and Biogenesis [J].

Gong, Jing ;

Tong, Yin ;

Zhang, Hong-Mei ;

Wang, Kai ;

Hu, Tao ;

Shan, Ge ;

Sun, Jun ;

Guo, An-Yuan .

HUMAN MUTATION, 2012, 33 (01) :254-263

[22] Mapping cis- and trans-regulatory effects across multiple tissues in twins [J].

Grundberg, Elin ;

Small, Kerrin S. ;

Hedman, Asa K. ;

Nica, Alexandra C. ;

Buil, Alfonso ;

Keildson, Sarah ;

Bell, Jordana T. ;

Yang, Tsun-Po ;

Meduri, Eshwar ;

Barrett, Amy ;

Nisbett, James ;

Sekowska, Magdalena ;

Wilk, Alicja ;

Shin, So-Youn ;

Glass, Daniel ;

Travers, Mary ;

Min, Josine L. ;

Ring, Sue ;

Ho, Karen ;

Thorleifsson, Gudmar ;

Kong, Augustine ;

Thorsteindottir, Unnur ;

Ainali, Chrysanthi ;

Dimas, Antigone S. ;

Hassanali, Neelam ;

Ingle, Catherine ;

Knowles, David ;

Krestyaninova, Maria ;

Lowe, Christopher E. ;

Di Meglio, Paola ;

Montgomery, Stephen B. ;

Parts, Leopold ;

Potter, Simon ;

Surdulescu, Gabriela ;

Tsaprouni, Loukia ;

Tsoka, Sophia ;

Bataille, Veronique ;

Durbin, Richard ;

Nestle, Frank O. ;

O'Rahilly, Stephen ;

Soranzo, Nicole ;

Lindgren, Cecilia M. ;

Zondervan, Krina T. ;

Ahmadi, Kourosh R. ;

Schadt, Eric E. ;

Stefansson, Kari ;

Smith, George Davey ;

McCarthy, Mark I. ;

Deloukas, Panos ;

Dermitzakis, Emmanouil T. .

NATURE GENETICS, 2012, 44 (10) :1084-+

[23]

He L., 2004, NAT REV GENET, V5, P522

[24] Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution [J].

Heid, Iris M. ;

Jackson, Anne U. ;

Randall, Joshua C. ;

Winkler, Thomas W. ;

Qi, Lu ;

Steinthorsdottir, Valgerdur ;

Thorleifsson, Gudmar ;

Zillikens, M. Carola ;

Speliotes, Elizabeth K. ;

Maegi, Reedik ;

Workalemahu, Tsegaselassie ;

White, Charles C. ;

Bouatia-Naji, Nabila ;

Harris, Tamara B. ;

Berndt, Sonja I. ;

Ingelsson, Erik ;

Willer, Cristen J. ;

Weedon, Michael N. ;

Luan, Jianan ;

Vedantam, Sailaja ;

Esko, Tonu ;

Kilpelaeinen, Tuomas O. ;

Kutalik, Zoltan ;

Li, Shengxu ;

Monda, Keri L. ;

Dixon, Anna L. ;

Holmes, Christopher C. ;

Kaplan, Lee M. ;

Liang, Liming ;

Min, Josine L. ;

Moffatt, Miriam F. ;

Molony, Cliona ;

Nicholson, George ;

Schadt, Eric E. ;

Zondervan, Krina T. ;

Feitosa, Mary F. ;

Ferreira, Teresa ;

Allen, Hana Lango ;

Weyant, Robert J. ;

Wheeler, Eleanor ;

Wood, Andrew R. ;

Estrada, Karol ;

Goddard, Michael E. ;

Lettre, Guillaume ;

Mangino, Massimo ;

Nyholt, Dale R. ;

Purcell, Shaun ;

Smith, Albert Vernon ;

Visscher, Peter M. ;

Yang, Jian .

NATURE GENETICS, 2010, 42 (11) :949-U160

[25] Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion [J].

Heni, Martin ;

Haupt, Axel ;

Schaefer, Silke A. ;

Ketterer, Caroline ;

Thamer, Claus ;

Machicao, Fausto ;

Stefan, Norbert ;

Staiger, Harald ;

Haering, Hans-Ulrich ;

Fritsche, Andreas .

BMC MEDICAL GENETICS, 2010, 11

[26] Evaluation of four novel genetic variants affecting hemoglobin A1c levels in a population-based type 2 diabetes cohort (the HUNT2 study) [J].

Hertel, Jens K. ;

Johansson, Stefan ;

Raeder, Helge ;

Platou, Carl G. P. ;

Midthjell, Kristian ;

Hveem, Kristian ;

Molven, Anders ;

Njolstad, Pal R. .

BMC MEDICAL GENETICS, 2011, 12

[27] Patrocles: a database of polymorphic miRNA-mediated gene regulation in vertebrates [J].

Hiard, Samuel ;

Charlier, Carole ;

Coppieters, Wouter ;

Georges, Michel ;

Baurain, Denis .

NUCLEIC ACIDS RESEARCH, 2010, 38 :D640-D651

[28] The Rotterdam Study: 2014 objectives and design update [J].

Hofman, Albert ;

Murad, Sarwa Darwish ;

van Duijn, Cornelia M. ;

Franco, Oscar H. ;

Goedegebure, Andre ;

Ikram, M. Arfan ;

Klaver, Caroline C. W. ;

Nijsten, Tamar E. C. ;

Peeters, Robin P. ;

Stricker, Bruno H. Ch. ;

Tiemeier, Henning W. ;

Uitterlinden, Andre G. ;

Vernooij, Meike W. .

EUROPEAN JOURNAL OF EPIDEMIOLOGY, 2013, 28 (11) :889-926

[29] Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs [J].

Jima, Dereje D. ;

Zhang, Jenny ;

Jacobs, Cassandra ;

Richards, Kristy L. ;

Dunphy, Cherie H. ;

Choi, William W. L. ;

Au, Wing Yan ;

Srivastava, Gopesh ;

Czader, Magdalena B. ;

Rizzieri, David A. ;

Lagoo, Anand S. ;

Lugar, Patricia L. ;

Mann, Karen P. ;

Flowers, Christopher R. ;

Bernal-Mizrachi, Leon ;

Naresh, Kikkeri N. ;

Evens, Andrew M. ;

Gordon, Leo I. ;

Luftig, Micah ;

Friedman, Daphne R. ;

Weinberg, J. Brice ;

Thompson, Michael A. ;

Gill, Javed I. ;

Liu, Qingquan ;

How, Tam ;

Grubor, Vladimir ;

Gao, Yuan ;

Patel, Amee ;

Wu, Han ;

Zhu, Jun ;

Blobe, Gerard C. ;

Lipsky, Peter E. ;

Chadburn, Amy ;

Dave, Sandeep S. .

BLOOD, 2010, 116 (23) :E118-E127

[30] SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap [J].

Johnson, Andrew D. ;

Handsaker, Robert E. ;

Pulit, Sara L. ;

Nizzari, Marcia M. ;

O'Donnell, Christopher J. ;

de Bakker, Paul I. W. .

BIOINFORMATICS, 2008, 24 (24) :2938-2939

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