OBJECTIVE: MicroRNAs (miRNAs) have been implicated in the regulation of cardiometabolic disorders. Given the crucial role of miRNAs in gene expression, genetic variation within miRNA genes is expected to affect miRNA function and substantially contribute to disease risk. METHODS: 2,320 variants in miRNA-encoding sequences were systematically retrieved, and their associations with 17 cardiometabolic traits/diseases were investigated, using genome-wide association studies (GWAS) on glycemic indices, anthropometric measures, lipid traits, blood pressure, coronary artery disease, and type 2 diabetes. Next, target genes of the identified miRNAs that may mediate their effect on the phenotypes were examined. Furthermore, trans- expression quantitative trait loci analysis and luciferase reporter assay to provide functional evidence for our findings were performed. RESULTS: rs11614913:C/T in miR-196a2 was associated with waist to hip ratio (P-value=1.7 × 10(-5) , β = 0.023). Two target genes, SFMBT1 and HOXC8, which may mediate this association were identfied, and they were shown experimentally as direct targets of miR-196a2. Moreover, rs174561:C/T in miR-1908 was found to be associated with total cholesterol (P-value=6.5 × 10(-16) , β=0.044), LDL-cholesterol (P-value=4.3 × 10(-18) , β=0.049), HDL-cholesterol (P-value=1.7 × 10(-6) , β=0.026), triglyceride (P-value=7.8 × 10(-14) , β=0.038), and fasting glucose (P-value=4.3 × 10(-10) , β=0.02). In addition, a number of miR-1908 target genes were highlighted as potential mediators. CONCLUSIONS: The results indicated miRNA-dependent regulation of fat distribution by miR-196a2 and of lipid metabolism by miR-1908.
OBJECTIVE: MicroRNAs (miRNAs) have been implicated in the regulation of cardiometabolic disorders. Given the crucial role of miRNAs in gene expression, genetic variation within miRNA genes is expected to affect miRNA function and substantially contribute to disease risk. METHODS: 2,320 variants in miRNA-encoding sequences were systematically retrieved, and their associations with 17 cardiometabolic traits/diseases were investigated, using genome-wide association studies (GWAS) on glycemic indices, anthropometric measures, lipid traits, blood pressure, coronary artery disease, and type 2 diabetes. Next, target genes of the identified miRNAs that may mediate their effect on the phenotypes were examined. Furthermore, trans- expression quantitative trait loci analysis and luciferase reporter assay to provide functional evidence for our findings were performed. RESULTS:rs11614913:C/T in miR-196a2 was associated with waist to hip ratio (P-value=1.7 × 10(-5) , β = 0.023). Two target genes, SFMBT1 and HOXC8, which may mediate this association were identfied, and they were shown experimentally as direct targets of miR-196a2. Moreover, rs174561:C/T in miR-1908 was found to be associated with total cholesterol (P-value=6.5 × 10(-16) , β=0.044), LDL-cholesterol (P-value=4.3 × 10(-18) , β=0.049), HDL-cholesterol (P-value=1.7 × 10(-6) , β=0.026), triglyceride (P-value=7.8 × 10(-14) , β=0.038), and fasting glucose (P-value=4.3 × 10(-10) , β=0.02). In addition, a number of miR-1908 target genes were highlighted as potential mediators. CONCLUSIONS: The results indicated miRNA-dependent regulation of fat distribution by miR-196a2 and of lipid metabolism by miR-1908.
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Authors: Paul S de Vries; Daniel I Chasman; Maria Sabater-Lleal; Ming-Huei Chen; Jennifer E Huffman; Maristella Steri; Weihong Tang; Alexander Teumer; Riccardo E Marioni; Vera Grossmann; Jouke J Hottenga; Stella Trompet; Martina Müller-Nurasyid; Jing Hua Zhao; Jennifer A Brody; Marcus E Kleber; Xiuqing Guo; Jie Jin Wang; Paul L Auer; John R Attia; Lisa R Yanek; Tarunveer S Ahluwalia; Jari Lahti; Cristina Venturini; Toshiko Tanaka; Lawrence F Bielak; Peter K Joshi; Ares Rocanin-Arjo; Ivana Kolcic; Pau Navarro; Lynda M Rose; Christopher Oldmeadow; Helene Riess; Johanna Mazur; Saonli Basu; Anuj Goel; Qiong Yang; Mohsen Ghanbari; Gonneke Willemsen; Ann Rumley; Edoardo Fiorillo; Anton J M de Craen; Anne Grotevendt; Robert Scott; Kent D Taylor; Graciela E Delgado; Jie Yao; Annette Kifley; Charles Kooperberg; Rehan Qayyum; Lorna M Lopez; Tina L Berentzen; Katri Räikkönen; Massimo Mangino; Stefania Bandinelli; Patricia A Peyser; Sarah Wild; David-Alexandre Trégouët; Alan F Wright; Jonathan Marten; Tatijana Zemunik; Alanna C Morrison; Bengt Sennblad; Geoffrey Tofler; Moniek P M de Maat; Eco J C de Geus; Gordon D Lowe; Magdalena Zoledziewska; Naveed Sattar; Harald Binder; Uwe Völker; Melanie Waldenberger; Kay-Tee Khaw; Barbara Mcknight; Jie Huang; Nancy S Jenny; Elizabeth G Holliday; Lihong Qi; Mark G Mcevoy; Diane M Becker; John M Starr; Antti-Pekka Sarin; Pirro G Hysi; Dena G Hernandez; Min A Jhun; Harry Campbell; Anders Hamsten; Fernando Rivadeneira; Wendy L Mcardle; P Eline Slagboom; Tanja Zeller; Wolfgang Koenig; Bruce M Psaty; Talin Haritunians; Jingmin Liu; Aarno Palotie; André G Uitterlinden; David J Stott; Albert Hofman; Oscar H Franco; Ozren Polasek; Igor Rudan; Pierre-Emmanuel Morange; James F Wilson; Sharon L R Kardia; Luigi Ferrucci; Tim D Spector; Johan G Eriksson; Torben Hansen; Ian J Deary; Lewis C Becker; Rodney J Scott; Paul Mitchell; Winfried März; Nick J Wareham; Annette Peters; Andreas Greinacher; Philipp S Wild; J Wouter Jukema; Dorret I Boomsma; Caroline Hayward; Francesco Cucca; Russell Tracy; Hugh Watkins; Alex P Reiner; Aaron R Folsom; Paul M Ridker; Christopher J O'Donnell; Nicholas L Smith; David P Strachan; Abbas Dehghan Journal: Hum Mol Genet Date: 2015-11-10 Impact factor: 6.150