Messenger RNA and MicroRNA transcriptomic signatures of cardiometabolic risk factors.
Cardiometabolic (CM) risk factors are heritable and cluster in individuals. We hypothesized that CM risk factors are associated with multiple shared and unique mRNA and microRNA (miRNA) signatures. We examined associations of mRNA and miRNA levels with 6 CM traits: body mass index, HDL-cholesterol and triglycerides, fasting glucose, and systolic and diastolic blood pressures through cross-sectional analysis of 2812 Framingham Heart Study who had whole blood collection for RNA isolation for mRNA and miRNA expression studies and who consented to genetic research. We excluded participants taking medication for hypertension, dyslipidemia, or diabetes. We measured mRNA (n = 17,318; using the Affymetrix GeneChip Human Exon 1.0 ST Array) and miRNA (n = 315; using qRT-PCR) expression in whole blood. We used linear regression for mRNA analyses and a combination of linear and logistic regression for miRNA analyses. We conducted miRNA-mRNA coexpression and gene ontology enrichment analyses to explore relations between pleiotropic miRNAs, mRNA expression, and CM trait clustering.



We identified hundreds of significant associations between mRNAs, miRNAs, and individual CM traits. Four mRNAs (FAM13A, CSF2RB, HIST1H2AC, WNK1) were associated with all 6 CM traits (FDR < 0.001) and four miRNAs (miR-197-3p, miR-328, miR-505-5p, miR-145-5p) were associated with four CM traits (FDR < 0.05). Twelve mRNAs, including WNK1, that were coexpressed with the four most pleiotropic miRNAs, were also miRNA targets. mRNAs coexpressed with pleiotropic miRNAs were enriched for RNA metabolism (miR-505-5p), ubiquitin-dependent protein catabolism (miR-197-3p, miR-328) and chromatin assembly (miR-328).



We identified mRNA and miRNA signatures of individual CM traits and their clustering. Implicated transcripts may play causal roles in CM risk or be downstream consequences of CM risk factors on the transcriptome. Studies are needed to establish whether or not pleiotropic circulating transcripts illuminate causal pathways for CM risk.
Cardiology Division, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA. mcmanusd@ummhc.org.|National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA. mcmanusd@ummhc.org.|Epidemiology Division, Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USA. mcmanusd@ummhc.org.|, 55 Lake Avenue North, Worcester, MA, 01655, USA. mcmanusd@ummhc.org.
David D
DD
McManus
National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.|Neurology Division, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Jian
J
Rong
National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Population Sciences Branch and Division of Intramural Research, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MA, USA.
Tianxiao
T
Huan
National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Sean
S
Lacey
Cardiology Division, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Kahraman
K
Tanriverdi
Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD, USA.
Peter J
PJ
Munson
National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.|Department of Mathematics and Statistics, Boston University, Boston, MA, USA.
Martin G
MG
Larson
Population Sciences Branch and Division of Intramural Research, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MA, USA.|Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD, USA.|Hebrew SeniorLife, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Roby
R
Joehanes
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Venkatesh
V
Murthy
Cardiology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Ravi
R
Shah
Cardiology Division, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Jane E
JE
Freedman
National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Population Sciences Branch and Division of Intramural Research, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MA, USA.
Daniel
D
Levy
D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics*; D015331:Cohort Studies; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016015:Logistic Models; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D059467:Transcriptome
D035683:MicroRNAs; D012333:RNA, Messenger
Cardiovascular disease risk factors; Epidemiology, Circulation; mRNA; microRNA