Peripheral Blood Transcriptomic Signatures of Fasting Glucose and Insulin Concentrations.
Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q <0.05, we identified three transcripts associated with fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes-imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis.
Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD.|Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD.
Brian H
BH
Chen
Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA.|Diabetes Research Center, Department of Medicine, Massachusetts General Hospital, Boston, MA.|Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Marie-France
MF
Hivert
Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.|Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, the Netherlands.
Marjolein J
MJ
Peters
Epidemiology and Public Health Group, Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, U.K.
Luke C
LC
Pilling
Program in Bioinformatics, Boston University, Boston, MA.
John D
JD
Hogan
Program in Bioinformatics, Boston University, Boston, MA.
Lisa M
LM
Pham
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, U.K.
Lorna W
LW
Harries
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD.
Caroline S
CS
Fox
Geriatric Rehabilitation Unit, Azienda Sanitaria di Firenze, Florence, Italy.
Stefania
S
Bandinelli
Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
Abbas
A
Dehghan
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD.
Dena G
DG
Hernandez
Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
Albert
A
Hofman
Department of Biostatistics, Boston University School of Public Health, Boston, MA.
Jaeyoung
J
Hong
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD.|Hebrew SeniorLife, Harvard Medical School, Boston, MA.
Roby
R
Joehanes
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD.
Andrew D
AD
Johnson
Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD.
Peter J
PJ
Munson
Data Coordinating Center, Boston University, Boston, MA.
Denis V
DV
Rybin
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD.
Andrew B
AB
Singleton
Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.|Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, the Netherlands.|Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
André G
AG
Uitterlinden
Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD.
Saixia
S
Ying
Epidemiology and Public Health Group, Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, U.K.
David
D
Melzer
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD.
Daniel
D
Levy
Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.|Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging, Leiden and Rotterdam, the Netherlands.
Joyce B J
JB
van Meurs
Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD.
Luigi
L
Ferrucci
Diabetes Research Center, Department of Medicine, Massachusetts General Hospital, Boston, MA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA.|Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Department of Medicine, Harvard Medical School, Boston, MA.
Jose C
JC
Florez
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA.
Josée
J
Dupuis
Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA jmeigs@partners.org kolaczyk@bu.edu.|Department of Medicine, Harvard Medical School, Boston, MA.|Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.
James B
JB
Meigs
Program in Bioinformatics, Boston University, Boston, MA jmeigs@partners.org kolaczyk@bu.edu.|Department of Mathematics and Statistics, Boston University, MA.
Eric D
ED
Kolaczyk
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D005215:Fasting / Q000097:blood*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
D001786:Blood Glucose; C498779:IGF2BP2 protein, human; D007328:Insulin; D012333:RNA, Messenger; D016601:RNA-Binding Proteins