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Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

Journal article
Authors A. Teumer
Q. Qi
Maria Nethander
H. Aschard
S. Bandinelli
M. Beekman
S. I. Berndt
M. Bidlingmaier
L. Broer
A. Cappola
G. P. Ceda
S. Chanock
M. H. Chen
T. C. Chen
Y. D. I. Chen
J. Chung
F. Del Greco Miglianico
Joel Eriksson
L. Ferrucci
N. Friedrich
C. Gnewuch
M. O. Goodarzi
N. Grarup
T. Guo
E. Hammer
R. B. Hayes
A. A. Hicks
A. Hofman
J. J. Houwing-Duistermaat
F. Hu
D. J. Hunter
L. L. Husemoen
A. Isaacs
K. B. Jacobs
J. A. M. J. L. Janssen
John-Olov Jansson
N. Jehmlich
S. Johnson
A. Juul
M. Karlsson
T. O. Kilpelainen
P. Kovacs
P. Kraft
C. Li
A. Linneberg
Y. Liu
R. J. F. Loos
Mattias Lorentzon
Y. Lu
M. Maggio
R. Magi
J. Meigs
Dan Mellström
M. Nauck
A. B. Newman
M. N. Pollak
P. P. Pramstaller
I. Prokopenko
B. M. Psaty
M. Reincke
E. B. Rimm
J. I. Rotter
A. Saint Pierre
C. Schurmann
S. Seshadri
Klara Sjögren
P. E. Slagboom
H. D. Strickler
M. Stumvoll
Y. Suh
Q. Sun
C. Zhang
Johan Svensson
T. Tanaka
A. Tare
A. Tönjes
H. W. Uh
C. M. Van Duijn
D. van Heemst
Liesbeth Vandenput
R. S. Vasan
U. Völker
Sara M. Willems
Claes Ohlsson
H. Wallaschofski
R. C. Kaplan
Published in Aging Cell
Volume 15
Issue 5
Pages 811-824
ISSN 1474-9718
Publication year 2016
Published at Institute of Neuroscience and Physiology, Department of Physiology
Core Facilities, Bioinformatics
Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 811-824
Language en
Links dx.doi.org/10.1111/acel.12490
Keywords aging, genomewide association study, growth hormone axis, IGF-I, IGFBP-3, longevity
Subject categories Medical Genetics, Endocrinology

Abstract

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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