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

Teumer, Alexander; Qi, Qibin; Nethander, Maria; Aschard, Hugues; Bandinelli, Stefania; Beekman, Marian; Berndt, Sonja I.; Bidlingmaier, Martin; Broer, Linda and Cappola, Anne, et al. (2016) In Aging Cell 15(5). p.811-824
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... (More)

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.

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publication status
published
subject
keywords
aging, genomewide association study, growth hormone axis, IGF-I, IGFBP-3, longevity
in
Aging Cell
volume
15
issue
5
pages
14 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:84986232247
  • wos:000383715600003
ISSN
1474-9718
DOI
10.1111/acel.12490
language
English
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yes
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a6671480-24db-4d09-a28f-7c879806584f
date added to LUP
2016-10-28 09:21:26
date last changed
2017-09-10 05:11:00
@article{a6671480-24db-4d09-a28f-7c879806584f,
  abstract     = {<p>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.</p>},
  author       = {Teumer, Alexander and Qi, Qibin and Nethander, Maria and Aschard, Hugues and Bandinelli, Stefania and Beekman, Marian and Berndt, Sonja I. and Bidlingmaier, Martin and Broer, Linda and Cappola, Anne and Ceda, Gian Paolo and Chanock, Stephen and Chen, Ming Huei and Chen, Tai C. and Chen, Yii Der Ida and Chung, Jonathan and Del Greco Miglianico, Fabiola and Eriksson, Joel and Ferrucci, Luigi and Friedrich, Nele and Gnewuch, Carsten and Goodarzi, Mark O. and Grarup, Niels and Guo, Tingwei and Hammer, Elke and Hayes, Richard B. and Hicks, Andrew A. and Hofman, Albert and Houwing-Duistermaat, Jeanine J. and Hu, Frank and Hunter, David J. and Husemoen, Lise L. and Isaacs, Aaron and Jacobs, Kevin B. and Janssen, Joop A M J L and Jansson, John Olov and Jehmlich, Nico and Johnson, Simon and Juul, Anders and Karlsson, Magnus and Kilpelainen, Tuomas O. and Kovacs, Peter and Kraft, Peter and Li, Chao and Linneberg, Allan and Liu, Yongmei and Loos, Ruth J F and Lorentzon, Mattias and Lu, Yingchang and Maggio, Marcello and Magi, Reedik and Meigs, James and Mellström, Dan and Nauck, Matthias and Newman, Anne B. and Pollak, Michael N. and Pramstaller, Peter P. and Prokopenko, Inga and Psaty, Bruce M. and Reincke, Martin and Rimm, Eric B. and Rotter, Jerome I. and Saint Pierre, Aude and Schurmann, Claudia and Seshadri, Sudha and Sjögren, Klara and Slagboom, P. Eline and Strickler, Howard D. and Stumvoll, Michael and Suh, Yousin and Sun, Qi and Zhang, Cuilin and Svensson, Johan and Tanaka, Toshiko and Tare, Archana and Tönjes, Anke and Uh, Hae Won and van Duijn, Cornelia M. and van Heemst, Diana and Vandenput, Liesbeth and Vasan, Ramachandran S. and Völker, Uwe and Willems, Sara M. and Ohlsson, Claes and Wallaschofski, Henri and Kaplan, Robert C.},
  issn         = {1474-9718},
  keyword      = {aging,genomewide association study,growth hormone axis,IGF-I,IGFBP-3,longevity},
  language     = {eng},
  month        = {10},
  number       = {5},
  pages        = {811--824},
  publisher    = {Wiley-Blackwell},
  series       = {Aging Cell},
  title        = {Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits},
  url          = {http://dx.doi.org/10.1111/acel.12490},
  volume       = {15},
  year         = {2016},
}