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Physiol Genomics. 2016 Jan;48(1):1-11. doi: 10.1152/physiolgenomics.00054.2015. Epub 2015 Oct 20.

Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons.

Author information

1
Epidemiology and Public Health Group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom;
2
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Population Studies Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland;
3
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany;
4
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, the Netherlands;
5
Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands;
6
Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts;
7
RNA mechanisms of complex diseases group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom;
8
Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St. Lucia, Brisbane, Australia;
9
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts;
10
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts;
11
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; The Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, Maryland;
12
Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy;
13
Institute for Health Services Research, University of Exeter Medical School, Exeter, United Kingdom;
14
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland;
15
Clinical Research Branch, National Institute on Aging, Baltimore, Maryland;
16
The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Center Rotterdam, the Netherlands;
17
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Center Rotterdam, the Netherlands;
18
Department of Prosthetic Dentistry, Gerostomatology and Dental Materials, University Medicine Greifswald, Greifswald, Germany;
19
Department of Internal Medicine B - Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University of Greifswald, Greifswald, Germany;
20
Unit of Periodontology, Department of Restorative Dentistry, Periodontology and Endodontology, University Medicine Greifswald, Greifswald, Germany; and.
21
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; General Internal Medicine Section, Boston University, Boston, Massachusetts.
22
Epidemiology and Public Health Group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom; D.Melzer@exeter.ac.uk.

Abstract

Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (≥ 60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength.

KEYWORDS:

blood; gene-expression; human; leukocyte; muscle; strength

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