TY - JOUR
T1 - Exploring the underlying biology of intrinsic cardiorespiratory fitness through integrative analysis of genomic variants and muscle gene expression profiling
AU - Ghosh, Sujoy
AU - Hota, Monalisa
AU - Chai, Xiaoran
AU - Kiranya, Jencee
AU - Ghosh, Palash
AU - He, Zihong
AU - Ruiz-Ramie, Jonathan J.
AU - Sarzynski, Mark A.
AU - Bouchard, Claude
N1 - Funding Information:
This research was partially funded by National Heart, Lung, and Blood Institute Grants HL-45670, HL-47317, HL-47321, HL-47323, and HL-47327, all in support of the HERITAGE Family Study). C. Bouchard is partially funded by the John W. Barton Sr. Chair in Genetics and Nutrition. Z. He is funded by the China Scholarship Council (File No. 201603620001) and China Institute of Sport Science (2015-01, 2016-01). S. Ghosh and C. Bouchard are partially supported by the National Institute of General Medical Sciences (NIGMS)-funded COBRE Grant 8-P30-GM-118430-01. S. Ghosh is supported in part by NIGMS Grant 2-U54-GM-104940, which funds the Louisiana Clinical and Translational Science Center. M. A. Sarzynski is partially supported by NIGMS Grant P20-GM-103499, which funds the South Carolina IDeA Network of Biomedical Research Excellence. This research was also supported by the National Medical Research Council, Ministry of Health, Singapore (WBS R913200076263; to S. Ghosh).
Funding Information:
We thank Drs. Arthur S. Leon, D.C. Rao, James S. Skinner, Tuomo Rankinen, Jacques Gagnonm, and the late Jack H. Wilmore for contributions to the planning, data collection, and conduct of the HERITAGE project. This research was partially funded by National Heart, Lung, and Blood Institute Grants HL-45670, HL-47317, HL-47321, HL-47323, and HL-47327, all in support of the HERITAGE Family Study). C. Bouchard is partially funded by the John W. Barton Sr. Chair in Genetics and Nutrition. Z. He is funded by the China Scholarship Council (File No. 201603620001) and China Institute of Sport Science (2015-01, 2016-01). S. Ghosh and C. Bouchard are partially supported by the National Institute of General Medical Sciences (NIGMS)-funded COBRE Grant 8-P30-GM-118430-01. S. Ghosh is supported in part by NIGMS Grant 2-U54-GM-104940, which funds the Louisiana Clinical and Translational Science Center. M. A. Sarzynski is partially supported by NIGMS Grant P20-GM-103499, which funds the South Carolina IDeA Network of Biomedical Research Excellence. This research was also supported by the National Medical Research Council, Ministry of Health, Singapore (WBS R913200076263; to S. Ghosh).
Publisher Copyright:
Copyright © 2019 the American Physiological Society.
PY - 2019/5
Y1 - 2019/5
N2 - Intrinsic cardiorespiratory fitness (CRF) is defined as the level of CRF in the sedentary state. There are large individual differences in intrinsic CRF among sedentary adults. The physiology of variability in CRF has received much attention, but little is known about the genetic and molecular mechanisms that impact intrinsic CRF. These issues were explored in the present study by interrogating intrinsic CRF-associated DNA sequence variation and skeletal muscle gene expression data from the HERITAGE Family Study through an integrative bioinformatics guided approach. A combined analytic strategy involving genetic association, pathway enrichment, tissue-specific network structure, cis-regulatory genome effects, and expression quantitative trait loci was used to select and rank genes through a variation-adjusted weighted ranking scheme. Prioritized genes were further interrogated for corroborative evidence from knockout mouse phenotypes and relevant physiological traits from the HERITAGE cohort. The mean intrinsic V O2max was 33.1 ml O2·kg1·min1 (SD 8.8) for the sample of 493 sedentary adults. Suggestive evidence was found for gene loci related to cardiovascular physiology (ATE1, CASQ2, NOTO, and SGCG), hematopoiesis (PICALM, SSB, CA9, and CASQ2), skeletal muscle phenotypes (SGCG, DMRT2, ADARB1, and CASQ2), and metabolism (ATE1, PICALM, RAB11FIP5, GBA2, SGCG, PRADC1, ARL6IP5, and CASQ2). Supportive evidence for a role of several of these loci was uncovered via association between DNA variants and muscle gene expression levels with exercise cardiovascular and muscle physiological traits. This initial effort to define the underlying molecular substrates of intrinsic CRF warrants further studies based on appropriate cohorts and study designs, complemented by functional investigations. NEW & NOTEWORTHY Intrinsic cardiorespiratory fitness (CRF) is measured in the sedentary state and is highly variable among sedentary adults. The physiology of variability in intrinsic cardiorespiratory fitness has received much attention, but little is known about the genetic and molecular mechanisms that impact intrinsic CRF. These issues were explored computationally in the present study, with further corroborative evidence obtained from analysis of phenotype data from knockout mouse models and human cardiovascular and skeletal muscle measurements.
AB - Intrinsic cardiorespiratory fitness (CRF) is defined as the level of CRF in the sedentary state. There are large individual differences in intrinsic CRF among sedentary adults. The physiology of variability in CRF has received much attention, but little is known about the genetic and molecular mechanisms that impact intrinsic CRF. These issues were explored in the present study by interrogating intrinsic CRF-associated DNA sequence variation and skeletal muscle gene expression data from the HERITAGE Family Study through an integrative bioinformatics guided approach. A combined analytic strategy involving genetic association, pathway enrichment, tissue-specific network structure, cis-regulatory genome effects, and expression quantitative trait loci was used to select and rank genes through a variation-adjusted weighted ranking scheme. Prioritized genes were further interrogated for corroborative evidence from knockout mouse phenotypes and relevant physiological traits from the HERITAGE cohort. The mean intrinsic V O2max was 33.1 ml O2·kg1·min1 (SD 8.8) for the sample of 493 sedentary adults. Suggestive evidence was found for gene loci related to cardiovascular physiology (ATE1, CASQ2, NOTO, and SGCG), hematopoiesis (PICALM, SSB, CA9, and CASQ2), skeletal muscle phenotypes (SGCG, DMRT2, ADARB1, and CASQ2), and metabolism (ATE1, PICALM, RAB11FIP5, GBA2, SGCG, PRADC1, ARL6IP5, and CASQ2). Supportive evidence for a role of several of these loci was uncovered via association between DNA variants and muscle gene expression levels with exercise cardiovascular and muscle physiological traits. This initial effort to define the underlying molecular substrates of intrinsic CRF warrants further studies based on appropriate cohorts and study designs, complemented by functional investigations. NEW & NOTEWORTHY Intrinsic cardiorespiratory fitness (CRF) is measured in the sedentary state and is highly variable among sedentary adults. The physiology of variability in intrinsic cardiorespiratory fitness has received much attention, but little is known about the genetic and molecular mechanisms that impact intrinsic CRF. These issues were explored computationally in the present study, with further corroborative evidence obtained from analysis of phenotype data from knockout mouse models and human cardiovascular and skeletal muscle measurements.
KW - Bioinformatics
KW - Cardiovascular physiology
KW - In silico exploration of the biology of cardiorespiratory fitness
KW - Intrinsic cardiorespiratory fitness
KW - Skeletal muscle biology
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U2 - 10.1152/japplphysiol.00035.2018
DO - 10.1152/japplphysiol.00035.2018
M3 - Article
C2 - 30605401
AN - SCOPUS:85065863516
SN - 8750-7587
VL - 126
SP - 1292
EP - 1314
JO - Journal of Applied Physiology Respiratory Environmental and Exercise Physiology
JF - Journal of Applied Physiology Respiratory Environmental and Exercise Physiology
IS - 5
ER -