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203. Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans

Author

Timmons, James A., primary, Knudsen, Steen, additional, Rankinen, Tuomo, additional, Koch, Lauren G., additional, Sarzynski, Mark, additional, Jensen, Thomas, additional, Keller, Pernille, additional, Scheele, Camilla, additional, Vollaard, Niels B. J., additional, Nielsen, Søren, additional, Åkerström, Thorbjörn, additional, MacDougald, Ormond A., additional, Jansson, Eva, additional, Greenhaff, Paul L., additional, Tarnopolsky, Mark A., additional, van Loon, Luc J. C., additional, Pedersen, Bente K., additional, Sundberg, Carl Johan, additional, Wahlestedt, Claes, additional, Britton, Steven L., additional, and Bouchard, Claude, additional

Published
2010
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209. Uncovering physiological mechanisms for health disparities in type 2 diabetes.

Author

Staiano, Amanda E, Harrington, Deirdre M, Johannsen, Neil M, Newton Jr, Robert L, Sarzynski, Mark A, Swift, Damon L, Katzmarzyk, Peter T, and Newton, Robert L Jr

Abstract

Type 2 diabetes (T2D) prevalence in the United States is significantly higher in African Americans vs Whites. Yet, the physiological mechanisms contributing to this health disparity have been poorly described. To design effective strategies to reduce this disparity, there is a need to determine whether racial differences in diabetes prevalence are attributable to modifiable or non-modifiable factors. This review synthesizes and critically evaluates the potential physiological and genetic mechanisms that may contribute to the higher susceptibility of African Americans to T2D. These mechanisms include: 1) obesity and fat distribution; 2) metabolic flexibility; 3) muscle physiology; 4) energy expenditure and fitness; and 5) genetics. We focus on the clinical significance of findings and limitations of the recent literature. [ABSTRACT FROM AUTHOR]

Published
2015

210. Plasma Proteomic Kinetics in Response to Acute Exercise

Author

Mi, Michael Y., Barber, Jacob L., Rao, Prashant, Farrell, Laurie A., Sarzynski, Mark A., Bouchard, Claude, Robbins, Jeremy M., and Gerszten, Robert E.

Abstract

Regular exercise has many favorable effects on human health, which may be mediated in part by the release of circulating bioactive factors during each bout of exercise. Limited data exist regarding the kinetic responses of plasma proteins during and after acute exercise. Proteomic profiling of 4163 proteins was performed using a large-scale, affinity-based platform in 75 middle-aged adults who were referred for treadmill exercise stress testing. Plasma proteins were quantified at baseline, peak exercise, and 1-h postexercise, and those with significant changes at both exercise timepoints were further examined for their associations with cardiometabolic traits and change with aerobic exercise training in the HEalth, RIsk factors, exercise Training And GEnetics Family Study, a 20-week exercise intervention study. A total of 765 proteins changed (false discovery rate < 0.05) at peak exercise compared to baseline, and 128 proteins changed (false discovery rate < 0.05) at 1-h postexercise. The 56 proteins that changed at both timepoints included midkine, brain-derived neurotrophic factor, metalloproteinase inhibitor 4, and coiled-coil domain-containing protein 126 and were enriched for secreted proteins. The majority had concordant direction of change at both timepoints. Across all proteins assayed, gene set enrichment analysis showed increased abundance of coagulation-related proteins at 1-h postexercise. Forty-five proteins were associated with at least one measure of adiposity, lipids, glucose homeostasis, or cardiorespiratory fitness in HEalth, RIsk factors, exercise Training And GEnetics, and 20 proteins changed with aerobic exercise training. We identified hundreds of novel proteins that change during acute exercise, most of which resolved by 1 h into recovery. Proteins with sustained changes during exercise and recovery may be of particular interest as circulating biomarkers and pathways for further investigation in cardiometabolic diseases. These data will contribute to a biochemical roadmap of acute exercise that will be publicly available for the entire scientific community.

Published
2023
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211. Abstract 15316: Associations Between Plasma Proteins With Body Composition Traits and Their Responses to Exercise Training

Author

Clarkson, William A, Barber, Jacob L, Robbins, Jeremy M, Cai, Guoshuai, Rao, Prashant, Mi, Michael, Dev, Prasun, Ghosh, Sujoy, Katz, Daniel H, Clish, Clary, Bouchard, Claude, Sarzynski, Mark A, and Gerszten, Robert E

Abstract

Introduction:Although exercise training is known to alter body composition, the molecular biomarkers and mechanisms related to these changes have not been fully elucidated. The purpose of this study was to examine the associations between plasma proteins and body composition traits before and after exercise training.Methods:Measurements were taken before and after 20 weeks of standardized, endurance training in self-identified Black and White adults of the HERITAGE Family Study (n=647). Plasma proteins were measured using an affinity-based platform (n=4979 aptamers). 11 body composition traits were measured using underwater weighing, CT scans, and anthropometry: BMI, body surface area, fat mass, fat free mass, %fat, waist circumference, waist-to-hip ratio, body weight, and abdominal visceral, subcutaneous, and total fat. Linear mixed models were used to test the association between plasma proteins and each trait at baseline and in response to training with full covariate adjustment (Table 1). Significance was set to FDR<0.05.Results:On average, subjects were [mean and (SD)] 35 (14) years old, 33% Black, 54% female, and had BMI 26.2 (5.2) kg/m2. The number of significant associations between proteins and traits at baseline and in response to exercise training ranged from 645-1714 and 0-42, respectively (Table 1). While leptin was among the top associated proteins at both time points for almost all traits, our analysis revealed many novel associations between changes in proteins with changes in body composition. Changes in DLK-1 significantly associated with changes in 9 of 11 traits but was not associated with baseline measures.Conclusions:Numerous plasma proteins were associated with body composition traits at baseline, with fewer associated with trait responses to training. Notably, we identified a subset of proteins uniquely associated with exercise-induced changes in body composition traits.

Published
2022
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212. Abstract 13353: Association of Plasma Metabolites With Inflammatory Markers CRP and GlycA and Their Responses to Exercise Training

Author

Hoffmann, William G, Barber, Jacob L, Dev, Prasun, Clarkson, William A, Cai, Guoshuai, Rao, Prashant, Mi, Michael, Katz, Daniel H, Ghosh, Sujoy, Clish, Clary, Robbins, Jeremy M, Bouchard, Claude, Gerszten, Robert E, and Sarzynski, Mark A

Abstract

Introduction.C-reactive protein (CRP) and GlycA are established biomarkers of inflammation. Regular exercise tends to decrease CRP and GlycA levels. However, the spectrum of molecules associated with the anti-inflammatory effects of regular exercise are less well understood. Hypothesis.We hypothesized that distinct metabolite signatures exist for both baseline levels and exercise responsiveness of CRP and GlycA. Methods.Measures were performed before and after 20 weeks of endurance exercise training in 652 Black and White adults from the HERITAGE Family Study. A total of 300 targeted plasma metabolites were measured using LC-MS. High-sensitivity CRP and GlycA were measured using automated assays and NMR spectroscopy (LabCorp), respectively. Linear mixed models were used to test: 1) Association of baselinemetabolites with baselinehsCRP and GlycA and 2) Association of changesin metabolite with changesin hsCRP and GlycA. Models were adjusted for age, sex, race, BMI, with family membership as a random variable, with change models also adjusting for baseline trait value. Significance was determined as FDR<0.05. Results.Baseline levels and changes of hsCRP and GlycA were moderately correlated (r=0.51 and 0.31, p<0.0001 for both, respectively). At baseline, 40 and 94 metabolites were associated with hsCRP and GlycA, respectively, with 30 metabolites associated with both phenotypes. The top baseline associations for both traits included multiple species of lysophosphatidylcholine (LPC) and phosphatidylethanolamine (PE), while cortisol, biliverdin, and bilirubin were among the metabolites associated with GlycA only. The changes in only one metabolite were associated with concomitant changes in CRP, while no associations were found for change in GlycA. Conclusions.Plasma metabolite associations with baseline hsCRP overlapped with those associated with baseline GlycA levels. Several unique metabolite associations with baseline GlycA were identified, including molecules in established inflammatory pathways. Metabolite changes with exercise were not associated with changes in either measure. These findings have implications for the use of metabolites as signatures of systemic inflammation vs as targets of lifestyle interventions.

Published
2022
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213. Abstract 10710: Plasma Proteomic Profiles of the Blood Pressure Response During Exercise Are Associated With Incident Hypertension

Author

Rao, Prashant, Keyes, Michelle, Mi, Michael, Barber, Jacob, Tahir, Usman A, Deng, Shuliang, Clish, Clary, Shen, Dongxiao, Farrell, Laurie, Xanthakis, Vanessa, Ramachandran, Vasan S, Bouchard, Claude, Sarzynski, Mark A, Gerszten, Robert E, and Robbins, Jeremy

Abstract

Introduction:The blood pressure (BP) response during acute exercise (acute exercise blood pressure (AEBP)) is related to future risk of hypertension (HTN) and cardiovascular disease (CVD). Biochemical characterization of AEBP could identify novel biomarkers of CVD risk and inform understanding of its biology.Methods:We applied an aptamer-based proteomics platform to assay ~5000 proteins at rest in 681 healthy individuals of the HERITAGE Family Study (mean age 34y, 54% women) who underwent an acute exercise perturbation. AEBP was measured during submaximal exercise on a cycle ergometer. We then performed a proteomic association study of resting BP and AEBP. Top protein associations with acute exercise SBP and DBP were analyzed for their association with incident HTN and CVD in the Framingham Heart Study (FHS). Putative causal effects of AEBP-related proteins were investigated by Mendelian randomization (MR), using cis-protein quantitative loci genetic instruments.Results:We identified new markers of AEBP, many of which are secreted proteins that span biological processes relevant to vascular function including transforming-growth factor beta-receptor 3 (β = -3.39, p = 2.33e-6), prostaglandin D2-synthase (β = -2.50, p = 1.18e-10-9), and angiopoietin-related protein 4 (β = 2.44, p = 1.05e-4). The addition of 12 AEBP-associated proteins to clinical information informed future risk of HTN and CVD among normotensive community-dwelling individuals (clinical model, clinical proteomic model AUCs: incident HTN 0.69, 0.73; coronary heart disease 0.73, 0.76; heart failure 0.83, 0.87). MR analysis of AEBP-associated proteins supported a potential causal relationship between 5 proteins and BP regulation (TGFBR3, ANGPTL4, CGA FSHB, PTGDS, KLK8).Conclusions:We identified new blood biomarkers of BP regulation that were elicited only by an acute exercise perturbation and highlight novel potential causal pathways.

Published
2022
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214. Abstract 13514: Associations Between Plasma Metabolites With Body Composition Traits and Their Responses to Exercise Training

Author

Dev, Prasun, Barber, Jacob L, Clarkson, William A, Robbins, Jeremy M, Rao, Prashant, Mi, Michael, Ghosh, Sujoy, Katz, Daniel H, Clish, Clary, Bouchard, Claude, Gerszten, Robert E, and Sarzynski, Mark A

Abstract

INTRODUCTION:Although exercise training can improve body composition, the molecular biomarkers and mechanisms related to these changes have not been fully elucidated.HYPOTHESIS:We hypothesized that distinct metabolite signatures exist for both baseline levels and exercise responsiveness of body composition traits, with substantial overlap across traits.METHODS:Measurements were taken before and after 20 weeks of endurance training in self-identified Black and White adults of the HERITAGE Family Study (n=652). 300 targeted plasma metabolites were measured using LC-MS. Underwater weighing, CT scans, and anthropometric measurements were used to derive the 11 body composition traits included in this study: BMI, body surface area, fat mass, fat free mass, %fat, waist circumference, waist-to-hip ratio, body weight, and abdominal visceral, subcutaneous, and total fat. Linear mixed models were used to test the association between plasma metabolites and each body composition trait at baseline and in response to training with full covariate adjustment. Significance was set to FDR<0.05.Results:On average, subjects were [mean and (SD)] 35 (14) years old, 33% Black, 54% female, and had BMI of 26.2 (5.2) kg/m2. The number of metabolites significantly associated with body composition traits at baseline ranged from 57-141 (Table 1). DMGV was among the top 3 associated metabolites at baseline for all 11 traits, while SM(d18:1/16:1) was associated with 8 of 11 baseline traits. Few if any significant associations were found between change in metabolites and change in body composition measures in response to exercise training (range: 0-10) (Table 1).CONCLUSIONS:Although numerous metabolites were associated with body composition traits at baseline, few associations were observed with trait responses to training. These results suggest that intrinsic body composition and its response to exercise training may have differing underlying metabolic signatures.

Published
2022
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215. Abstract 15399: Proteomic Landscape of Plasma Lipoprotein Responses to Regular Exercise

Author

Barber, Jacob L, Cai, Guoshuai, Robbins, Jeremy M, Rao, Prashant, Mi, Michael, Ghosh, Sujoy, Clish, Clary, Katz, Daniel H, Bouchard, Claude, Gerszten, Robert E, and Sarzynski, Mark A

Abstract

Introduction:Lipoproteins are among the strongest predictors of CVD and are altered through regular exercise. However, the molecular changes underlying the potential benefits of exercise on plasma lipoproteins are unclear.Methods:Proteins (n=4979) were quantified from the plasma of 647 Black and White adults (56% women, mean age = 34.9 yrs) before and after 20-weeks of endurance exercise training using SomaScan. All subjects had complete data for 7 lipoprotein traits that improved with training: HDL-C, TG, large TG rich lipoprotein particles (LTRLP), small LDL particles (SLDLP), large HDL particles (LHDLP), TRLP size, and LDLP size. Fully adjusted linear mixed models were used to test the association of 1) baseline proteins with baseline lipoproteins and 2) delta proteins with delta lipoproteins (delta = post training - baseline value). Significance was determined as FDR<0.05.Results:We identified numerous proteins associated with baseline levels of at least one of the seven lipoprotein traits (range: 48-1099) and whose changes in response to regular exercise were associated with concomitant changes in lipoproteins (range: 4-95) (Table 1). Substantial overlap was found between proteins associated with lipoproteins across timepoints, with 16 proteins associated with 4 or more lipoprotein traits at both timepoints. Plasma abundance of 12/16 proteins significantly changed with training (FDR <0.05). Additionally, for these proteins plasma abundance changed in concordance with the beneficial direction of the associated lipoprotein trait (e.g., proteins associated with atheroprotective lipoprotein traits increased with training and proteins associated with atherogenic traits decreased).Conclusions:Beneficial alterations to plasma lipoproteins with regular exercise are reflected in changes to the plasma proteome. Proteins identified here may represent novel markers of the benefits of regular exercise and of systemic lipoprotein metabolism.

Published
2022
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216. Abstract 13308: Complementary Investigations of Plasma Proteomics Identify Novel Protein Associations With Incident Diabetes and Glucose Metabolism

Author

Mi, Michael Y, Cronje, Helene T, Austin, Thomas R, Biggs, Mary L, Siscovick, David S, Lemaitre, Rozenn N, Psaty, Bruce M, Tracy, Russell P, Djousse, Luc, Kizer, Jorge R, IX, Joachim H, Sotoodehnia, Nona, Rao, Prashant, Robbins, Jeremy M, Barber, Jacob L, Sarzynski, Mark A, Clish, Clary, Bouchard, Claude, Mukamal, Ken J, Jensen, Majken K, and Gerszten, Robert E

Abstract

Introduction:Type 2 diabetes (T2D) is a cardiovascular disease risk equivalent and likely results from broad metabolic changes, which high throughput proteomics have helped to unravel. Prior studies are limited by proteomic coverage, cross sectional design, and lack of physiologic phenotyping.Hypothesis:Complementary proteomic studies of incident T2D and physiologic responses to an intravenous glucose tolerance test (IVGTT) will identify novel proteins with roles in glucose homeostasis and future risk of T2D.Methods:Cardiovascular Health Study (CHS) and HERITAGE study participants without diabetes underwent SomaScan®profiling of 4,776 plasma proteins. HERITAGE participants underwent IVGTT, from which insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG) were derived. We used Cox regression to test protein associations with 18-year incident T2D in CHS, and multivariable linear regression to test protein associations with IVGTT measures in HERITAGE.Results:In CHS (N = 2631, 74 ± 5 years, 62% female, 14% Black), 57 proteins were significantly associated with incident T2D after comprehensive covariate and multiple testing adjustment. Of these, 44, 9, and 8 were associated with SI, AIRG, and SGrespectively in HERITAGE (N = 752, 35 ± 14 years, 55% female, 38% Black) (Figure). Notable findings include beta-glucuronidase, which associated with increased T2D risk (HR 1.46 per SD increase in log2protein level) and lower SG, suggesting a role in insulin-independent glucose disposal, and thrombospondin-2, which associated with increased T2D risk (HR 1.26 per SD), lower AIRG, and not with SI, indicating that it may be a marker of pancreatic dysfunction.Conclusions:By integrating proteomics from two complementary prospective cohorts using different but related outcomes, we identified 34 novel protein-T2D associations, and characterized their relationship with physiologic axes of glucose metabolism.

Published
2022
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217. Abstract 15168: Plasma Metabolomic Profiling Identifies Markers of Cardiorespiratory Fitness Responsive to Endurance Exercise Training

Author

Rao, Prashant, Mi, Michael, Barber, Jacob, Deng, Shuliang, Farrell, Laurie, Bouchard, Claude, Clish, Clary, Sarzynski, Mark A, Gerszten, Robert E, and Robbins, Jeremy

Abstract

Background:High-throughput metabolite profiling allows for the assessment of thousands of metabolites that may participate in exercise-related pathways. Here, we characterize plasma metabolite changes in healthy individuals undergoing endurance exercise training (ET) to identify biochemical features of VO2max and/or those responsive to ET.Methods:We measured 444 known metabolites and 3221 non-targeted metabolite peaks using liquid chromatography tandem mass spectrometry and VO2max using CPET before and after 20 weeks of supervised, endurance ET in 654 sedentary participants (mean age=34y; 39% self-identified Black) from the HERITAGE Study. Multivariate linear regression assessed the relation between metabolites and baseline VO2max (ml·kg–1·min–1), adjusting for age, sex, and race. Changes after ET were determined using paired ttests. We used a false discovery rate (q) <0.05 to determine statistical significance.Results:494 metabolites were associated with VO2max, the majority (375/494) of which were non-targeted (unknown) metabolites with greater effect sizes than targeted peaks [β range: -29.66 - 17.80 and -22.76 - 12.87 for unknown and known metabolites]. We recapitulated known metabolite associations with VO2max including DMGV, branched chain amino acids, and uric acid (Figure 1). 110 of 560 metabolites that changed after ET were associated with VO2max, including non-targeted peaks that concordantly changed after ET (e.g. metabolite peaks positively associated with VO2max that increased with ET; m/z385.3056 and 695.5086; β for VO2max = 9.82 and -19.33, q= 5.56e-7 and 2.61e-17, and log fold-change = 0.03 and -0.01, q=9.58e-13 and 1.93e-4, respectively).Conclusions:We identified novel metabolite peaks associated with VO2max that concordantly changed after ET. Non-targeted metabolomic profiling reveals new markers related to VO2max and exercise response, motivating ongoing work to unambiguously identify these compounds.

Published
2022
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218. Integrative pathway analysis of a genome-wide association study of VO2max response to exercise training.

Author

Ghosh, Sujoy, Vivar, Juan C., Sarzynski, Mark A., Yun Ju Sung, Timmons, James A., Bouchard, Claude, and Rankinen, Tuomo

Subjects
GENOMES, AEROBIC capacity
Abstract

We previously reported the findings from a genome-wide association study of the response of maximal oxygen uptake (Vo2max) to an exercise program. Here we follow up on these results to generate hypotheses on genes, pathways, and systems involved in the ability to respond to exercise training. A systems biology approach can help us better establish a comprehensive physiological description of what underlies Vo2max trainability. The primary material for this exploration was the individual single-nucleotide polymorphism (SNP), SNP-gene mapping, and statistical significance levels. We aimed to generate novel hypotheses through analyses that go beyond statistical association of single-locus markers. This was accomplished through three complementary approaches: 1) building de novo evidence of gene candidacy through informatics-driven literature mining; 2) aggregating evidence from statistical associations to link variant enrichment in biological pathways to Vo2max trainability; and 3) predicting possible consequences of variants residing in the pathways of interest. We started with candidate gene prioritization followed by pathway analysis focused on overrepresentation analysis and gene set enrichment analysis. Subsequently, leads were followed using in silico analysis of predicted SNP functions. Pathways related to cellular energetics (pantothenate and CoA biosynthesis; PPAR signaling) and immune functions (complement and coagulation cascades) had the highest levels of SNP burden. In particular, long-chain fatty acid transport and fatty acid oxidation genes and sequence variants were found to influence differences in Vo2max trainability. Together, these methods allow for the hypothesis-driven ranking and prioritization of genes and pathways for future experimental testing and validation. [ABSTRACT FROM AUTHOR]

Published
2013
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219. Genomic predictors of the maximal O2 uptake response to standardized exercise training programs.

Author

Bouchard, Claude, Sarzynski, Mark A., Rice, Treva K., Kraus, William E., Church, Timothy S., Yun Ju Sung, Rao, D. C., and Rankinen, Tuomo

Subjects
CARDIOVASCULAR diseases, DISEASES, MORTALITY, EXERCISE, PHYSICAL fitness, GENOMES
Abstract

Low cardiorespiratory fitness is a powerful predictor of morbidity and cardiovascular mortality. In 473 sedentary adults, all whites, from 99 families of the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study, the heritability of gains in maximal O2 uptake (V̇o2max) after exposure to a standardized 20-wk exercise program was estimated at 47%. A genomewide association study based on 324,611 single-nucleotide polymorphisms (SNPs) was undertaken to identify SNPs associated with improvements in V̇o2max Based on single-SNP analysis, 39 SNPs were associated with the gains with P < 1.5 x 10-4. Stepwise multiple regression analysis of the 39 SNPs identified a panel of 21 SNPs that accounted for 49% of the variance in V̇o2max trainability. Subjects who carried ≤9 favorable alleles at these 21 SNPs improved their V̇o2max by 221 ml/min, whereas those who carried ≥19 of these alleles gained, on average, 604 ml/min. The strongest association was with rs6552828, located in the acyl-CoA synthase long-chain member 1 (ACSL1) gene, which accounted by itself for ~6% of the training response of V̇o2max. The genes nearest to the SNPs that were the strongest predictors were PR domain-containing 1 with ZNF domain (PRDMI); glutamate receptor, ionotropic, N-methyl-D-aspartate 3A (GRIN3A); K+ channel, voltage gated, subfamily H, member 8 (KCNH8); and zinc finger protein of the cerebellum 4 (ZIC4). The association with the SNP nearest to ZIC4 was replicated in 40- to 65-yr-old, sedentary, overweight, and dyslipidemic subjects trained in Studies of a Targeted Risk Reduction Intervention Through Defined Exercise (STRRIDE; n = 183). Two SNPs were replicated in sedentary obese white women exercise trained in the Dose Response to Exercise (DREW) study (n = 112): rs1956197 near dishevelled associated activator of morphogenesis 1 (DAAM1) and rs17117533 in the vicinity of necdin (NDN). The association of SNPs rs884736 in the calmodulin-binding transcription activator 1 (CAMTA1) locus and rs17581162 ~68 kb upstream from regulator of G protein signaling 18 (RGS18) with the gains in V̇o2max in HERITAGE whites were replicated in HERITAGE blacks (n = 247). These genomic predictors of the response of V̇o2max to regular exercise provide new targets for the study of the biology of fitness and its adaptation to regular exercise. Large-scale replication studies are warranted. [ABSTRACT FROM AUTHOR]

Published
2011
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220. Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 Gene Expression in Muscle after Maximal Acute Aerobic Exercise.

Author

CARPENTER, RICHARD L., LEMMER, JEFFREY T., FRANCIS, RYAN M., KNOUS, JEREMY L., SARZYNSKI, MARK A., and WOMACK, CHRISTOPHER J.

Subjects
TISSUE plasminogen activator, GENE expression, SKELETAL muscle, AEROBIC exercises, FIBRINOLYSIS, BLOOD coagulation, DNA microarrays
Abstract

Carpenter RL, Lemmer JT, Francis RM, Knous JL, Sarzynski MA, Womack CJ. Tissue Plasminogen Activator And Plasminogen Activator Inhibitor-1 Gene Expression in Muscle After Maximal Acute Aerobic Exercise. JEPonline 2010;13(6):35-44. Animal studies suggest plasminogen activation in skeletal muscle is necessary for muscle repair. However, plasminogen activators have been studied little in humans. Therefore, the purposes of this study were to: 1) assess changes in skeletal muscle gene expression of fibrinolytic and coagulation factors 2) assess plasma activity of tPA and PAI-1 in response to an acute bout of maximal aerobic exercise, 3) determine if there is any relationship between muscle gene expression of tPA and PAI-1 with plasma activity levels. Six healthy, college-aged males volunteered blood and muscle samples prior to and immediately following a maximal treadmill exercise test. Muscle tissue was homogenized and purified RNA underwent RT- PCR using gene-specific primers for tPA and PAI-1 as well as biotynylation for microarray. Blood was analyzed via biofunctional immunosorbent assays for tPA and PAI-1 activity. A significant increase in tPA mRNA was seen with exercise (p=0.038) while PAI-1 mRNA showed no changes with the exercise. Muscle tPA activity showed no changes with the exercise bout. Plasma tPA showed a significant increase in activity (p<0.0001) while plasma PAI-1 activity had no change with the exercise bout. In conclusion, tPA synthesis increases in muscle following acute, high-intensity exercise and muscle production does not significantly contribute to plasma tPA increases seen with acute, high-intensity exercise. [ABSTRACT FROM AUTHOR]

Published
2010

221. Abstract 237: Association Between The HDL-sized And Circulating Plasma Proteomes

Author

Reasons, Riley J, Hamid, Zeeshan, Barber, Jacob L, Kass, Alec I, Dev, Prasun K, Wallis, Kit, Bouchard, Claude, Robbins, Jeremy, Gerszten, Robert E, Olivier, Michael, and Sarzynski, Mark A

Abstract

Background:Mass spectrometry (MS) profiling has identified over 250 proteins associated with HDL that are thought to underlie the diverse atheroprotective properties of HDL particles and thus may be important biomarkers of cardiovascular disease (CVD) risk. Likewise, recent studies have identified circulating plasma proteins as biomarkers of CVD risk factors and health outcomes. However, few studies have compared the HDL proteome with the circulating plasma proteome.Purpose:The purpose of this analysis was to examine the relationship between the abundance of individual proteins measured in whole plasma and the HDL-sized plasma fraction.Methods:We examined the HDL-sized and circulating plasma proteomes in 156 Black (30%) and White men and women (61%) from the HERITAGE Family Study. HDL was isolated from plasma via gel filtration chromatography and untargeted MS analysis was performed via nano-HPLC-MS/MS. The whole plasma proteome was measured using a modified aptamer (SOMAscan) assay. The correlations between protein abundances in HDL and whole plasma were examined for 101 HDL-associated proteins present in at least 40% of the sample.Results:The abundance of 56 proteins in HDL-sized and whole plasma were significantly (5% FDR) correlated with the strongest correlation for Haptoglobin levels (r=0.83, p=1.1x10-40) (Table 1). The remaining significant correlations ranged from weak to moderate (r= 0.18-0.64) and were found among a mix of frequently and occasionally observed HDL proteins.Discussion:We found that protein abundance measured in HDL-sized and whole plasma were moderately to strongly correlated for several proteins, whereas 45% of protein levels showed no association between HDL-sized and whole plasma fractions. Given the inherit differences in measurement techniques and sources of proteins, it appears that the plasma HDL-sized proteome is mostly distinct from the circulating whole plasma proteome as measured by the SOMAscan assay.

Published
2022
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224. New genetic loci link adipose and insulin biology to body fat distribution

Author

Shungin, Dmitry, Winkler, Thomas W, Croteau-Chonka, Damien C, Ferreira, Teresa, Locke, Adam E, Mägi, Reedik, Strawbridge, Rona J, Pers, Tune H, Fischer, Krista, Justice, Anne E, Workalemahu, Tsegaselassie, Wu, Joseph M.W., Buchkovich, Martin L, Heard-Costa, Nancy L, Roman, Tamara S, Drong, Alexander W, Song, Ci, Gustafsson, Stefan, Day, Felix R, Esko, Tonu, Fall, Tove, Kutalik, Zoltán, Luan, Jian’an, Randall, Joshua C, Scherag, André, Vedantam, Sailaja, Wood, Andrew R, Chen, Jin, Fehrmann, Rudolf, Karjalainen, Juha, Kahali, Bratati, Liu, Ching-Ti, Schmidt, Ellen M, Absher, Devin, Amin, Najaf, Anderson, Denise, Beekman, Marian, Bragg-Gresham, Jennifer L, Buyske, Steven, Demirkan, Ayse, Ehret, Georg B, Feitosa, Mary F, Goel, Anuj, Jackson, Anne U, Johnson, Toby, Kleber, Marcus E, Kristiansson, Kati, Mangino, Massimo, Leach, Irene Mateo, Medina-Gomez, Carolina, Palmer, Cameron D, Pasko, Dorota, Pechlivanis, Sonali, Peters, Marjolein J, Prokopenko, Inga, Stančáková, Alena, Sung, Yun Ju, Tanaka, Toshiko, Teumer, Alexander, Van Vliet-Ostaptchouk, Jana V, Yengo, Loïc, Zhang, Weihua, Albrecht, Eva, Ärnlöv, Johan, Arscott, Gillian M, Bandinelli, Stefania, Barrett, Amy, Bellis, Claire, Bennett, Amanda J, Berne, Christian, Blüher, Matthias, Böhringer, Stefan, Bonnet, Fabrice, Böttcher, Yvonne, Bruinenberg, Marcel, Carba, Delia B, Caspersen, Ida H, Clarke, Robert, Daw, E Warwick, Deelen, Joris, Deelman, Ewa, Delgado, Graciela, Doney, Alex SF, Eklund, Niina, Erdos, Michael R, Estrada, Karol, Eury, Elodie, Friedrich, Nele, Garcia, Melissa E, Giedraitis, Vilmantas, Gigante, Bruna, Go, Alan S, Golay, Alain, Grallert, Harald, Grammer, Tanja B, Gräßler, Jürgen, Grewal, Jagvir, Groves, Christopher J, Haller, Toomas, Hallmans, Goran, Hartman, Catharina A, Hassinen, Maija, Hayward, Caroline, Heikkilä, Kauko, Herzig, Karl-Heinz, Helmer, Quinta, Hillege, Hans L, Holmen, Oddgeir, Hunt, Steven C, Isaacs, Aaron, Ittermann, Till, James, Alan L, Johansson, Ingegerd, Juliusdottir, Thorhildur, Kalafati, Ioanna-Panagiota, Kinnunen, Leena, Koenig, Wolfgang, Kooner, Ishminder K, Kratzer, Wolfgang, Lamina, Claudia, Leander, Karin, Lee, Nanette R, Lichtner, Peter, Lind, Lars, Lindström, Jaana, Lobbens, Stéphane, Lorentzon, Mattias, Mach, François, Magnusson, Patrik KE, Mahajan, Anubha, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Moayyeri, Alireza, Monda, Keri L, Mooijaart, Simon P, Mühleisen, Thomas W, Mulas, Antonella, Müller, Gabriele, Müller-Nurasyid, Martina, Nagaraja, Ramaiah, Nalls, Michael A, Narisu, Narisu, Glorioso, Nicola, Nolte, Ilja M, Olden, Matthias, Rayner, Nigel W, Renstrom, Frida, Ried, Janina S, Robertson, Neil R, Rose, Lynda M, Sanna, Serena, Scharnagl, Hubert, Scholtens, Salome, Sennblad, Bengt, Seufferlein, Thomas, Sitlani, Colleen M, Smith, Albert Vernon, Stirrups, Kathleen, Stringham, Heather M, Sundström, Johan, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tayo, Bamidele O, Thorand, Barbara, Thorleifsson, Gudmar, Tomaschitz, Andreas, Troffa, Chiara, van Oort, Floor VA, Verweij, Niek, Vonk, Judith M, Waite, Lindsay L, Wennauer, Roman, Wilsgaard, Tom, Wojczynski, Mary K, Wong, Andrew, Zhang, Qunyuan, Zhao, Jing Hua, Brennan, Eoin P., Choi, Murim, Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Gharavi, Ali G, Hedman, Åsa K, Hivert, Marie-France, Huang, Jinyan, Kanoni, Stavroula, Karpe, Fredrik, Keildson, Sarah, Kiryluk, Krzysztof, Liang, Liming, Lifton, Richard P, Ma, Baoshan, McKnight, Amy J, McPherson, Ruth, Metspalu, Andres, Min, Josine L, Moffatt, Miriam F, Montgomery, Grant W, Murabito, Joanne M, Nicholson, George, Nyholt, Dale R, Olsson, Christian, Perry, John RB, Reinmaa, Eva, Salem, Rany M, Sandholm, Niina, Schadt, Eric E, Scott, Robert A, Stolk, Lisette, Vallejo, Edgar E., Westra, Harm-Jan, Zondervan, Krina T, Amouyel, Philippe, Arveiler, Dominique, Bakker, Stephan JL, Beilby, John, Bergman, Richard N, Blangero, John, Brown, Morris J, Burnier, Michel, Campbell, Harry, Chakravarti, Aravinda, Chines, Peter S, Claudi-Boehm, Simone, Collins, Francis S, Crawford, Dana C, Danesh, John, de Faire, Ulf, de Geus, Eco JC, Dörr, Marcus, Erbel, Raimund, Eriksson, Johan G, Farrall, Martin, Ferrannini, Ele, Ferrières, Jean, Forouhi, Nita G, Forrester, Terrence, Franco, Oscar H, Gansevoort, Ron T, Gieger, Christian, Gudnason, Vilmundur, Haiman, Christopher A, Harris, Tamara B, Hattersley, Andrew T, Heliövaara, Markku, Hicks, Andrew A, Hingorani, Aroon D, Hoffmann, Wolfgang, Hofman, Albert, Homuth, Georg, Humphries, Steve E, Hyppönen, Elina, Illig, Thomas, Jarvelin, Marjo-Riitta, Johansen, Berit, Jousilahti, Pekka, Jula, Antti M, Kaprio, Jaakko, Kee, Frank, Keinanen-Kiukaanniemi, Sirkka M, Kooner, Jaspal S, Kooperberg, Charles, Kovacs, Peter, Kraja, Aldi T, Kumari, Meena, Kuulasmaa, Kari, Kuusisto, Johanna, Lakka, Timo A, Langenberg, Claudia, Le Marchand, Loic, Lehtimäki, Terho, Lyssenko, Valeriya, Männistö, Satu, Marette, André, Matise, Tara C, McKenzie, Colin A, McKnight, Barbara, Musk, Arthur W, Möhlenkamp, Stefan, Morris, Andrew D, Nelis, Mari, Ohlsson, Claes, Oldehinkel, Albertine J, Ong, Ken K, Palmer, Lyle J, Penninx, Brenda W, Peters, Annette, Pramstaller, Peter P, Raitakari, Olli T, Rankinen, Tuomo, Rao, DC, Rice, Treva K, Ridker, Paul M, Ritchie, Marylyn D., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Saramies, Jouko, Sarzynski, Mark A, Schwarz, Peter EH, Shuldiner, Alan R, Staessen, Jan A, Steinthorsdottir, Valgerdur, Stolk, Ronald P, Strauch, Konstantin, Tönjes, Anke, Tremblay, Angelo, Tremoli, Elena, Vohl, Marie-Claude, Völker, Uwe, Vollenweider, Peter, Wilson, James F, Witteman, Jacqueline C, Adair, Linda S, Bochud, Murielle, Boehm, Bernhard O, Bornstein, Stefan R, Bouchard, Claude, Cauchi, Stéphane, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Cooper, Richard S, Dedoussis, George, Ferrucci, Luigi, Froguel, Philippe, Grabe, Hans-Jörgen, Hamsten, Anders, Hui, Jennie, Hveem, Kristian, Jöckel, Karl-Heinz, Kivimaki, Mika, Kuh, Diana, Laakso, Markku, Liu, Yongmei, März, Winfried, Munroe, Patricia B, Njølstad, Inger, Oostra, Ben A, Palmer, Colin NA, Pedersen, Nancy L, Perola, Markus, Pérusse, Louis, Peters, Ulrike, Power, Chris, Quertermous, Thomas, Rauramaa, Rainer, Rivadeneira, Fernando, Saaristo, Timo E, Saleheen, Danish, Sinisalo, Juha, Slagboom, P Eline, Snieder, Harold, Spector, Tim D, Stefansson, Kari, Stumvoll, Michael, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, van der Harst, Pim, Veronesi, Giovanni, Walker, Mark, Wareham, Nicholas J, Watkins, Hugh, Wichmann, H-Erich, Abecasis, Goncalo R, Assimes, Themistocles L, Berndt, Sonja I, Boehnke, Michael, Borecki, Ingrid B, Deloukas, Panos, Franke, Lude, Frayling, Timothy M, Groop, Leif C, Hunter, David J., Kaplan, Robert C, O’Connell, Jeffrey R, Qi, Lu, Schlessinger, David, Strachan, David P, Thorsteinsdottir, Unnur, van Duijn, Cornelia M, Willer, Cristen J, Visscher, Peter M, Yang, Jian, Hirschhorn, Joel N, Zillikens, M Carola, McCarthy, Mark I, Speliotes, Elizabeth K, North, Kari E, Fox, Caroline S, Barroso, Inês, Franks, Paul W, Ingelsson, Erik, Heid, Iris M, Loos, Ruth JF, Cupples, L Adrienne, Morris, Andrew P, Lindgren, Cecilia M, and Mohlke, Karen L

Abstract

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Published
2014
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225. Abstract 13409: Glycine Levels are Associated With Improvements in Submaximal Blood Pressure Response After Endurance Exercise Training

Author

Robbins, Jeremy M, Peterson, Bennet, Morningstar, Jordan, Rankinen, Tuomo, Sarzynski, Mark A, Bouchard, Claude, and Gerszten, Robert E

Abstract

Background:Glycine is a non-essential amino acid that has been inversely associated to coronary heart disease (CHD), with recent data suggesting that this relationship may be mediated by lower blood pressure. Here we tested the hypothesis that circulating levels of glycine are inversely associated with both resting blood pressure (BP) and BP response to exercise - a future predictor of hypertension, and that levels would increase after an endurance exercise training (ET) program.Methods:We used targeted mass spectrometry to measure glycine levels before and after ET in 441 normotensive Caucasian individuals (mean age = 36) from the HERITAGE Family Study. Subjects performed graded supervised cycle ergometry, such that they exercised at 75% VO2max, 50 min/session, 3x/week over the final 6 weeks of a 20-week program. Multivariate linear regression was performed to assess the relationship between glycine and both resting systolic (SBP) and diastolic blood pressure (DBP) at rest and at 50 Watts (W) of cycle ergometry, both before and after the ET program. Changes in plasma glycine levels after ET were determined using paired ttests. Statistical significance was set at p <0.05.Results:Baseline glycine levels were inversely associated with baseline SBP (? = -1.65, p = 0.001) and DBP (? = -1.11, p = 0.002) as well as SBP and DBP at 50W prior to ET (? = -2.33 and -1.35, p = 0.008 and 0.004, respectively) after adjusting for age, sex and BMI. Baseline glycine levels were inversely associated with the changes in SBP and DBP at 50W after ET (? = -2.07 and -1.16, p = 7.1 x 10-6and p = 5.1 x 10-5) after adjustment for age, sex, BMI, and the baseline value of each outcome variable. Glycine levels had a -1.6% median percent change after ET (p-value for paired Student ttest = 0.008).Conclusions:Glycine levels are inversely related to both resting BP and BP during submaximal exercise in apparently healthy subjects, and decrease after chronic ET. Baseline glycine levels are associated with decreased BP responses to submaximal exercise after endurance ET. Additional studies are needed to test for a causal relationship between glycine and blood pressure reduction, and whether alternative exercise modalities may influence glycine levels to a greater extent.

Published
2019
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226. The Effects of Regular Exercise on Circulating Cardiovascular-related MicroRNAs.

Author

Barber, Jacob L., Zellars, Kia N., Barringhaus, Kurt G., Bouchard, Claude, Spinale, Francis G., and Sarzynski, Mark A.

Abstract

The purpose of the present study was to examine the effects of regular exercise on the abundance of targeted circulating microRNAs (miRNAs). The present analysis examined 20 previously sedentary adults from the HERITAGE Family Study who completed 20 weeks of endurance exercise training. The expression of 53 miRNAs related to cardiovascular disease were measured in serum collected at baseline and post-training by performing RT-qPCR on the Human Cardiovascular Disease miRNA array (Qiagen, Germany). The effect of regular exercise on circulating miRNAs was assessed using paired t-tests of baseline and post-training expression levels. A false discovery rate threshold of 5% was used to determine significance. Regular exercise resulted in significantly decreased mean serum expression of nine miRNAs (miR-486-5p, let-7b-5p, miR-29c-3p, let-7e-5p, miR-93-5p, miR-7-5p, miR-25-3p, miR-92a-3p, and miR-29b-3p; fold change range: 0.64–83, p = 0.0002–0.01) and increased mean expression of five miRNAs (miR-142-3p, miR-221-3p, miR-126-3p, miR-146a-5p, and miR-27b-3p; fold change range: 1.41–3.60, p = 0.001–0.006). Enrichment analysis found that these 14 miRNAs target genes related to over 345 different biological pathways. These results provide further evidence of the effects of regular exercise on the circulating miRNA profile. [ABSTRACT FROM AUTHOR]

Published
2019
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228. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults

Author

Graff, Mariaelisa, Scott, Robert A, Justice, Anne E, Young, Kristin L, Feitosa, Mary F, Barata, Llilda, Winkler, Thomas W, Chu, Audrey Y, Mahajan, Anubha, Hadley, David, Xue, Luting, Workalemahu, Tsegaselassie, Heard-Costa, Nancy L, Den Hoed, Marcel, Ahluwalia, Tarunveer S, Qi, Qibin, Ngwa, Julius S, Renström, Frida, Quaye, Lydia, Eicher, John D, Hayes, James E, Cornelis, Marilyn, Kutalik, Zoltan, Lim, Elise, Luan, Jian'an, Huffman, Jennifer E, Zhang, Weihua, Zhao, Wei, Griffin, Paula J, Haller, Toomas, Ahmad, Shafqat, Marques-Vidal, Pedro M, Bien, Stephanie, Yengo, Loic, Teumer, Alexander, Smith, Albert Vernon, Kumari, Meena, Harder, Marie Neergaard, Justesen, Johanne Marie, Kleber, Marcus E, Hollensted, Mette, Lohman, Kurt, Rivera, Natalia V, Whitfield, John B, Zhao, Jing Hua, Stringham, Heather M, Lyytikäinen, Leo-Pekka, Huppertz, Charlotte, Willemsen, Gonneke, Peyrot, Wouter J, Wu, Ying, Kristiansson, Kati, Demirkan, Ayse, Fornage, Myriam, Hassinen, Maija, Bielak, Lawrence F, Cadby, Gemma, Tanaka, Toshiko, Mägi, Reedik, Van Der Most, Peter J, Jackson, Anne U, Bragg-Gresham, Jennifer L, Vitart, Veronique, Marten, Jonathan, Navarro, Pau, Bellis, Claire, Pasko, Dorota, Johansson, Åsa, Snitker, Søren, Cheng, Yu-Ching, Eriksson, Joel, Lim, Unhee, Aadahl, Mette, Adair, Linda S, Amin, Najaf, Balkau, Beverley, Auvinen, Juha, Beilby, John, Bergman, Richard N, Bergmann, Sven, Bertoni, Alain G, Blangero, John, Bonnefond, Amélie, Bonnycastle, Lori L, Borja, Judith B, Brage, Søren, Busonero, Fabio, Buyske, Steve, Campbell, Harry, Chines, Peter S, Collins, Francis S, Corre, Tanguy, Smith, George Davey, Delgado, Graciela E, Dueker, Nicole, Dörr, Marcus, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tõnu, Faul, Jessica D, Fu, Mao, Færch, Kristine, Gieger, Christian, Gläser, Sven, Gong, Jian, Gordon-Larsen, Penny, Grallert, Harald, Grammer, Tanja B, Grarup, Niels, Van Grootheest, Gerard, Harald, Kennet, Hastie, Nicholas D, Havulinna, Aki S, Hernandez, Dena, Hindorff, Lucia, Hocking, Lynne J, Holmens, Oddgeir L, Holzapfel, Christina, Hottenga, Jouke Jan, Huang, Jie, Huang, Tao, Hui, Jennie, Huth, Cornelia, Hutri-Kähönen, Nina, James, Alan L, Jansson, John-Olov, Jhun, Min A, Juonala, Markus, Kinnunen, Leena, Koistinen, Heikki A, Kolcic, Ivana, Komulainen, Pirjo, Kuusisto, Johanna, Kvaløy, Kirsti, Kähönen, Mika, Lakka, Timo A, Launer, Lenore J, Lehne, Benjamin, Lindgren, Cecilia M, Lorentzon, Mattias, Luben, Robert, Marre, Michel, Milaneschi, Yuri, Monda, Keri L, Montgomery, Grant W, De Moor, Marleen HM, Mulas, Antonella, Müller-Nurasyid, Martina, Musk, AW, Männikkö, Reija, Männistö, Satu, Narisu, Narisu, Nauck, Matthias, Nettleton, Jennifer A, Nolte, Ilja M, Oldehinkel, Albertine J, Olden, Matthias, Ong, Ken K, Padmanabhan, Sandosh, Paternoster, Lavinia, Perez, Jeremiah, Perola, Markus, Peters, Annette, Peters, Ulrike, Peyser, Patricia A, Prokopenko, Inga, Puolijoki, Hannu, Raitakari, Olli T, Rankinen, Tuomo, Rasmussen-Torvik, Laura J, Rawal, Rajesh, Ridker, Paul M, Rose, Lynda M, Rudan, Igor, Sarti, Cinzia, Sarzynski, Mark A, Savonen, Kai, Scott, William R, Sanna, Serena, Shuldiner, Alan R, Sidney, Steve, Silbernagel, Günther, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Stančáková, Alena, Sternfeld, Barbara, Swift, Amy J, Tammelin, Tuija, Tan, Sian-Tsung, Thorand, Barbara, Thuillier, Dorothée, Vandenput, Liesbeth, Vestergaard, Henrik, Van Vliet-Ostaptchouk, Jana V, Vohl, Marie-Claude, Völker, Uwe, Waeber, Gérard, Walker, Mark, Wild, Sarah, Wong, Andrew, Wright, Alan F, Zillikens, M Carola, Zubair, Niha, Haiman, Christopher A, Lemarchand, Loic, Gyllensten, Ulf, Ohlsson, Claes, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, André G, Pérusse, Louis, Wilson, James F, Hayward, Caroline, Polasek, Ozren, Cucca, Francesco, Hveem, Kristian, Hartman, Catharina A, Tönjes, Anke, Bandinelli, Stefania, Palmer, Lyle J, Kardia, Sharon LR, Rauramaa, Rainer, Sørensen, Thorkild IA, Tuomilehto, Jaakko, Salomaa, Veikko, Penninx, Brenda WJH, De Geus, Eco JC, Boomsma, Dorret I, Lehtimäki, Terho, Mangino, Massimo, Laakso, Markku, Bouchard, Claude, Martin, Nicholas G, Kuh, Diana, Liu, Yongmei, Linneberg, Allan, März, Winfried, Strauch, Konstantin, Kivimäki, Mika, Harris, Tamara B, Gudnason, Vilmundur, Völzke, Henry, Qi, Lu, Järvelin, Marjo-Riitta, Chambers, John C, Kooner, Jaspal S, Froguel, Philippe, Kooperberg, Charles, Vollenweider, Peter, Hallmans, Göran, Hansen, Torben, Pedersen, Oluf, Metspalu, Andres, Wareham, Nicholas J, Langenberg, Claudia, Weir, David R, Porteous, David J, Boerwinkle, Eric, Chasman, Daniel I, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Abecasis, Gonçalo R, Barroso, Inês, McCarthy, Mark I, Frayling, Timothy M, O'Connell, Jeffrey R, Van Duijn, Cornelia M, Boehnke, Michael, Heid, Iris M, Mohlke, Karen L, Strachan, David P, Fox, Caroline S, Liu, Ching-Ti, Hirschhorn, Joel N, Klein, Robert J, Johnson, Andrew D, Borecki, Ingrid B, Franks, Paul W, North, Kari E, Cupples, L Adrienne, Loos, Ruth JF, and Kilpeläinen, Tuomas O

Subjects
Epigenomics, Male, Genotype, Waist-Hip Ratio, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, 3. Good health, Body Mass Index, Humans, Female, Genetic Predisposition to Disease, Obesity, Waist Circumference, Exercise, Adiposity, Genome-Wide Association Study
Abstract

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

229. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, De Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P, Vandenput, Liesbeth, Van Der Laan, Sander W, Van Der Velde, Nathalie, Van Setten, Jessica, Van Vliet-Ostaptchouk, Jana V, Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L, Wang, Sophie R, Wang, Zhaoming, Wild, Sarah H, Willenborg, Christina, Wilson, James F, Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M, Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A, Bakker, Stephan JL, Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L, Boyd, Heather A, Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S, Claudi-Boehm, Simone, Cole, John, Collins, Francis S, De Geus, Eco JC, De Groot, Lisette CPGM, Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G, Friedrich, Nele, Gejman, Pablo V, Gigante, Bruna, Glorioso, Nicola, Go, Alan S, Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C, Hansen, Torben, Harris, Tamara B, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T, Heath, Andrew C, Henders, Anjali K, Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L, Hutri-Kähönen, Nina, Hysi, Pirro G, Illig, Thomas, De Jager, Philip L, Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J, Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T, Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J, Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W, Morris, Andrew P, Narisu, Narisu, Nelis, Mari, Ong, Ken K, Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G, Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M, Rice, Treva K, Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Scott, William R, Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P Eline, Smit, Jan H, Sparsø, Thomas H, Stirrups, Kathleen, Stolk, Ronald P, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, Van Der Most, Peter J, Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M, Waldenberger, Melanie, Walker, Ryan W, Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F, Zillikens, M Carola, Van Dijk, Suzanne C, Van Schoor, Natasja M, Asselbergs, Folkert W, De Bakker, Paul IW, Beckmann, Jacques S, Beilby, John, Bennett, David A, Bergman, Richard N, Bergmann, Sven, Böger, Carsten A, Boehm, Bernhard O, Boerwinkle, Eric, Boomsma, Dorret I, Bornstein, Stefan R, Bottinger, Erwin P, Bouchard, Claude, Chambers, John C, Chanock, Stephen J, Chasman, Daniel I, Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G, Evans, Denis A, De Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W, Froguel, Philippe, Gansevoort, Ron T, Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, Van Der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A, Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V, Hveem, Kristian, James, Alan L, Jordan, Joanne M, Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus ALM, Kivimaki, Mika, Knekt, Paul B, Koistinen, Heikki A, Kooner, Jaspal S, Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F, Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D, Moll, Frans L, Murray, Jeffrey C, Musk, Arthur W, Nieminen, Markku S, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Oostra, Ben A, Palmer, Lyle J, Pankow, James S, Pasterkamp, Gerard, Pedersen, Nancy L, Pedersen, Oluf, Penninx, Brenda W, Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P, Psaty, Bruce M, Qi, Lu, Quertermous, Thomas, Raitakari, Olli T, Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M, Rioux, John D, Rivadeneira, Fernando, Rotter, Jerome I, Rudan, Igor, Den Ruijter, Hester M, Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter EH, Shuldiner, Alan R, Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild IA, Spector, Tim D, Staessen, Jan A, Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Verbeek, André LM, Vermeulen, Sita H, Viikari, Jorma S, Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J, Watkins, Hugh, Zeggini, Eleftheria, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Chakravarti, Aravinda, Clegg, Deborah J, Cupples, L Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E, Rao, DC, Abecasis, Goncalo R, Assimes, Themistocles L, Barroso, Inês, Berndt, Sonja I, Boehnke, Michael, Deloukas, Panos, Fox, Caroline S, Groop, Leif C, Hunter, David J, Ingelsson, Erik, Kaplan, Robert C, McCarthy, Mark I, Mohlke, Karen L, O'Connell, Jeffrey R, Schlessinger, David, Strachan, David P, Stefansson, Kari, Van Duijn, Cornelia M, Hirschhorn, Joel N, Lindgren, Cecilia M, Heid, Iris M, North, Kari E, Borecki, Ingrid B, Kutalik, Zoltán, and Loos, Ruth JF

Subjects
Adult, Male, Sex Characteristics, Waist-Hip Ratio, Age Factors, Chromosome Mapping, Middle Aged, Polymorphism, Single Nucleotide, White People, 3. Good health, Body Mass Index, Body Size, Humans, Female, Genetic Predisposition to Disease, Aged, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR

230. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Loos, Ruth J. F., Kanoni, Stavroula, Fatemifar, Ghazaleh, Laatikainen, Tiina, Menni, Cristina, Lu, Yingchang, Vinkhuyzen, Anna A. E., Blüher, Matthias, Mägi, Reedik, Harris, Tamara B., Ahluwalia, Tarunveer Singh, Cederholm, Tommy, Leach, Irene Mateo, Perry, John R. B., Dehghan, Abbas, Luan, Jian'an, De Jager, Philip L., Spector, Tim D., Eriksson, Johan G., Friedrich, Nele, Wareham, Nicholas J., Hillege, Hans, Bishop, D. Timothy, McKenzie, Colin A., Jula, Antti, Boehnke, Michael, Justice, Anne E., Döring, Angela, Dhonukshe-Rutten, Rosalie A. M., Spira, Dominik, Esko, Toñu, Rudan, Igor, Stumvoll, Michael, Loh, Marie, Palmer, Cameron D., Czerwinski, Stefan A., Fumeron, Frédéric, Vartiainen, Erkki, Bouchard, Claude, Forouhi, Nita G., Kovacs, Peter, Liu, Tian, Bertram, Lars, Lichtner, Peter, Havulinna, Aki S., Widén, Elisabeth, Sung, Yun Ju, Kähönen, Mika, Kumari, Meena, Choi, Hyung Jin, Knekt, Paul B., Srikanth, Priya, Hansen, Torben, Lyytikaïnen, Leo-Pekka, Forrester, Terrence, Schadt, Eric E., Van Der Velde, Nathalie, Zhu, Zhihong, Kiel, Douglas P., Li, Xin, Orwoll, Eric S., Langenberg, Claudia, Pérusse, Louis, Ohlsson, Claes, Franke, Lude, Buchkovich, Martin L., Van Duijn, Cornelia M., Naranäiä, Nina Smolej, Cho, Nam H., Enneman, Anke W., Viikari, Jorma S., Vohl, Marie-Claude, Peters, Annette, Heliövaara, Markku, Cousminer, Diana L., Vandenput, Liesbeth, Day, Felix R., Eckardt, Rahel, Uitterlinden, André G., Palotie, Aarno, Nielson, Carrie M., Raitakari, Olli T., Fox, Caroline, Bishop, Julia A. N., Murabito, Joanne M., Hysi, Pirro G., Verweij, Niek, Rice, Treva K., Michaëlsson, Karl, Sarzynski, Mark A., Wright, Alan F., Cupples, L. Adrienne, Kent, Jack W., Luke, Amy, Karpe, Fredrik, Gansevoort, Ron T., Lobbens, Stéphane, Männistö, Satu, Na, Jianbo, Blangero, John, Qi, Qibin, Schmidt, Ellen M., Gärtner, Simone, Tayo, Bamidele O., Yang, Jian, Campbell, Harry, Pers, Tune H., Taittonen, Leena, Jackson, Anne U., Oostra, Ben A., Hayward, Caroline, Osmond, Clive, Han, Bok-Ghee, Tanaka, Toshiko, Swart, Karin M. A., Morris, Andrew P., Cooper, Richard S., McCarthy, Mark I., Wilson, James F., Yengo, Loïc, Lind, Lars, Gustafsson, Stefan, Curran, Joanne E., Zhang, Weihua, Boettcher, Yvonne, Salomaa, Veikko, Hunter, David J., Wallaschofski, Henri, Bataille, Veronique, Strauch, Konstantin, Pospisilik, John Andrew, Zmuda, Joseph M., Jørgensen, Torben, Tikkanen, Emmi, Kajantie, Eero, Rao, Karjalainen, Juha, Ried, Janina S., Lehtimäki, Terho, Jousilahti, Pekka, Kooner, Jaspal S., Ferreira, Teresa, Hingorani, Aroon, Oozageer, Laticia, Scott, William R., Buchman, Aron S., Kristiansson, Kati, Demuth, Ilja, Falchi, Mario, Bennett, David A., Haring, Robin, Demirkan, Ayse, Walker, Ryan W., Kivimaki, Mika, Borecki, Ingrid B., Liu, Youfang, Choh, Audrey C., Furey, Terrence S., Koskinen, Seppo, Kuulasmaa, Teemu, Drong, Alexander W., Li, Rui, Shuldiner, Alan R., Kuusisto, Johanna, Sørensen, Thorkild I. A., McKnight, Barbara, Rivadeneira, Fernando, Ingelsson, Erik, Hofman, Albert, Linneberg, Allan, Rankinen, Tuomo, Tönjes, Anke, North, Kari E., O'Connell, Jeffrey R., Hastie, Nicholas, Vollenweider, Peter, De Groot, Lisette C. P. G. M., Paternoster, Lavinia, Mahajan, Anubha, Richards, J. Brent, Kaplan, Robert C., Eklund, Niina, Gudnason, Vilmundur, Deloukas, Panos, Kühnel, Brigitte, Han, Jiali, Scott, Robert A., Grarup, Niels, Garcia, Melissa E., Nalls, Mike A., Song, Kijoung, Lindgren, Cecilia, Wagner, Peter J., Franco, Oscar H., Perola, Markus, Evans, David M., Evans, Daniel S., Tranah, Gregory J., Grallert, Harald, Iles, Mark M., Westra, Harm-Jan, Dastani, Zari, Zhang, Mingfeng, Lee, Jong-Young, Vitart, Veronique, Kilpelaïnen, Tuomas Oskari, Wild, Sarah, Pascoe, Laura, Borodulin, Katja, Tremblay, Angelo, Hernandez, Dena, Lu, Chen, Chambers, John C., Ong, Ken K., Hedman, Åsa K., Afzal, Uzma, Froguel, Philippe, Yu, Lei, Pedersen, Oluf, Zillikens, M. Carola, Bellis, Claire, Shungin, Dmitry, Liu, Yongmei, Shin, Chan Soo, Gieger, Christian, Forsen, Tom, Ferrucci, Luigi, Lee, Christine G., Hirschhorn, Joel N., Laakso, Markku, Prokopenko, Inga, Mohlke, Karen L., Sanna, Marianna, Cummings, Steven R., Stancáková, Alena, Medina-Gomez, Carolina, Eury, Elodie, Ripatti, Samuli, Feitosa, Mary F., Van Schoor, Natasja M., Walker, Mark, Bakker, Stephan J. L., Van Der Harst, Pim, Locke, Adam, Lahti, Jari, Willer, Cristen J., White, Charles C., Jordan, Joanne M., Steinhagen-Thiessen, Elisabeth, Kolcic, Ivana, Mangino, Massimo, Towne, Bradford, Bonnefond, Amélie, Zhao, Jing Hua, Polašek, Ozren, Ittermann, Till, Völzke, Henry, Lagou, Vasiliki, and Teumer, Alexander

Subjects
3. Good health
Abstract

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P

231. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Ried, Janina S, Jeff M, Janina, Chu, Audrey Y, Bragg-Gresham, Jennifer L, Van Dongen, Jenny, Huffman, Jennifer E, Ahluwalia, Tarunveer S, Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Tõnu, Feitosa, Mary F, Goel, Anuj, Gorski, Mathias, Hayward, Caroline, Heard-Costa, Nancy L, Jackson, Anne U, Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'an, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina-Gomez, Carolina, Monda, Keri L, Nolte, Ilja M, Pérusse, Louis, Prokopenko, Inga, Qi, Lu, Rose, Lynda M, Salvi, Erika, Smith, Megan T, Snieder, Harold, Stančáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, Van Der Harst, Pim, Walker, Ryan W, Wang, Sophie R, Wild, Sarah H, Willems, Sara M, Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan JL, Barlassina, Cristina, Bartz, Traci M, Beilby, John, Bellis, Claire, Bergman, Richard N, Bergmann, Sven, Blangero, John, Blüher, Matthias, Boerwinkle, Eric, Bonnycastle, Lori L, Bornstein, Stefan R, Bruinenberg, Marcel, Campbell, Harry, Chen, Yii-Der Ida, Chiang, Charleston WK, Chines, Peter S, Collins, Francis S, Cucca, Fracensco, Cupples, L Adrienne, D'Avila, Francesca, De Geus, Eco JC, Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G, Farmaki, Aliki-Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G, Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Anders, Harder, Marie Neergaard, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew Tym, Havulinna, Aki S, Heliövaara, Markku, Hillege, Hans, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke-Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G, Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L, Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E, Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen-Kiukaanniemi, Sirkka M, Kinnunen, Leena, Knekt, Paul B, Koistinen, Heikki A, Kolcic, Ivana, Kooner, Ishminder K, Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosios, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M, Lichtner, Peter, Lindgren, Cecilia M, Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattias, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, McArdle, Wendy L, Mcknight, Barbara, Mohlke, Karen L, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E, Morris, Andrew P, Müller, Gabriele, Musk, Arthur W, Narisu, Narisu, Ong, Ken K, Oostra, Ben A, Osmond, Clive, Palotie, Aarno, Pankow, James S, Paternoster, Lavinia, Penninx, Brenda W, Pichler, Irene, Pilia, Maria G, Polašek, Ozren, Pramstaller, Peter P, Raitakari, Olli T, Rankinen, Tuomo, Rao, DC, Rayner, Nigel W, Ribel-Madsen, Rasmus, Rice, Treva K, Richards, Marcus, Ridker, Paul M, Rivadeneira, Fernando, Ryan, Kathy A, Sanna, Serena, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P, Strauch, Konstantin, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Tönjes, Anke, Tsafantakis, Emmanouil, Van Der Most, Peter J, Van Vliet-Ostaptchouk, Jana V, Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S, Vitart, Veronique, Vohl, Marie-Claude, Vonk, Judith M, Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W, Wright, Alan F, Yerges-Armstrong, Laura M, Hua Zhao, Jing, Zillikens, M Carola, Boomsma, Dorret I, Bouchard, Claude, Chambers, John C, Chasman, Daniel I, Cusi, Daniele, Gansevoort, Ron T, Gieger, Christian, Hansen, Torben, Hicks, Andrew A, Hu, Frank, Hveem, Kristian, Jarvelin, Marjo-Riitta, Kajantie, Eero, Kooner, Jaspal S, Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Metspalu, Andres, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Palmer, Lyle J, Pedersen, Oluf, Perola, Markus, Peters, Annette, Psaty, Bruce M, Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter EH, Shudiner, Alan R, Smit, Jan H, Sørensen, Thorkild IA, Spector, Timothy D, Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J, Watkins, Hugh, Wilson, James F, Zeggini, Eleftheria, Abecasis, Goncalo R, Boehnke, Michael, Borecki, Ingrid B, Deloukas, Panos, Van Duijn, Cornelia M, Fox, Caroline, Groop, Leif C, Heid, Iris M, Hunter, David J, Kaplan, Robert C, McCarthy, Mark I, North, Kari E, O'Connell, Jeffrey R, Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P, Frayling, Timothy, Hirschhorn, Joel N, Müller-Nurasyid, Martina, and Loos, Ruth JF

Subjects
2. Zero hunger, Principal Component Analysis, Anthropometry, Genotype, Models, Genetic, Body Size, Humans, Genome-Wide Association Study
Abstract

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

232. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, De Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P, Vandenput, Liesbeth, Van Der Laan, Sander W, Van Der Velde, Nathalie, Van Setten, Jessica, Van Vliet-Ostaptchouk, Jana V, Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L, Wang, Sophie R, Wang, Zhaoming, Wild, Sarah H, Willenborg, Christina, Wilson, James F, Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M, Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A, Bakker, Stephan JL, Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L, Boyd, Heather A, Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S, Claudi-Boehm, Simone, Cole, John, Collins, Francis S, De Geus, Eco JC, De Groot, Lisette CPGM, Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G, Friedrich, Nele, Gejman, Pablo V, Gigante, Bruna, Glorioso, Nicola, Go, Alan S, Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C, Hansen, Torben, Harris, Tamara B, Hartman, Catharina A, Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T, Heath, Andrew C, Henders, Anjali K, Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L, Hutri-Kähönen, Nina, Hysi, Pirro G, Illig, Thomas, De Jager, Philip L, Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J, Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T, Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J, Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W, Morris, Andrew P, Narisu, Narisu, Nelis, Mari, Ong, Ken K, Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G, Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M, Rice, Treva K, Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R, Sarzynski, Mark A, Scholtens, Salome, Scott, Robert A, Scott, William R, Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P Eline, Smit, Jan H, Sparsø, Thomas H, Stirrups, Kathleen, Stolk, Ronald P, Stringham, Heather M, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, Van Der Most, Peter J, Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M, Waldenberger, Melanie, Walker, Ryan W, Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F, Zillikens, M Carola, Van Dijk, Suzanne C, Van Schoor, Natasja M, Asselbergs, Folkert W, De Bakker, Paul IW, Beckmann, Jacques S, Beilby, John, Bennett, David A, Bergman, Richard N, Bergmann, Sven, Böger, Carsten A, Boehm, Bernhard O, Boerwinkle, Eric, Boomsma, Dorret I, Bornstein, Stefan R, Bottinger, Erwin P, Bouchard, Claude, Chambers, John C, Chanock, Stephen J, Chasman, Daniel I, Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G, Evans, Denis A, De Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W, Froguel, Philippe, Gansevoort, Ron T, Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, Van Der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A, Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V, Hveem, Kristian, James, Alan L, Jordan, Joanne M, Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus ALM, Kivimaki, Mika, Knekt, Paul B, Koistinen, Heikki A, Kooner, Jaspal S, Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G, Laakso, Markku, Lakka, Timo A, Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F, Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D, Moll, Frans L, Murray, Jeffrey C, Musk, Arthur W, Nieminen, Markku S, Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J, Oostra, Ben A, Palmer, Lyle J, Pankow, James S, Pasterkamp, Gerard, Pedersen, Nancy L, Pedersen, Oluf, Penninx, Brenda W, Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P, Psaty, Bruce M, Qi, Lu, Quertermous, Thomas, Raitakari, Olli T, Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M, Rioux, John D, Rivadeneira, Fernando, Rotter, Jerome I, Rudan, Igor, Den Ruijter, Hester M, Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter EH, Shuldiner, Alan R, Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild IA, Spector, Tim D, Staessen, Jan A, Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, Verbeek, André LM, Vermeulen, Sita H, Viikari, Jorma S, Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J, Watkins, Hugh, Zeggini, Eleftheria, ArcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Chakravarti, Aravinda, Clegg, Deborah J, Cupples, L Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E, Rao, DC, Abecasis, Goncalo R, Assimes, Themistocles L, Barroso, Inês, Berndt, Sonja I, Boehnke, Michael, Deloukas, Panos, Fox, Caroline S, Groop, Leif C, Hunter, David J, Ingelsson, Erik, Kaplan, Robert C, McCarthy, Mark I, Mohlke, Karen L, O'Connell, Jeffrey R, Schlessinger, David, Strachan, David P, Stefansson, Kari, Van Duijn, Cornelia M, Hirschhorn, Joel N, Lindgren, Cecilia M, Heid, Iris M, North, Kari E, Borecki, Ingrid B, Kutalik, Zoltán, and Loos, Ruth JF

Subjects
GLGC Consortium, Global-BPGen Consortium, MAGIC Consortium, CHARGE Consortium, ICBP Consortium, DIAGRAM Consortium, 3. Good health, arcOGEN Consortium
Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

233. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W., Justice, Anne E., Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F., Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O., Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H., Rüeger, Sina, Teumer, Alexander, Ehret, Georg B., Ferreira, Teresa, Heard-Costa, Nancy L., Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D., Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M., Jansen, Rick, Westra, Harm-Jan, White, Charles C., Absher, Devin, Ahluwalia, Tarunveer S., Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L., de Craen, Anton J. M., Bis, Joshua C., Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston W. K., Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E., Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B., Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E., Jackson, Anne U., Jacobs, Kevin B., Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E., Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela A. F., Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L., Montasser, May E., Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M., Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W., Renström, Frida, Rizzi, Federica, Rose, Lynda M., Ryan, Kathy A., Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J., Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P., Vandenput, Liesbeth, van der Laan, Sander W., van der Velde, Nathalie, van Setten, Jessica, van Vliet-Ostaptchouk, Jana V., Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L., Wang, Sophie R., Wang, Zhaoming, Wild, Sarah H., Willenborg, Christina, Wilson, James F., Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M., Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A., Bakker, Stephan J. L., Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L., Boyd, Heather A., Bruinenberg, Marcel, Buchman, Aron S., Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S., Claudi-Boehm, Simone, Cole, John, Collins, Francis S., de Geus, Eco J. C., de Groot, Lisette C. P. G. M., Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G., Friedrich, Nele, Gejman, Pablo V., Gigante, Bruna, Glorioso, Nicola, Go, Alan S., Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C., Hansen, Torben, Harris, Tamara B., Hartman, Catharina A., Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T., Heath, Andrew C., Henders, Anjali K., Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G., Hui, Jennie, Husemoen, Lise L., Hutri-Kähönen, Nina, Hysi, Pirro G., Illig, Thomas, De Jager, Philip L., Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J. Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J., Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T., Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J., Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K., McArdle, Wendy L., Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W., Morris, Andrew P., Narisu, Narisu, Nelis, Mari, Ong, Ken K., Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G., Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M., Rice, Treva K., Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R., Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Scott, William R., Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P. Eline, Smit, Jan H., Sparsø, Thomas H., Stirrups, Kathleen, Stolk, Ronald P., Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, van der Most, Peter J., Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M., Waldenberger, Melanie, Walker, Ryan W., Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F., Zillikens, M. Carola, van Dijk, Suzanne C., van Schoor, Natasja M., Asselbergs, Folkert W., de Bakker, Paul I. W., Beckmann, Jacques S., Beilby, John, Bennett, David A., Bergman, Richard N., Bergmann, Sven, Böger, Carsten A., Boehm, Bernhard O., Boerwinkle, Eric, Boomsma, Dorret I., Bornstein, Stefan R., Bottinger, Erwin P., Bouchard, Claude, Chambers, John C., Chanock, Stephen J., Chasman, Daniel I., Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G., Evans, Denis A., de Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W., Froguel, Philippe, Gansevoort, Ron T., Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, van der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A., Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V., Hveem, Kristian, James, Alan L., Jordan, Joanne M., Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus A. L. M., Kivimaki, Mika, Knekt, Paul B., Koistinen, Heikki A., Kooner, Jaspal S., Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G., Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F., Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D., Moll, Frans L., Murray, Jeffrey C., Musk, Arthur W., Nieminen, Markku S., Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J., Oostra, Ben A., Palmer, Lyle J., Pankow, James S., Pasterkamp, Gerard, Pedersen, Nancy L., Pedersen, Oluf, Penninx, Brenda W., Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P., Psaty, Bruce M., Qi, Lu, Quertermous, Thomas, Raitakari, Olli T., Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M., Rioux, John D., Rivadeneira, Fernando, Rotter, Jerome I., Rudan, Igor, den Ruijter, Hester M., Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter E. H., Shuldiner, Alan R., Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Staessen, Jan A., Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Verbeek, André L. M., Vermeulen, Sita H., Viikari, Jorma S., Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J., Watkins, Hugh, Zeggini, Eleftheria, Charge Consortium, Diagram Consortium, Glgc Consortium, Global-BPGen Consortium, Icbp Consortium, Magic Consortium, Chakravarti, Aravinda, Clegg, Deborah J., Cupples, L. Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E., Rao, D. C., Abecasis, Goncalo R., Assimes, Themistocles L., Barroso, Inês, Berndt, Sonja I., Boehnke, Michael, Deloukas, Panos, Fox, Caroline S., Groop, Leif C., Hunter, David J., Ingelsson, Erik, Kaplan, Robert C., McCarthy, Mark I., Mohlke, Karen L., O'Connell, Jeffrey R., Schlessinger, David, Strachan, David P., Stefansson, Kari, van Duijn, Cornelia M., Hirschhorn, Joel N., Lindgren, Cecilia M., Heid, Iris M., North, Kari E., Borecki, Ingrid B., Kutalik, Zoltán, and Loos, Ruth J. F.

Subjects
3. Good health

234. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Farmaki, Aliki-Eleni, Hui, Jennie, Gräßler, Jürgen, Van Der Most, Peter J., Walker, Ryan W., Cupples, L Adrienne, Holmen, Oddgeir, Hassinen, Maija, Pedersen, Oluf, Lichtner, Peter, Tachmazidou, Ioanna, Hillege, Hans, Tremblay, Angelo, Musk, Arthur W., Heard-Costa, Nancy L., Sørensen, Thorkild I. A., Völker, Uwe, Sebert, Sylvain, Eriksson, Joel, Bellis, Claire, Willemsen, Gonneke, Chen, Yii-Der Ida, Hofman, Albert, Pankow, James S., Huffman, Jennifer E., Boehnke, Michael, Jeff, Janina M., Qi, Lu, Thorsteinsdottir, Unnur, Hunter, David J., Ried, Janina S., Monda, Keri L., Hirschhorn, Joel N., Uusitupa, Matti, Grarup, Niels, Salvi, Erika, Mccarthy, Mark I., Laakso, Markku, Wright, Alan F., Feitosa, Mary F., Stefansson, Kari, Widén, Elisabeth, Friedrich, Nele, O'connell, Jeffrey R., Kyriakou, Theodosios, Lyssenko, Valeriya, Zeggini, Eleftheria, Teumer, Alexander, Justice, Anne E., Cadby, Gemma, Hu, Frank, Lindström, Jaana, Tee Khaw, Kay, Kovacs, Peter, Marie Justesen, Johanne, Mcardle, Wendy L., Willems, Sara M., Stringham, Heather M., Montasser, May E., Kuh, Diana, Isaacs, Aaron, Karaleftheri, Maria, Scott, Robert A., Rauramaa, Rainer, Jokinen, Eero, Schlessinger, David, Pilia, Maria G., North, Kari E., Ong, Ken K., Ittermann, Till, Lorbeer, Roberto, Couto Alves, Alexessander, Salomaa, Veikko, Luben, Robert, Hartman, Catharina A., Bouchard, Claude, Rayner, Nigel W., Hayward, Caroline, Rao, Ridker, Paul M., Peters, Annette, Hveem, Kristian, Vohl, Marie-Claude, Ribel-Madsen, Rasmus, Albrecht, Eva, Wilsgaard, Tom, Lorentzon, Mattias, Fox, Caroline, Palmer, Lyle J., Stolk, Ronald P., Carola Zillikens, Stirrups, Kathleen, Southam, Lorraine, Chasman, Daniel I., Forouhi, Nita G., Ryan, Kathy A., Esko, Toñu, Linneberg, Allan, Hastie, Nicholas, Wild, Sarah H., Palotie, Aarno, Mohlke, Karen L., Wareham, Nicholas J., Lakka, Timo A., Koistinen, Heikki A., Paternoster, Lavinia, Prokopenko, Inga, Osmond, Clive, Oostra, Ben A., Borecki, Ingrid B., Tuomilehto, Jaakko, Van Dongen, Jenny, Collins, Francis S, Grallert, Harald, Bragg-Gresham, Jennifer L., Smith, Megan T., Medina-Gomez, Carolina, Boerwinkle, Eric, Müller, Gabriele, Bornstein, Stefan R., Heliövaara, Markku, Jousilahti, Pekka, Kinnunen, Leena, Kooner, Jaspal S., Swift, Amy J., Kuusisto, Johanna, Loos, Ruth J. F., Zhao, Jing Hua, Ju Sung, Yun, Rankinen, Tuomo, Grewal, Jagvir, Bartz, Traci M., Hamsten, Anders, Döring, Angela, Hicks, Andrew A., Mägi, Reedik, Njølstad, Inger, Rudan, Igor, Rice, Treva K., Strachan, David P., De Geus, Eco J.C., Chiang, Charleston W. K., Watkins, Hugh, Kaplan, Robert C., Blüher, Matthias, Standáková, Alena, Luan, Jian'an, Cusi, Daniele, Homuth, Georg, Sarzynski, Mark A., Jarvelin, Marjo-Riitta, Ohlsson, Claes, Stumvoll, Michael, Groop, Leif C., Chambers, John C., Gjesing, Anette Prior, Penninx, Brenda W., Bruinenberg, Marcel, Strauch, Konstantin, Waeber, Gérard, Knekt, Paul B., Kolcic, Ivana, Husemoen, Lise Lotte, Dedoussis, George, Mahajan, Anubha, Fischer, Krista, Chu, Audrey Y., Lahti, Jari, Lehtimäki, Terho, Morris, Andrew P., Nolte, Ilja M., Havulinna, Aki S., Spector, Timothy D., Vitart, Veronique, Keinanen-Kiukaanniemi, Sirkka M., Gieger, Christian, Abecasis, Goncalo R., Metspalu, Andres, Sanna, Serena, Psaty, Bruce M., Goel, Anuj, Thorleifsson, Gudmar, Scholtens, Salome, Ferreira, Teresa, Viikari, Jorma S., Lewin, Alexandra M., Glorioso, Nicola, Mcknight, Barbara, Richards, Marcus, Winkler, Thomas W., Snieder, Harold, Männistö, Satu, Kähönen, Mika, Harder, Marie Neergaard, Laitinen, Tomi, Bergmann, Sven, Oldehinkel, Albertine J., Langenberg, Claudia, Wilson, James F., Pérusse, Louis, Kutalik, Zoltán, Dimitriou, Maria, Farrall, Martin, Zhang, Weihua, Tönjes, Anke, Wang, Sophie R., Verweij, Niek, Jackson, Anne U., Lindgren, Cecilia M., Bonnycastle, Lori L., Narisu, Narisu, Eklund, Niina, Müller-Nurasyid, Martina, Polašek, Ozren, Kooner, Ishminder K., Pichler, Irene, Pramstaller, Peter P., Smit, Jan H., Perola, Markus, Tsafantakis, Emmanouil, Beilby, John, Rivadeneira, Fernando, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Graff, Mariaelisa, Manunta, Paolo, Wong, Andrew, Hottenga, Jouke-Jan, Raitakari, Olli T, Leach, Irene Mateo, Milani, Lili, Swertz, Morris A., Boomsma, Dorret I., Yerges-Armstrong, Laura M., James, Alan L., Ahluwalia, Tarunveer S., Vartiainen, Erkki, Blangero, John, Campbell, Harry, Uitterlinden, André G., Puolijoki, Hannu, Frayling, Timothy, Jula, Antti, Kristiansson, Kati, Eriksson, Johan G., Gansevoort, Ron T., Heid, Iris M., Kajantie, Eero, Bakker, Stephan J. L., Rose, Lynda M., Gorski, Mathias, Mangino, Massimo, Vollenweider, Peter, Van Der Harst, Pim, Van Duijn, Cornelia M., Koskinen, Seppo, Venturini, Cristina, Van Vliet-Ostaptchouk, Jana V., Mills, Rebecca, Jørgensen, Torben, Mihailov, Evelin, Vandenput, Liesbeth, Shudiner, Alan R., Barlassina, Cristina, Hattersley, Andrew Tym, Chines, Peter S., Hansen, Torben, D'avila, Francesca, Deloukas, Panos, Cucca, Fracensco, Vonk, Judith M., Hysi, Pirro G., Kanoni, Stavroula, Schwarz, Peter E. H., Jalilzadeh, Shapour, and Bergman, Richard N.

Subjects
2. Zero hunger
Abstract

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

235. Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Author

Ong, Ken K., Smith, Blair H., McKnight, Barbara, Pe'russe, Louis, Grabe, Hans-Jörgen, Marques-Vidal, Pedro, Kooner, Jaspal S., Wareham, Nicholas J., Morris, Andrew P., Grammer, Tanja B., Chittani, Martina, Hassinen, Maija, Trompet, Stella, Juonala, Markus, Kooperberg, Charles, Peters, Annette, Wu, Joseph, Kuusisto, Johanna, Zillikens, M. Carola, Bruinenberg, Marcel, Eriksson, Anna L., Manichaikul, Ani, Fox, Caroline S., Snieder, Harold, Barata, Llilda, Vestergaard, Henrik, Polasek, Ozren, Borecki, Ingrid B., Martin, Nicholas G., Ahluwalia, Tarunveer S., Sattar, Naveed, Mellström, Dan, Franks, Paul W., Hirschhorn, Joel N., Stringham, Heather M., Kivimaki, Mika, Jarvelin, Marjo-Riitta, Cucca, Francesco, Chu, Audrey Y., Hocking, Lynne J., Holmen, Oddgeir L., Corre, Tanguy, Männikkö, Reija, Jukema, J. Wouter, Tuomilehto, Jaakko, Pasterkamp, Gerard, Wolffenbuttel, Bruce H.R., Hernandez, Dena, James, Alan L., Ford, Ian, Heid, Iris M., Barroso, Inês, Rawal, Rajesh, Amin, Najaf, Hartman, Catharina A., Tayo, Bamidele O., Gertow, Karl, Direk, Nese, Lorentzon, Mattias, Esko, Toñu, Eriksson, Joel, Afaq, Saima, Van Duijn, Cornelia M., Waldenberger, Melanie, Balkau, Beverley, Gong, Jian, Pervjakova, Natalia, Young, Kristin, Baldassarre, Damiano, Yengo, Loic, Justice, Anne E., Luan, Jian'an, Teumer, Alexander, Gigante, Bruna, Horikoshi, Momoko, Launer, Lenore J., Grallert, Harald, Ngwa, Julius S., Wu, Ying, Ludolph-Donislawski, Anja, Rao, Thuillier, Dorothee, Renström, Frida, Hindorff, Lucia, Chines, Peter S., Lobbens, Stephane, Kanoni, Stavroula, Müller-Nurasyid, Martina, Jansson, John-Olov, Navarro, Pau, De Geus, Eco J.C., Rose, Lynda M., Savonen, Kai, Lim, Unhee, Hunter, David J., Sarti, Cinzia, Bielak, Lawrence F., Rauramaa, Rainer, Whitfield, John B., Hastie, Nicholas D., Bandinelli, Stefania, Swertz, Morris A., Cooper, Richard S., Swift, Amy J., Kähönen, Mika, Deng, Xuan, Gorski, Mathias, De Faire, Ulf, Karlsson, Magnus, Siemelink, Marten A., Narisu, Narisu, Johnson, Andrew D., Lubke, Gitta, Wong, Andrew, Perez, Jeremiah, Verweij, Niek, Grarup, Niels, Scholtens, Salome, Kvaloy, Kirsti, McCarthy, Mark I., Boerwinkle, Eric, Laakso, Markku, Bakker, Stephan J.L., Tyrrell, Jessica, Chasman, Daniel I., De Craen, Anton J.M., Chambers, John C., Krämer, Bernhard K., Huang, Tao, Eicher, John D., Hutri-Kähönen, Nina, Loh, Marie, Bergmann, Sven, Weir, David R., Nauck, Matthias, März, Winfried, Lindgren, Cecilia M., Smith, Jennifer A., Middelberg, Rita P.S., Kutalik, Zolta'n, Qi, Qibin, Spector, Tim D., Hveem, Kristian, Psaty, Bruce M., Bergman, Richard N., Hansen, Torben, Homuth, Georg, Strawbridge, Rona J., Strauch, Konstantin, Haitjema, Saskia, Zhang, Weihua, Jackson, Anne U., Buckley, Brendan M., De Borst, Gert J., Staessen, Jan A., Vollenweider, Peter, Liu, Ching-Ti, Schurmann, Claudia, Cupples, L. Adrienne, Marchini, Jonathan, Ohlsson, Claes, Wright, Alan F., Wild, Sarah, Hollensted, Mette, North, Kari E., Bragg, Jennifer, Hung, Joseph, Gordon-Larsen, Penny, Koistinen, Heikki A., Olden, Matthias, Fischer, Krista, Hottenga, Jouke Jan, Thorand, Barbara, Harder, Marie Neergaard, Silbernagel, Günther, Huffman, Jennifer E., Hallmans, Göran, Nolte, Ilja M., Le Marchand, Loic, Zimmermann, Martina E., Coggeshall, Scott, Boomsma, Dorret I., Strachan, David P., Qi, Lu, Jorgensen, Marit E., Cadby, Gemma, Vandenput, Liesbeth, Tremoli, Elena, Porteous, David J., Abecasis, Gonçalo R., McKenzie, Colin A., Dedoussis, George, Kuh, Diana, Hamsten, Anders, Bonnycastle, Lori L., Linneberg, Allan, Van Der Laan, Sander W., Rasmussen-Torvik, Laura J., Lind, Lars, Faul, Jessica D., Winkler, Thomas W., Jhun, Min A., Westendorp, Zhao, Jing Hua, Sung, Yun Ju, Kolovou, Genovefa, Rudan, Igor, Langenberg, Claudia, Kardia, Sharon L.R., Madden, Pamela A.F., Curran, Joanne E., Afzal, Uzma, Mahajan, Anubha, Lyytikäinen, Leo-Pekka, Adair, Linda S., Alfred, Tamuno, Van Der Harst, Pim, Mohlke, Karen L., Völzke, Henry, Cusi, Daniele, Peyser, Patricia A., Frayling, Timothy M., Komulainen, Pirjo, Ferrucci, Luigi, Stanča'kova, Alena, Eiriksdottir, Gudny, Metspalu, Andres, Scott, Robert A., Ida Chen, Yii-Der, Fisher, Virginia A., Lupoli, Sara, Ahmad, Shafqat, Bartz, Traci M., Campbell, Harry, Peters, Ulrike, Van Vliet-Ostaptchouk, Jana V., Blangero, John, Musk, Tanaka, Toshiko, Rankinen, Tuomo, Kilpeläinen, Tuomas O., Sanna, Serena, Boehnke, Michael, Harris, Tamara B., Kleber, Marcus E., Ridker, Paul M., Kinnunen, Leena, Hayward, Caroline, Menni, Cristina, Braga, Daniele, Tiemeier, Henning, Böger, Carsten A., Vitart, Veronique, Rice, Treva, Zhao, Wei, Taylor, Kent D., Deloukas, Panagiotis, Vink, Jacqueline M., Graff, Misa, Wilson, James F., Sorensen, Thorkild I.A., Vedantam, Sailaja L., Biffar, Reiner, Kolcic, Ivana, Willemsen, Gonneke, Bonnefond, Amelie, Vonk, Judith M., Glorioso, Nicola, Lakka, Timo A., Xue, Luting, Lim, Elise, Heath, Andrew C., Loos, Ruth J.F., Haiman, Christopher A., Palmer, Lyle J., Forrester, Terrence, Sennblad, Bengt, Van Der Most, Peter J., Gudnason, Vilmundur, Collins, Francis S., Lee, Nanette R., Leander, Karin, Delgado, Graciela E., Beilby, John, Luben, Robert, Bien, Stephanie A., Pisinger, Charlotta, Uitterlinden, Andre G., Oldehinkel, Albertine J., Zubair, Niha, Montgomery, Grant W., Vohl, Marie-Claude, Mangino, Massimo, Sarzynski, Mark A., Waeber, Ge'rard, Raitakari, Olli T., Justesen, Johanne Marie, Hadley, David, Smith, Albert Vernon, Kumari, Meena, Schlessinger, David, Lehtimäki, Terho, Feitosa, Mary F., Heard-Costa, Nancy L., Den Ruijter, Hester M., Bottinger, Erwin, Padmanabhan, Sandosh, Czajkowski, Jacek, Pedersen, Oluf, Bouchard, Claude, Slagboom, P. Eline, Buyske, Steve, Stott, David J., Marten, Jonathan, Froguel, Philippe, Huang, Jie, and Ingelsson, Erik

Subjects
3. Good health
Abstract

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

236. Left ventricle function and post-transcriptional events with exercise training in pigs.

Author

Samani, Stephanie L., Barlow, Shayne C., Freeburg, Lisa A., Jones, Traci L., Poole, Marlee, Sarzynski, Mark A., Zile, Michael R., Shazly, Tarek, and Spinale, Francis G.

Subjects
*EXERCISE therapy, *SPECKLE tracking echocardiography, *ECHOCARDIOGRAPHY, *CARDIOVASCULAR fitness, *SWINE, *ISOMETRIC exercise
Abstract

Background: Standardized exercise protocols have been shown to improve overall cardiovascular fitness, but direct effects on left ventricular (LV) function, particularly diastolic function and relation to post-transcriptional molecular pathways (microRNAs (miRs)) are poorly understood. This project tested the central hypothesis that adaptive LV remodeling resulting from a large animal exercise training protocol, would be directly associated with specific miRs responsible for regulating pathways relevant to LV myocardial stiffness and geometry. Methods and results: Pigs (n = 9; 25 Kg) underwent a 4 week exercise training protocol (10 degrees elevation, 2.5 mph, 10 min, 5 days/week) whereby LV chamber stiffness (KC) and regional myocardial stiffness (rKm) were measured by Doppler/speckle tracking echocardiography. Age and weight matched non-exercise pigs (n = 6) served as controls. LV KC fell by approximately 50% and rKm by 30% following exercise (both p < 0.05). Using an 84 miR array, 34 (40%) miRs changed with exercise, whereby 8 of the changed miRs (miR-19a, miR-22, miR-30e, miR-99a, miR-142, miR-144, miR-199a, and miR-497) were correlated to the change in KC (r ≥ 0.5 p < 0.05) and mapped to matrix and calcium handling processes. Additionally, miR-22 and miR-30e decreased with exercise and mapped to a localized inflammatory process, the inflammasome (NLRP-3, whereby a 2-fold decrease in NLRP-3 mRNA occurred with exercise (p < 0.05). Conclusion: Chronic exercise reduced LV chamber and myocardial stiffness and was correlated to miRs that map to myocardial relaxation processes as well as local inflammatory pathways. These unique findings set the stage for utilization of myocardial miR profiling to identify underlying mechanisms by which exercise causes changes in LV myocardial structure and function. [ABSTRACT FROM AUTHOR]

Published
2024
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238. Proteomic characterization of high-density lipoprotein particles in patients with non-alcoholic fatty liver disease.

Author

Rao, Prahlad K., Merath, Kate, Drigalenko, Eugene, Jadhav, Avinash Y. L., Komorowski, Richard A., Goldblatt, Matthew I., Rohatgi, Anand, Sarzynski, Mark A., Gawrieh, Samer, and Olivier, Michael

Subjects
THERAPEUTICS, FATTY liver, HIGH density lipoproteins, ANTITHROMBIN III, CARDIOTONIC agents, PROTEOMICS
Abstract

Background: Metabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function. Recent studies suggested that patients with non-alcoholic fatty liver disease (NAFLD), including individuals with non-alcoholic steatohepatitis (NASH), have smaller HDL particles when compared to individuals without liver pathologies. However, no studies have investigated potential changes in HDL particle protein composition in patients with NAFLD, in addition to changes related to obesity, to explore putative functional changes of HDL which may increase the risk of cardiovascular complications. Methods: From a cohort of morbidly obese females who were diagnosed with simple steatosis (SS), NASH, or normal liver histology, we selected five matched individuals from each condition for a preliminary pilot HDL proteome analysis. HDL particles were enriched using size-exclusion chromatography, and the proteome of the resulting fraction was analyzed by liquid chromatography tandem mass spectrometry. Differences in the proteomes between the three conditions (normal, SS, NASH) were assessed using label-free quantitative analysis. Gene ontology term analysis was performed to assess the potential impact of proteomic changes on specific functions of HDL particles. Results: Of the 95 proteins identified, 12 proteins showed nominally significant differences between the three conditions. Gene ontology term analysis revealed that severity of the liver pathology may significantly impact the anti-thrombotic functions of HDL particles, as suggested by changes in the abundance of HDL-associated proteins such as antithrombin III and plasminogen. Conclusions: The pilot data from this study suggest that changes in the HDL proteome may impact the functionality of HDL particles in NAFLD and NASH patients. These proteome changes may alter cardio-protective properties of HDL, potentially contributing to the increased cardiovascular disease risk in affected individuals. Further validation of these protein changes by orthogonal approaches is key to confirming the role of alterations in the HDL proteome in NAFLD and NASH. This will help elucidate the mechanistic effects of the altered HDL proteome on cardioprotective properties of HDL particles. [ABSTRACT FROM AUTHOR]

Published
2018
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239. Omics-driven investigation of the biology underlying intrinsic submaximal working capacity and its trainability.

Author

Hota, Monalisa, Barber, Jacob L., Ruiz-Ramie, Jonathan J., Schwartz, Charles S., Lam, Do Thuy Uyen Ha, Rao, Prashant, Mi, Michael Y., Katz, Daniel H., Robbins, Jeremy M., Clish, Clary B., Gerszten, Robert E., Sarzynski, Mark A., Ghosh, Sujoy, and Bouchard, Claude

Subjects
*HEART beat, *EXERCISE intensity, *AEROBIC capacity, *BIOLOGY, *ERYTHROCYTES, *CARDIOPULMONARY fitness
Abstract

Submaximal exercise capacity is an indicator of cardiorespiratory fitness with clinical and public health implications. Submaximal exercise capacity and its response to exercise programs are characterized by heritability levels of about 40%. Using physical working capacity (power output) at a heart rate of 150 beats/min (PWC150) as an indicator of submaximal exercise capacity in subjects of the HERITAGE Family Study, we have undertaken multi-omics and in silico explorations of the underlying biology of PWC150 and its response to 20 wk of endurance training. Our goal was to illuminate the biological processes and identify panels of genes associated with human variability in intrinsic PWC150 (iPWC150) and its trainability (dPWC150). Our bioinformatics approach was based on a combination of genome-wide association, skeletal muscle gene expression, and plasma proteomics and metabolomics experiments. Genes, proteins, and metabolites showing significant associations with iPWC150 or dPWC150 were further queried for the enrichment of biological pathways. We compared genotype-phenotype associations of emerging candidate genes with reported functional consequences of gene knockouts in mouse models. We investigated the associations between DNA variants and multiple muscle and cardiovascular phenotypes measured in HERITAGE subjects. Two panels of prioritized genes of biological relevance to iPWC150 (13 genes) and dPWC150 (6 genes) were identified, supporting the hypothesis that genes and pathways associated with iPWC150 are different from those underlying dPWC150. Finally, the functions of these genes and pathways suggested that human variation in submaximal exercise capacity is mainly driven by skeletal muscle morphology and metabolism and red blood cell oxygen-carrying capacity. NEW & NOTEWORTHY Multi-omics and in silico explorations of the genes and underlying biology of submaximal exercise capacity and its response to 20 wk of endurance training were undertaken. Prioritized genes were identified: 13 genes for variation in submaximal exercise capacity in the sedentary state and 5 genes for the response level to endurance training, with no overlap between them. Genes and pathways associated with submaximal exercise capacity in the sedentary state are different from those underlying trainability. [ABSTRACT FROM AUTHOR]

Published
2023
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240. Longitudinal Patterns of Cardiorespiratory Fitness Predict the Development of Hypertension Among Men and Women.

Author

Sui, Xuemei, Sarzynski, Mark A., Lee, Duck-chul, Lavie, Carl J., Zhang, Jiajia, Kokkinos, Peter F., Payne, Jonathan, and Blair, Steven N.

Subjects
*CARDIOPULMONARY system physiology, *HYPERTENSION, *THERAPEUTICS, *DISEASES in women, *DISEASES in men, *PERIODIC health examinations, *DISEASE incidence, *HYPERTENSION epidemiology, *LONGITUDINAL method, *RESEARCH funding, *BODY mass index
Abstract

Background: Most of the existing literature has linked a baseline cardiorespiratory fitness or change between baseline and one follow-up measurement of cardiorespiratory fitness to hypertension. The purpose of the study is to assess the association between longitudinal patterns of cardiorespiratory fitness changes with time and incident hypertension in adult men and women.Methods: Participants were aged 20 to 82 years, were free of hypertension during the first 3 examinations, and received at least 4 preventive medical examinations at the Cooper Clinic in Dallas, Texas, from 1971 to 2006. They were classified into 1 of 5 groups based on all of the measured cardiorespiratory fitness values (in metabolic equivalents) during maximal treadmill tests. Logistic regression was used to compute odds ratios and 95% confidence intervals.Results: Among 4932 participants (13% women), 1954 developed hypertension. After controlling for baseline potential confounders, follow-up duration, and number of follow-up visits, odds ratios (95% confidence intervals) for hypertension were 1.00 for the decreasing group (referent), 0.64 (0.52-0.80) for the increasing group, 0.89 (0.70-1.12) for the bell-shape group, 0.78 (0.62-0.98) for the U-shape group, and 0.83 (0.69-1.00) for the inconsistent group. The general pattern of the association was consistent regardless of participants' baseline cardiorespiratory fitness or body mass index levels.Conclusions: An increasing pattern of cardiorespiratory fitness provides the lowest risk of hypertension in this middle-aged relatively healthy population. Identifying specific pattern(s) of cardiorespiratory fitness change may be important for determining associations with comorbidity, such as hypertension. [ABSTRACT FROM AUTHOR]

Published
2017
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242. Changes in HDL Particle Traits in Response to Regular Exercise: Results from the HERITAGE Family Study.

Author

Sarzynski, Mark A., Rankinen, Tuomo, Leon, Arthur S., Rao, Dabeeru C., Skinner, James S., Després, Jean-Pierre, and Bouchard, Claude

Subjects
*SYSTOLIC blood pressure, *EXERCISE, *PHYSICAL training & conditioning
Abstract

Given the controversy around HDL-C as a therapeutic target, there is a need to investigate other features of HDL and how they respond to various preventive interventions. We tested the hypothesis that regular exercise would have beneficial effects on HDL particle (HDL-P) traits in sedentary adults. Methods: The following HDL-P traits were measured via NMR (Liposcience Inc.) before and after completion of a 20-week exercise program in the HERITAGE Family Study (N=715): concentration of total, large, medium, and small HDL-P and mean HDL-P size. ANCOVA was used to test for aggregation of HDL-P trait responses in families controlling for age, sex, and baseline BMI and trait value. Results: The concentration of large HDL-P significantly increased in response to regular exercise in both Black and White participants, while the increase was significantly larger in females compared to males (Table 1). In general, regular exercise decreased the concentration of medium and small HDL-P. Together, these responses contributed to a significant increase in the average cholesterol content of HDL particles. Exercise-induced changes in large HDL-P were inversely correlated with changes in fat mass and systolic blood pressure. Moreover, changes in BMI were significantly associated with changes in all of the HDL-P traits, but not with HDL-C. We found significant evidence of familial aggregation for the exerciseinduced changes in HDL-P traits in both races, as there was 1.4 to 1.6 times more variance between than within families for the changes in total (p=0.02 in Whites) and large HDL-P (p=0.004 in Whites, p=0.02 in Blacks) and HDL-P size (p=0.0009 in Whites, p=0.009 in Blacks). Conclusion: The HDL-P subclass profile favorably responded to regular exercise in sedentary Black and White adults, highlighted by increases in the concentration of large HDL-P, and may be influenced by a significant genetic component. We provide evidence that regular exercise could potentially be used as an HDL-based therapy designed to target beneficial subfractions. [ABSTRACT FROM AUTHOR]

Published
2014

243. Effect of individual characteristics and aerobic training on the %HRR-%V̇O2R relationship.

Author

Ferri Marini, Carlo, Sisti, Davide, Skinner, James S., Sarzynski, Mark A., Bouchard, Claude, Amatori, Stefano, Rocchi, Marco B. L., Piccoli, Giovanni, Stocchi, Vilberto, Federici, Ario, and Lucertini, Francesco

Subjects
*EXERCISE tests, *STATISTICS, *AEROBIC exercises, *OXYGEN consumption, *MULTIPLE regression analysis, *EXERCISE physiology, *REGRESSION analysis, *T-test (Statistics), *EXERCISE intensity, *HEART beat, *DESCRIPTIVE statistics, *RESEARCH funding, *DATA analysis
Abstract

This study aimed to assess if, during incremental exercise, considering individual characteristics can make the relationship between the percentages of heart rate (HRR) and oxygen uptake (V̇O2R) reserve either 1:1 or more accurate. Cycle ergometer data of the maximal incremental exercise tests performed by 450 healthy and sedentary participants (17-66 years) of the HERITAGE Family Study, grouped for sex, ethnicity, age, body fat, resting HR, and V̇O2max, were used to calculate the individual linear regressions between %HRR and %V̇O2R. The mean slope and intercept of the individual linear regressions of each subgroup were compared with 1 and 0 (identity line), respectively, using Hotelling tests followed by post-hoc one-sample t-tests. Two multiple linear regressions were also performed, using either the slopes or intercepts of the individual linear regressions as dependent variables and sex, age, resting HR, and V̇O2max as independent variables. The mean %HRR-%V̇O2R relationships of all subgroups differed from the identity line. Moreover, individual linear regression intercepts (8.9 ± 16.0) and slopes (0.971 ± 0.190) changed (p < 0.001) after 20 weeks of aerobic training (13.1 ± 11.1 and 0.891 ± 0.122). The multiple linear regressions could explain only 3.8% and 1.3% of the variance in the intercepts and slopes, whose variability remained high (standard error of estimate of 15.8 and 0.189). In conclusion, the %HRR-%V̇O2R relationship differs from the identity line regardless of individual characteristics and their difference increased after aerobic training. Moreover, due to the high interindividual variability, using a single equation for the whole population seems not suitable for representing the %HRR-%V̇O2R relationship of a given subject, even when several individual characteristics are considered. Highlights The association between %HRR and %V̇O2R is not 1:1 even when individuals are grouped by age, sex, ethnicity, body composition, HRrest, and V̇O2max. Using several subject characteristics to identify the individual's %HRR-%V̇O2R relationship does not meaningfully increase its prediction accuracy or reduce the interindividual variability of %HRR-%V̇O2R relationships Using a single equation for the whole population is not suitable for representing the relationship of a given subject; hence, individual relationships should be preferred when prescribing the intensity of aerobic exercise. The individual %HRR-%V̇O2R relationship should be periodically assessed due to the potential training induced changes in the relationship. [ABSTRACT FROM AUTHOR]

Published
2023
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244. Genetic Variation in Chromosome 8p23 is Associated With Sedentary Behavior in Humans.

Author

Rankinen, Tuomo, Sarzynski, Mark A., Sternfeld, Barbara, and Sidney, Steve

Subjects
*HUMAN behavior, *SEDENTARY behavior, *CHROMOSOMES, *SINGLE nucleotide polymorphisms, *NUCLEOTIDE sequence
Abstract

Sedentary behavior, usually quantified as sitting time, has been shown to be associated with several adverse health outcomes, even among individuals who meet the current recommendations for physical activity. Both twin and family studies have shown that sedentary behavior aggregates in families and is a heritable trait. However, little is known about genes and DNA sequence variants that contribute to propensity to be sedentary. The purpose of our study was to conduct a genomewide association study to identify genomic regions and DNA sequence variants associated with sedentary time. A total of 67,530 Caucasians (56% female, mean age 62.1 years [SD 12.5]) from the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) cohort were used for the discovery analyses. Other RPGEH ethnicities (African-Americans: N=2,500; East Asians: N=6,300; Hispanics: N=8,800) were used for replication studies. Information on daily sitting time outside of work was obtained by a questionnaire. A custom panel of 657,184 autosomal single nucleotide polymorphisms (SNPs) was genotyped using Affymetrix platform. Associations between sedentary time (dichotomized; cases 3 hours or more, controls less than 3 hours per day) and the SNPs were tested with PLINK logistic model using age, sex, BMI and admixture principal components as covariates. The strongest evidence of association was detected on chromosome 8p23.1. A total of 24 SNPs within a 1.34 Mb region were associated with sedentary time at genome-wide significance level (p<5x10-8), with SNP rs11774552 showing the peak association (OR=0.924, p= 1.7x10-12). Sex-specific analyses confirmed that the associations were present both in men and women. The same SNPs were not associated with sedentary time in other ethnicities. However, SNP rs28754712, which is located in the immediate vicinity (+456 bp) of rs11774552, showed a significant association with sedentary time (OR=0.795, p=1.2x10-3) in African- Americans. In summary, our results provide the first evidence of genomic region and DNA sequence variants associated with sedentary behavior in humans. If confirmed in additional replication studies, these findings will advance our understanding of biological mechanisms contributing to propensity to be sedentary. [ABSTRACT FROM AUTHOR]

Published
2014

245. Plasma Proteomic Risk Markers of Incident Type 2 Diabetes Reflect Physiologically Distinct Components of Glucose-Insulin Homeostasis.

Author

Cronjé, Héléne T., Mi, Michael Y., Austin, Thomas R., Biggs, Mary L., Siscovick, David S., Lemaitre, Rozenn N., Psaty, Bruce M., Tracy, Russell P., Djoussé, Luc, Kizer, Jorge R., Ix, Joachim H., Rao, Prashant, Robbins, Jeremy M., Barber, Jacob L., Sarzynski, Mark A., Clish, Clary B., Bouchard, Claude, Mukamal, Kenneth J., Gerszten, Robert E., and Jensen, Majken K.

Subjects
*TYPE 2 diabetes, *PROTEOMICS, *BLOOD proteins, *HOMEOSTASIS, *GLUCOSE tolerance tests
Abstract

High-throughput proteomics allows researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (N = 2,631) and IVGTT-derived measures in participants from the HERITAGE Family Study (N = 752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including β-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2, which also was associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk. Article Highlights: Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response. [ABSTRACT FROM AUTHOR]

Published
2023
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246. The Impact of Cardiorespiratory Fitness Levels on the Risk of Developing Atherogenic Dyslipidemia.

Author

Breneman, Charity B., Polinski, Kristen, Sarzynski, Mark A., Lavie, Carl J., Kokkinos, Peter F., Ahmed, Ali, and Sui, Xuemei

Subjects
*CARDIOPULMONARY system, *DYSLIPIDEMIA, *LOW density lipoproteins, *EPIDEMIOLOGY, *TREADMILL exercise tests, *DISEASE risk factors, *ATHEROSCLEROSIS, *EXERCISE tests, *HIGH density lipoproteins, *HYPERLIPIDEMIA, *LONGITUDINAL method, *RESEARCH funding, *TRIGLYCERIDES, *EXERCISE tolerance
Abstract

Background: Low cardiorespiratory fitness has been established as a risk factor for cardiovascular-related morbidity. However, research about the impact of fitness on lipid abnormalities, including atherogenic dyslipidemia, has produced mixed results. The purpose of this investigation is to examine the influence of baseline fitness and changes in fitness on the development of atherogenic dyslipidemia.Methods: All participants completed at least 3 comprehensive medical examinations performed by a physician that included a maximal treadmill test between 1976 and 2006 at the Cooper Clinic in Dallas, Texas. Atherogenic dyslipidemia was defined as a triad of lipid abnormalities: low high-density-lipoprotein cholesterol ([HDL-C] <40 mg/dL), high triglycerides ([TGs] ≥200 mg/dL), and high low-density-lipoprotein cholesterol ([LDL-C] ≥160 mg/dL).Results: A total of 193 participants developed atherogenic dyslipidemia during an average of 8.85 years of follow-up. High baseline fitness was protective against the development of atherogenic dyslipidemia in comparison with those with low fitness (odds ratio [OR] 0.57; 95% confidence interval [CI], 0.37-0.89); however, this relationship became nonsignificant after controlling for baseline HDL-C, LDL-C, and TG levels. Participants who maintained fitness over time had lower odds of developing atherogenic dyslipidemia than those with a reduction in fitness (OR 0.56; 95% CI, 0.34-0.91) after adjusting for baseline confounders and changes in known risk factors.Conclusions: High fitness at baseline and maintenance of fitness over time are protective against the development of atherogenic dyslipidemia. [ABSTRACT FROM AUTHOR]

Published
2016
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247. Associations of an HDL apolipoproteomic index with cardiometabolic risk factors before and after exercise training in the HERITAGE Family Study.

Author

Miranda Maravi, J. Sebastian, Leszczynski, Eric C., Schwartz, Charles S., Dev, Prasun K., Barber, Jacob L., Reasons, Riley J., Pearce, Ryan W., McPhaul, Michael J., Konrad, Robert J., Robbins, Jeremy M., Gerszten, Robert E., Collier, Timothy S., Bouchard, Claude, Rohatgi, Anand, and Sarzynski, Mark A.

Subjects
*EXERCISE therapy, *APOLIPOPROTEIN E4, *EXERCISE physiology, *CORONARY artery disease, *BODY composition, *BONFERRONI correction
Abstract

Previous studies have derived and validated an HDL apolipoproteomic score (pCAD) that predicts coronary artery disease (CAD) risk. However, the associations between pCAD and markers of cardiometabolic health in healthy adults are not known, nor are the effects of regular exercise on pCAD. A total of 641 physically inactive adults free of cardiovascular disease from the HERITAGE Family Study completed 20 weeks of exercise training. The pCAD index (range 0–100) was calculated using measurements of apolipoproteins A-I, C–I, C-II, C-III, and C-IV from ApoA-I-tagged serum (higher index = higher CAD risk). The associations between pCAD index and cardiometabolic traits at baseline and their training responses were assessed with Spearman correlation and general linear models. A Bonferroni correction of p < 8.9 × 10−04 was used to determine statistical significance. The mean ± SD baseline pCAD index was 29 ± 32, with 106 (16.5 %) participants classified as high CAD risk. At baseline, pCAD index was positively associated with blood pressure, systemic inflammation, and body composition. HDL size, VO 2 max, and HDL-C were negatively associated with pCAD index at baseline. Of those classified as high CAD risk at baseline, 52 (49 %) were reclassified as normal risk after training. Following training, pCAD index changes were inversely correlated (p < 1.4 × 10−04) with changes in HDL-C, HDL size, and LDL size. A higher pCAD index was associated with a worse cardiometabolic profile at baseline but improved with regular exercise. The results from this study highlight the potential role of HDL apolipoproteins as therapeutic targets for lifestyle interventions, particularly in high-risk individuals. [Display omitted] • A higher HDL apolipoproteomic index (pCAD) was associated with a worse cardiometabolic profile at baseline. • Individuals with the highest pCAD had the greatest reductions in pCAD following regular exercise. • HDL apolipoproteins are potential therapeutic targets for lifestyle interventions. [ABSTRACT FROM AUTHOR]

Published
2024
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248. Genomics and transcriptomics landscapes associated to changes in insulin sensitivity in response to endurance exercise training.

Author

Takeshita, Louise Y., Davidsen, Peter K., Herbert, John M., Antczak, Philipp, Hesselink, Matthijs K. C., Schrauwen, Patrick, Weisnagel, S. John, Robbins, Jeremy M., Gerszten, Robert E., Ghosh, Sujoy, Sarzynski, Mark A., Bouchard, Claude, and Falciani, Francesco

Subjects
*INSULIN sensitivity, *EXERCISE therapy, *LANDSCAPE changes, *GENETIC variation, *GENOMICS
Abstract

Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity. The genetic and molecular mechanisms underlying this phenomenon are currently not understood. By investigating genome-wide variants associated with baseline and exercise-induced changes (∆) in insulin sensitivity index (Si) in healthy volunteers, we have identified novel candidate genes whose mouse knockouts phenotypes were consistent with a causative effect on Si. An integrative analysis of functional genomic and transcriptomic profiles suggests genetic variants have an aggregate effect on baseline Si and ∆Si, focused around cholinergic signalling, including downstream calcium and chemokine signalling. The identification of calcium regulated MEF2A transcription factor as the most statistically significant candidate driving the transcriptional signature associated to ∆Si further strengthens the relevance of calcium signalling in EET mediated Si response. [ABSTRACT FROM AUTHOR]

Published
2021
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249. Association between Mitochondrial DNA Sequence Variants and V˙O2 max Trainability.

Author

VELLERS, HEATHER L., VERHEIN, KIRSTEN C., BURKHOLDER, ADAM B., LEE, JAEHOON, KIM, YOUNGMIN, LIGHTFOOT, J. TIMOTHY, SHI, MIN, WEINBERG, CLARICE R., SARZYNSKI, MARK A., BOUCHARD, CLAUDE, and KLEEBERGER, STEVEN R.

Subjects
*AEROBIC exercises, *COMPARATIVE studies, *DNA, *ENDURANCE sports training, *GENETIC polymorphisms, *MITOCHONDRIA, *POLYMERASE chain reaction, *OXYGEN consumption, *HAPLOTYPES, *DESCRIPTIVE statistics, *SEQUENCE analysis
Abstract

Supplemental digital content is available in the text. Purpose: We designed the study to determine whether mitochondrial DNA (mtDNA) haplogroup, sequence, and heteroplasmy differed between individuals previously characterized as low (LR) or high responders (HR) as defined by their maximal oxygen uptake response to a standardized aerobic exercise training program. Methods: DNA was isolated from whole blood in subjects from the HERITAGE Family Study that were determined to be either HR (n = 15) or LR (n = 15). mtDNA was amplified by long-range polymerase chain reaction, then tagged with Nextera libraries and sequenced on a MiSeq instrument. Results: Different mtDNA haplogroup subtypes were found in HR and LR individuals. Compared with HR subjects, significantly more LR subjects had variants in 13 sites, including 7 in hypervariable (HV) regions: HV2 (G185A: 0 vs 6, P = 0.02; G228A: 0 vs 5, P = 0.04; C295T: 0 vs 6; P = 0.04), HV3 (C462T: 0 vs 5, P = 0.04; T489C: 0 vs 5; P = 0.04), and HV1 (C16068T: 0 vs 6, P = 0.02; T16125C: 0 vs 6, P = 0.02). Remaining variants were in protein coding genes, mtND1 (1 vs 8, P = 0.02), mtND3 (A10397G: 0 vs 5, P = 0.04), mtND4 (A11250G: 1 vs 8, P = 0.02), mtND5 (G13707A: 0 vs 5, P = 0.04), and mtCYTB (T14797C: 0 vs 5, P = 0.04; C15451A: 1 vs 8, P = 0.02). Average total numbers of heteroplasmies (P = 0.83) and frequency of heteroplasmies (P = 0.05) were similar between the groups. Conclusions: Our findings provide specific sites across the mitochondrial genome that may be related to maximal oxygen uptake trainability. [ABSTRACT FROM AUTHOR]

Published
2020
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250. The effect of energy-matched exercise intensity on brain-derived neurotrophic factor and motor learning.

Author

Baird, Jessica F., Gaughan, Mary E., Saffer, Heath M., Sarzynski, Mark A., Herter, Troy M., Fritz, Stacy L., den Ouden, Dirk B., and Stewart, Jill Campbell

Subjects
*BRAIN-derived neurotrophic factor, *MOTOR learning, *GENOTYPES, *EXERCISE & psychology, *CALORIC expenditure
Abstract

Highlights • Exercise intensity did not affect post-exercise BDNF concentration. • Acute exercise did not enhance learning of a three-dimensional reach task. • Exercise intensity modified the kinematic approach that controlled reach movements. • BDNF genotype did not affect the BDNF response but influenced motor performance. Abstract Background Pairing a bout of high-intensity exercise with motor task practice can enhance motor learning beyond task practice alone, which is thought, in part, to be facilitated by an exercise-related increase in brain-derived neurotrophic factor (BDNF). The purpose of the current study was to examine the effect of different exercise intensities on BDNF levels and motor learning while controlling for exercise-related energy expenditure. Methods Forty-eight young, healthy participants were assigned to one of three groups: high-intensity exercise [High], low-intensity exercise [Low], or quiet rest [Rest]. The duration of the exercise bouts were individually adjusted so that each participant expended 200 kcals regardless of exercise intensity. BDNF was measured before and after exercise or rest. After exercise or rest, all participants practiced a 3-dimensional motor learning task, which involved reach movements made to sequentially presented targets. Retention was tested after 24-h. BDNF genotype was determined for each participant to explore its effects on BDNF and motor learning. Results All participants equally improved performance, indicated by a reduction in time to complete the task. However, the kinematic profile used to control the reach movement differed by group. The Rest group travelled the shortest distance between the targets, the High group had higher reach speed (peak velocity), and the Low group had earlier peak velocities. The rise in BDNF post-exercise was not significant, regardless of exercise intensity, and the change in BDNF was not associated with motor learning. The BDNF response to exercise did not differ by genotype. However, performance differed between those with the polymorphism (Met carriers) and those without (Val/Val). Compared to the Val/Val genotype, Met carriers had faster response times throughout task practice, which was supported by higher reach speeds and earlier peak velocities. Conclusion Results indicated that both low and high-intensity exercise can alter the kinematic approach used to complete a reach task, and these changes appear unrelated to a change in BDNF. In addition, the BDNF genotype did not influence BDNF concentration, but it did have an effect on motor performance of a sequential target reach task. [ABSTRACT FROM AUTHOR]

Published
2018
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