title: Physical Activity Benefits the Skeleton of Children Genetically Predisposed to Lower Bone Density in Adulthood.
abstract: Both genetics and physical activity (PA) contribute to bone mineral density (BMD), but it is unknown if the benefits of physical activity on childhood bone accretion depend on genetic risk. We, therefore, aimed to determine if PA influenced the effect of bone fragility genetic variants on BMD in childhood. Our sample comprised US children of European ancestry enrolled in the Bone Mineral Density in Childhood Study (N = 918, aged 5 to 19 years, and 52.4% female). We used a questionnaire to estimate hours per day spent in total, high-, and low-impact PA. We calculated a BMD genetic score (% BMD lowering alleles) using adult genome-wide association study (GWAS)-implicated BMD variants. We used dual-energy X-ray absorptiometry to estimate femoral neck, total hip, and spine areal-BMD and total body less head (TBLH) bone mineral content (BMC) Z-scores. The BMD genetic score was negatively associated with each bone Z-score (eg, TBLH-BMC: estimate = -0.03, p = 1.3 × 10(-6) ). Total PA was positively associated with bone Z-scores; these associations were driven by time spent in high-impact PA (eg, TBLH-BMC: estimate = 0.05, p = 4.0 × 10(-10) ) and were observed even for children with lower than average bone Z-scores. We found no evidence of PA-adult genetic score interactions (p interaction > 0.05) at any skeletal site, and there was no evidence of PA-genetic score-Tanner stage interactions at any skeletal site (p interaction > 0.05). However, exploratory analyses at the individual variant level revealed that PA statistically interacted with rs2887571 (ERC1/WNT5B) to influence TBLH-BMC in males (p interaction = 7.1 × 10(-5) ), where PA was associated with higher TBLH-BMC Z-score among the BMD-lowering allele carriers (rs2887571 AA homozygotes: estimate = 0.08 [95% CI 0.06, 0.11], p = 2.7 × 10(-9) ). In conclusion, the beneficial effect of PA on bone, especially high-impact PA, applies to the average child and those genetically predisposed to lower adult BMD (based on GWAS-implicated BMD variants). Independent replication of our exploratory individual variant findings is warranted. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Mitchell
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Chesi
authors.affiliation: Biostatistics and Data Management Core, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Okan
authors.initials: O
authors.lastname: Elci
authors.affiliation: Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Shana E
authors.initials: SE
authors.lastname: McCormack
authors.affiliation: Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Sani M
authors.initials: SM
authors.lastname: Roy
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Kalkwarf
authors.affiliation: Division of Endocrinology, Department of Medicine, Creighton University, Omaha, NE, USA.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Lappe
authors.affiliation: Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Vicente
authors.initials: V
authors.lastname: Gilsanz
authors.affiliation: Division of Pediatric Endocrinology, Diabetes, and Metabolism, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Oberfield
authors.affiliation: Department of Radiology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Shepherd
authors.affiliation: Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kelly
authors.affiliation: Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Struan Fa
authors.initials: SF
authors.lastname: Grant
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Babette S
authors.initials: BS
authors.lastname: Zemel
mesh_terms: D000293:Adolescent; D000328:Adult; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000502:physiology*; D002648:Child; D015331:Cohort Studies; D015444:Exercise; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
keywords: BONE MINERAL DENSITY; CHILDREN; EXERCISE; GENETIC; PHYSICAL ACTIVITY