TY - JOUR
T1 - Genetic potential and height velocity during childhood and adolescence do not fully account for shorter stature in cystic fibrosis
AU - Zysman-Colman, Zofia N.
AU - Kilberg, Marissa J.
AU - Harrison, Victor S.
AU - Chesi, Alessandra
AU - Grant, Struan F.A.
AU - Mitchell, Jonathan
AU - Sheikh, Saba
AU - Hadjiliadis, Denis
AU - Rickels, Michael R.
AU - Rubenstein, Ronald C.
AU - Kelly, Andrea
N1 - Funding Information:
We would like to thank the subjects with CF for their participation, Russell Localio, PhD of the University of Pennsylvania Department of Biostatistics, Epidemiology and Informatics for assistance with the statistical analyses and Rahul Agarwal for assistance with genetic sample collection. This work was supported by grants from the Cystic Fibrosis Foundation (to A.K., M.R.R., and M.J.K.), Public Health Services Research Grants R01 DK97830 (to A.K. and M.R.R.) and R01 DK085212 (to S.F.A.G.), UL1 TR000003 (Penn and CHOP Clinical & Translational Research Centers) and the Daniel
Publisher Copyright:
© 2020, International Pediatric Research Foundation, Inc.
PY - 2021/2
Y1 - 2021/2
N2 - Background: Despite improved health, shorter stature is common in cystic fibrosis (CF). We aimed to describe height velocity (HV) and contribution of height-related genetic variants to height (HT) in CF. Methods: HV cohort: standard deviation scores (-Z) for HT, mid-parental height-adjusted HT (MPAH), and HV were generated using our Pediatric Center’s CF Foundation registry data. HV-Z was compared with population means at each age (5–17 y), the relationship of HV-Z with HT-Z assessed, and HT-Z compared with MPAH-Z. GRS cohort: HT genetic risk-Z (HT-GRS-Z) were determined for pancreatic exocrine sufficient (PS) and insufficient (PI) youth and adults from our CF center and their relationships with HT-Z assessed. Results: HV cohort: average HV-Z was normal across ages in our cohort but was 1.5× lower (p < 0.01) for each SD decrease in HT-Z. MPAH-Z was lower than HT-Z (p < 0.001). GRS cohort: HT-GRS-Z more strongly correlated with HT-Z and better explained height variance in PS (rho = 0.42; R2= 0.25) vs. PI (rho = 0.27; R2 = 0.11). Conclusions: Despite shorter stature compared with peers and mid-parental height, youth with CF generally have normal linear growth in mid- and late childhood. PI tempered the heritability of height. These results suggest that, in CF, final height is determined early in life in CF and genetic potential is attenuated by other factors. Impact: Children with CF remain shorter than their healthy peers despite advances in care.Our study demonstrates that children with CF have persistent shorter stature from an early age and fail to reach their genetic potential despite height velocities comparable to those of average maturing healthy peers and similar enrichment in known height increasing single-nucleotide polymorphisms (SNPs).Genetic risk scores better explained variability in pancreatic sufficient than in pancreatic insufficient individuals, suggesting that other modifying factors are in play for pancreatic insufficient individuals with CF.Given the CF Foundation’s recommendation to target not only normal body mass index, but normal height percentiles as well, this study adds valuable insight to this discussion.
AB - Background: Despite improved health, shorter stature is common in cystic fibrosis (CF). We aimed to describe height velocity (HV) and contribution of height-related genetic variants to height (HT) in CF. Methods: HV cohort: standard deviation scores (-Z) for HT, mid-parental height-adjusted HT (MPAH), and HV were generated using our Pediatric Center’s CF Foundation registry data. HV-Z was compared with population means at each age (5–17 y), the relationship of HV-Z with HT-Z assessed, and HT-Z compared with MPAH-Z. GRS cohort: HT genetic risk-Z (HT-GRS-Z) were determined for pancreatic exocrine sufficient (PS) and insufficient (PI) youth and adults from our CF center and their relationships with HT-Z assessed. Results: HV cohort: average HV-Z was normal across ages in our cohort but was 1.5× lower (p < 0.01) for each SD decrease in HT-Z. MPAH-Z was lower than HT-Z (p < 0.001). GRS cohort: HT-GRS-Z more strongly correlated with HT-Z and better explained height variance in PS (rho = 0.42; R2= 0.25) vs. PI (rho = 0.27; R2 = 0.11). Conclusions: Despite shorter stature compared with peers and mid-parental height, youth with CF generally have normal linear growth in mid- and late childhood. PI tempered the heritability of height. These results suggest that, in CF, final height is determined early in life in CF and genetic potential is attenuated by other factors. Impact: Children with CF remain shorter than their healthy peers despite advances in care.Our study demonstrates that children with CF have persistent shorter stature from an early age and fail to reach their genetic potential despite height velocities comparable to those of average maturing healthy peers and similar enrichment in known height increasing single-nucleotide polymorphisms (SNPs).Genetic risk scores better explained variability in pancreatic sufficient than in pancreatic insufficient individuals, suggesting that other modifying factors are in play for pancreatic insufficient individuals with CF.Given the CF Foundation’s recommendation to target not only normal body mass index, but normal height percentiles as well, this study adds valuable insight to this discussion.
UR - http://www.scopus.com/inward/record.url?scp=85084417450&partnerID=8YFLogxK
U2 - 10.1038/s41390-020-0940-4
DO - 10.1038/s41390-020-0940-4
M3 - Article
C2 - 32386398
AN - SCOPUS:85084417450
SN - 0031-3998
VL - 89
SP - 653
EP - 659
JO - Pediatric research
JF - Pediatric research
IS - 3
ER -