Genetic potential and height velocity during childhood and adolescence do not fully account for shorter stature in cystic fibrosis

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 1.5x 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; R-2= 0.25) vs. PI (rho = 0.27; R-2 = 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.

Automated summary

Despite improvements in health, shorter stature remains common in cystic fibrosis (CF). Youth with CF generally experience normal linear growth in mid- and late childhood compared to their peers and mid-parental height. Pancreatic insufficiency plays a role in tempering the heritability of height in CF individuals. Genetic risk scores provide better insight into height variability in pancreatic sufficient individuals compared to pancreatic insufficient individuals, suggesting additional factors influence height outcomes in CF.