Study design: An association study to comprehensively clarify variations of genetic determinants of peak height velocity (PHV) during puberty in adolescent idiopathic scoliosis (AIS).
Objective: To investigate whether the genetic determinants of timing and magnitude of PHV during puberty are associated with the susceptibility or curve progression of the female patients with AIS.
Summary of background data: An involvement of abnormal pubertal growth pattern in the etiopathogenesis of AIS has been implicated in previous studies. However, there is no clear consensus on the anthropometric variations of stature or growth rate. The recent advance in the longitudinally identified genetic determinants of PHV offers new opportunities to facilitate analysis of the association of pubertal growth with the susceptibility or curve severity of AIS.
Methods: A gene-based association study was conducted using 9 single nucleotide polymorphisms (SNPs) in or near SOCS2, SF3B4/SV2A, C17orf67, CABLES1, DOT1L, CDK6, C6orf106, and LIN28B with confirmed association with PHV, peak growth age, or adult height. A total of 500 patients with AIS and 494 age-matched healthy controls were genotyped using the PCR-based Invader assay. Case-control study and case-only study were performed to define the contribution of the 9 SNPs to predisposition and curve severity of AIS.
Results: Strong associations between rs12459350 in DOT1L, rs4794665 in C17orf67, and susceptibility of AIS were found, with the PHV increasing allele G of rs12459350 and PHV/adult height increasing allele A of rs4794665 both being significant predisposition alleles of AIS (P = 0.001 for rs12459350, odds ratio = 1.16, 95% confidence interval = 1.06-1.27; P = 0.006 for rs4794665, odd ratio = 1.33, 95% confidence interval = 1.09-1.62). None of the genotyped SNPs was associated with curve severity in patients with AIS.
Conclusion: Polymorphisms of the rs4794665 in C17orf67 and rs12459350 in DOT1L were associated with combined predisposition to AIS susceptibility and higher pubertal PHV, which strongly mirrored the anthropometric findings of taller pubertal stature and accelerated growth rate described in AIS.