Genetic Polymorphisms Associated with Idiopathic Short Stature and First-Year Response to Growth Hormone Treatment.
BACKGROUND/AIMS
The term idiopathic short stature (ISS) describes short stature of unknown, but likely polygenic, etiology. This study aimed to identify genetic polymorphisms associated with the ISS phenotype, and with growth response to supplemental GH.


METHODS
Using a case-control analysis we compared the prevalence of "tall" versus "short" alleles at 52 polymorphic loci (17 in growth-related candidate genes, 35 identified in prior genome-wide association studies of adult height) in 94 children with ISS followed in the Genetics and Neuroendocrinology of Short Stature International Study, versus 143 controls from the Fels Longitudinal Study.


RESULTS
Four variants were nominally associated with ISS using a genotypic model, confirmed by a simultaneous confident inference approach: compared with controls children with ISS had lower odds of "tall" alleles (odds ratio, 95% CI) for GHR (0.52, 0.29-0.96); rs2234693/ESR1 (0.50, 0.25-0.98); rs967417/BMP2 (0.39, 0.17-0.93), and rs4743034/ZNF462 (0.40, 0.18-0.89). Children with ISS also had lower odds of the "tall" allele (A) at the IGFBP3 -202 promoter polymorphism (rs2855744; 0.40, 0.20-0.80) in the simultaneous confident inference analysis. A significant association with 1st-year height SD score increase during GH treatment was observed with rs11205277, located near 4 known genes: MTMR11, SV2A, HIST2H2AA3, and SF3B4; the latter, in which heterozygous mutations occur in Nager acrofacial dysostosis, appears the most relevant gene.


CONCLUSIONS
In children with ISS we identified associations with "short" alleles at a number of height-related loci. In addition, a polymorphic variant located near SF3B4 was associated with the GH treatment response in our cohort. The findings in our small study warrant further investigation.
['Quigley|Charmian A|CA|', 'Li|Ying Grace|YG|', 'Brown|Milton R|MR|', 'Pillai|Sreekumar G|SG|', 'Banerjee|Poulabi|P|', 'Scott|Robin S|RS|', 'Blum|Werner F|WF|', 'Parks|John S|JS|']
D000293:Adolescent D002648:Child D005260:Female D005500:Follow-Up Studies D056426:Genetic Loci D055106:Genome-Wide Association Study D006130:Growth Disorders D019382:Human Growth Hormone D006801:Humans D008137:Longitudinal Studies D008297:Male D011110:Polymorphism, Genetic
Idiopathic short stature Height Genetic variant Growth hormone response Single nucleotide polymorphism