ESPE Abstracts

Background: EPIGROW was a prospective European epidemio-genetic study in children with idiopathic short stature (ISS).

Objectives: To identify (1) differences in frequencies of single nucleotide polymorphisms (SNPs) in growth related genes between ISS children and controls, and (2) associations between growth characteristics, IGF status and SNPs in these genes.

Methods: Sequence data from EPIGROW was used to determine the difference in frequencies of SNPs/Indels in each of the 232 candidate genes between patients and controls. SNP/indel frequency was assessed for carriage of homozygous + heterozygous variants v wild type. To assess the genotype/phenotype relationships in the cases, we used PLINK, a whole genome association analysis toolset based on haplotype, a minimum allele frequency >2%, genotype present in >75% cases and a Hardy Weinberg equilibrium of 0.01. A Benjamini Hochberg corrected P value ≤0.05 was considered significant.

Results: About 30 genes were identified where SNP carriage frequencies were different (P ≤0.05). In ISS SNP frequencies were increased in 12 genes and decreased in 18. These included IGFALS(↓), HRAS(↑), STAT5b(↓) and FANCA(↓) which are associated with short stature conditions, MAP2K1(↑) and A2M(↓) associated with growth pathways and SDR16C5(↑) associated with adult height. In PLINK analyses, one SNP in A2M (Chr 12: 9154319, P=0.02) was associated with sitting height (SD score in those carrying a variant was −4.0 v −2.6 in wt), one SNP in DNM3 (Chr1: 170643255, P=0.05) with head circumference and one SNP in TP63 (Chr3: 191073565, P=0.05) associated with IGF-I levels.

Conclusion: A number of genes, including those known to cause short stature, carry different frequencies of variants in ISS compared to controls, while specific SNPs are related to phenotype. Notably, the A2M gene (alpha-2-macroglobulin, a protease inhibitor and cytokine transporter) was identified in both analyses, and could have a role in causing short stature.