Circulating asparagine and short stature: A case-control study and exploratory two-sample Mendelian randomization analysis.

Short stature is phenotypically heterogeneous, and the role of circulating amino acids remains unclear. We compared plasma asparagine concentrations in children with short stature and healthy controls and examined genetically predicted circulating metabolites using two-sample Mendelian randomization (MR). We included 96 children with a clinical record diagnosis of short stature and 96 healthy controls. Plasma asparagine was measured by enzyme-linked immunosorbent assay, and the 2 groups were compared using the Mann-Whitney U test. Summary statistics for 1091 plasma metabolites and 309 metabolite ratios were screened against a European-ancestry short-stature outcome using two-sample MR. Benjamini-Hochberg false discovery rate correction was applied across 1400 inverse-variance weighted tests. Median plasma asparagine was 54.80 ng/L (interquartile range = 50.38-64.60) in children with short stature and 84.06 ng/L (71.00-95.35) in controls (P < .001). Five metabolite exposures met the nominal inverse-variance weighted threshold and sensitivity filters. Genetically predicted plasma free asparagine was inversely associated with short stature (odds ratio = 0.565; 95% confidence interval = 0.420-0.759; P = .00015; q = .106). None of the 1400 tests met q < .10. Children with short stature had lower plasma asparagine than controls. The MR estimate was in the same direction but did not survive multiple-testing correction. These data do not establish causality or support asparagine supplementation.