Rare VDR variant rs1338135647 and lower vitamin D levels in autism spectrum disorder: An exploratory case-control study in Indonesian children.
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition arising from interactions between genetic susceptibility and environmental factors, including vitamin D status. This study investigated the associations of serum vitamin D levels and vitamin D receptor (VDR) gene variants with ASD in Indonesian children. This exploratory case-control study included 80 children aged 24-59 months from Surabaya, Indonesia, comprising 40 children with ASD and 40 typically developing controls. Serum 25-hydroxyvitamin D3 (25[OH]D3) concentrations were measured using an enzyme-linked immunosorbent assay, while the VDR region containing rs731236 was amplified by polymerase chain reaction and analyzed using bidirectional Sanger sequencing. Sequencing additionally identified rs11574113, rs7975232, and the rare missense variant rs1338135647 (p.Gly375Asp). Children with ASD had lower serum 25(OH)D3 concentrations than controls (median, 46.13 vs 69.27 ng/mL; p = 0.027), and the difference remained significant after adjustment for age and sex (adjusted median difference, -24.86 ng/mL; 95% confidence interval [CI], -42.42 to -7.30; p = 0.007). The rs1338135647 AG genotype was more frequent in children with ASD than in controls (22.5% vs 2.5%) and remained associated with ASD after adjustment for age and sex using Firth penalized logistic regression (odds ratio, 6.44; 95% CI, 1.21-67.64; p = 0.028). No significant associations were observed for the other VDR variants. Lower vitamin D levels and the rare rs1338135647 variant may independently co-occur with ASD in Indonesian children; however, these hypothesis-generating findings require replication and functional validation in larger independent cohorts.