Investigation of Liver X Receptor Gene Variants and Oxysterol Dysregulation in Autism Spectrum Disorder

The NR1H2 gene produces the Liver X Receptor Beta (LXRB) protein, which is crucial for brain cholesterol metabolism and neuronal development. However, its involvement in autism spectrum disorder (ASD) remains largely unexplored, aside from animal studies. This study is the first to explore the potential link between autism and rs2695121/rs17373080 single nucleotide polymorphisms (SNPs) in the regulatory regions of NR1H2, known for their association with neuropsychiatric functions. Additionally, we assessed levels of oxysterols (24-Hydroxycholesterol, 25-Hydroxycholesterol, 27-Hydroxycholesterol), crucial ligands of LXR, and lipid profiles. Our cohort comprised 107 children with ASD and 103 healthy children aged 2-18 years. Clinical assessment tools included the Childhood Autism Rating Scale, Autistic Behavior Checklist, and Repetitive Behavior Scale-Revised. Genotyping for SNPs was conducted using PCR-RFLP. Lipid profiles were analyzed with Beckman Coulter kits, while oxysterol levels were determined through liquid chromatography-tandem mass spectrometry. Significantly higher total cholesterol (p = 0.003), LDL (p = 0.008), and triglyceride (p < 0.001) levels were observed in the ASD group. 27-Hydroxycholesterol levels were markedly lower in the ASD group (p ≤ 0.001). ROC analysis indicated the potential of 27-Hydroxycholesterol to discriminate ASD diagnosis. The SNP genotype and allele frequencies were similar in both groups (p > 0.05). Our findings suggest that disturbances in oxysterol metabolism, previously linked to neurodegeneration, may constitute a risk factor for ASD and contribute to its heterogeneous phenotype.