GC1f Vitamin D Binding Protein Isoform as a Marker of Severity in Autism Spectrum Disorders

Abstract

Autism spectrum disorders (ASD) are characterized by a wide spectrum of clinical, behavioral, and cognitive manifestations. It is, therefore, crucial to investigate possible biomarkers associated with specific ASD phenotypes. Ample literature suggests a possible role for vitamin D (VD) in influencing ASD clinical phenotypes. We analyzed three vitamin D binding protein gene (DBP) functional polymorphisms (rs2282679, rs7041, and rs4588), which are involved in the modulation of vitamin D serum concentration in 309 ASD children and 831 healthy controls. Frequency comparisons of single nucleotide polymorphisms (SNPs) alleles, genotypes, and GC isoforms (GC1f, G1s, and GC2)—generated by the combination of rs7041 and rs4588 alleles—were correlated with ASD diagnostic, behavioral, and functioning scales. The GC1f isoform was significantly more frequent in ASD compared with controls (18.6% vs. 14.5% pc = 0.02). Significantly higher scores for item 15 of the Childhood Autism Rating Scale (CARS) and lower ones for the Children’s Global Assessment Scale (CGAS) functioning scales were seen in ASD carrying the GC1f isoform. In GC phenotype analysis, a gradient of severity for overall CARS scores and CARS item 15 was observed, with scores decreasing according to the presence of GC1f-GC1f > GC1f-GC1s > GC1s-GC1s > GC1f-GC2 > GC2-GC2 isoforms. Similarly, lower CGAS scores were seen in carriers of the GC1f-GC1f isoform, whereas higher scores were present in those carrying GC2-GC2 (p = 0.028). This is the first study to evaluate possible relationships between GC variants and the different aspects of ASD in Italian ASD children. Results, although needing to be validated in ampler cohorts, suggest that the GC1f isoform could be a marker of severity in ASD that may be useful in establishing the intensity of therapeutic and rehabilitative protocols.

Vitamin D and Child Neurodevelopment—A Post Hoc Analysis

“…Other studies have suggested that VDBP genotypes may play a role in neurodevelopmental disorders. For example, a recently published study shows associations between the VDBP genotype, specifically the presence of the Gc1f allele, and the worsening severity of autism spectrum disorder [25]. The present study is consistent with findings from this previous study and lends support to the idea that VDBP genotype may be implicated as a factor affecting various neurodevelopmental disorders.…”

“…Among children who received the recommended daily allowance of vitamin D in their diet, those with the Gc1s allele had the highest concentrations of circulating 25(OH)D, while those with the Gc1f allele were more likely to be vitamin D insufficient [24]. One recently published paper showing associations between VDBP genotype, specifically the presence of the Gc1f allele, and worsening severity of autism spectrum disorder suggests a link between VDBP genotype and neurodevelopment [25]. However, the potential link between VDBP genotype and neurodevelopment is not fully understood.…”

Between Dysbiosis, Maternal Immune Activation and Autism: Is There a Common Pathway?

“…DBP is encoded by the GC gene and involves different polymorphisms, which results in the binding of different vitamin D metabolites in the blood, regulation of serum concentration, and distribution in the body. Bolognesi et al showed that the occurrence of GC1f genotype was more probable in ASD-diagnosed individuals, as well as with worse clinical symptoms [ 231 ]. While acknowledging the limitations of this study, it is important to emphasize the need for more extensive investigations involving larger groups of both patients and controls, since this research area holds promise for the discovery of genetic markers associated with specific ASD phenotypes.…”

Vitamin D binding protein in psychiatric and neurological disorders: Implications for diagnosis and treatment

“…The occurrence of the GC1F variant, whether in the homozygous or heterozygous state, was discovered to be linked to heightened clinical symptoms of autism spectrum disorder and decreased overall functioning. 67 Yee et al observed that a comparative analysis of 31 individuals experiencing their initial episode of psychosis and exhibiting symptoms such as positive syndrome, negative syndrome, excitement, depression, or cognitive impairment, showed elevated levels of VDBP in contrast to controls. 68 …”