HLA-G coding region polymorphism is skewed in autistic spectrum disorders

Area of Science:

• Immunogenetics
• Neurodevelopmental Disorders

Background:

• Pregnancy involves complex immune interactions, with Human Leukocyte Antigen-G (HLA-G) playing a key role in maternal-fetal tolerance.
• Prenatal immune activation is hypothesized to contribute to the etiology of autistic spectrum disorders (ASD).

Purpose of the Study:

• To investigate the association between HLA-G allelic polymorphism and ASD in an Italian cohort.
• To explore potential links between HLA-G gene variants, immune responses during pregnancy, and ASD development.

Main Methods:

• DNA sequencing of HLA-G exons 2, 3, and 4 was performed on Italian children with ASD, their mothers, and healthy siblings.
• Allelic frequencies were compared to control groups from Brazil and Denmark.
• Statistical analyses, including p-values and odds ratios (OR) with 95% confidence intervals (CI), were used to assess significant differences.

Main Results:

• Significant differences in HLA-G allele distribution were observed between ASD children and both control groups.
• HLA-G*01:01 was significantly less frequent (p_c=1×10^-4; OR:0.5) and HLA-G*01:05N was significantly more frequent (p_c=2×10^-3; OR:7.3) in ASD children compared to controls.
• ASD mothers showed an HLA-G distribution similar to women with recurrent miscarriages, suggesting a link to pregnancy-related immune dysregulation.

Conclusions:

• Specific HLA-G alleles are associated with ASD, potentially through modulation of maternal-fetal immune interactions.
• An immune-activating prenatal environment, indicated by certain HLA-G variants, may be linked to ASD development.
• Findings suggest a parallel between immune profiles in ASD and recurrent miscarriage, highlighting the role of immune factors in both conditions.