HLA-class II haplotypes and Autism Spectrum Disorders

Meriem Bennabi,Ryad Tamouza,Wahid Boukouaci,Richard Delorme,Céline Manier,Rajagopal Krishnamoorthy,Nassima Si Mohammed,Djaouida Bengoufa,Marion Leboyer,Alexandru Gaman,Dominique Charron,Isabelle Scheid

doi:10.1038/s41598-018-25974-9

Abstract

Infections and autoimmunity are associated with autism spectrum disorders (ASD), with both strongly influenced by the genetic regulation of the human leukocyte antigen (HLA) system. The relationship between ASD and the HLA genetic diversity requires further investigation. Using a case control design, the distribution of HLA class II-DRB1 and DQB1 alleles, genotypes and haplotypes were investigated in ASD patients, versus healthy controls (HC). ASD patients meeting DSM-IV TR criteria and HC (474 and 350 respectively) were genotyped at medium resolution using a Luminex-based SSO technology. Comparisons of genotypes, allele frequencies associated with a haplotype analysis were performed. Results indicate: (i) the HLA-DRB1 *11-DQB1*07 haplotype was more prevalent in ASD patients, versus HC (Pc = 0.001), partially replicating previous data and possibly linking to gastro-intestinal (GI)-related pro-inflammatory processes, given that this haplotype associates with pediatric celiac disorders; (ii) the HLA-DRB1 *17-DQB1*02 haplotype was higher in HC, versus ASD patients (Pc = 0.002), indicating that this is a protective haplotype. Using the Autism Diagnostic Interview to assess clinical dimensions, higher scores on social (Pc = 0.006) and non-verbal functioning (Pc = 0.004) associated with the DRB1 *11 DQB1*07 haplotype. Our results support HLA involvement in ASD, with possible relevance to GI and gut-brain axis dysregulation.

Highlights

Autism Spectrum Disorders (ASD) are heterogeneous neurodevelopmental disorders characterized by deficits in social communication as well as by repetitive patterns of behaviors and interests[1]
Whilst no statistically significant differences at allele (Table 2) and genotype level were evident, the analysis of Human leukocyte antigen (HLA)-class II haplotype distribution showed that the HLA-DRB1 *11-DQB1*07 haplotype was more prevalent in autism spectrum disorders (ASD) patients, versus healthy controls (HC) (14.5% vs 8.7% respectively; Pc = 0.001) (Table 3)
We found that the frequency of the class II HLA-DRB1 *17-DQB1*02 haplotype was significantly higher in HC, versus ASD patients (13.1% vs 9.2% respectively; Pc = 0.002), thereby indicative of a protective haplotype (Table 3)

Summary

Introduction

Autism Spectrum Disorders (ASD) are heterogeneous neurodevelopmental disorders characterized by deficits in social communication as well as by repetitive patterns of behaviors and interests[1]. In order to provide additional information as to the role of HLA in ASD, we undertook a case-control study to more precisely explore the polymorphisms of the HLA class II loci, at allele, genotype and haplotype levels, using standardized molecular techniques. HLA class II haplotype distribution in ASD subjects and healthy controls.

Results

Conclusion