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

Different isoforms of HLA-G protein are endowed with a differential ability to induce allogenic tolerance during pregnancy. As prenatal immune activation is suggested to play a role in the onset of
autistic spectrum disorders (ASD), we evaluated HLA G*01:01-*01:06 allelic polymorphism in a
cohort of Italian children affected by ASD (N=111) their mothers (N=81), and their healthy siblings
(N=39). DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies; alleles distribution was compared with that of two control groups of Caucasoid couples of
multiparous women and their partners from Brazil and Denmark. HLA-G distribution was significantly different in ASD children compared to both control groups (Brazilian pc=1x10-4; Danish
pc=1x10-3). Since HLA-G distribution was similar in the two control groups, their data were pooled.
Results indicated that HLA-G*01:01 was significantly less frequent (pc=1x10-4; OR:0.5, 95%CI:
0.3-0.7) whereas HLA-G*01:05N was significantly more frequent (pc=2x10-3; OR:7.3, 95%CI: 2.4-
26.6) in ASD children compared to combined controls. Finally, no clear pattern emerged when
HLA-G allelic distribution was analyzed in healthy sibs. Notably, HLA-G allelic distribution found
in ASD mothers was similar to that observed in the control subgroup of women with recurrent miscarriages, whilst it was significantly different compared to women without miscarriages (pc=6x10-4
df=12). Since HLA-G*01:01 is associated with the elicitation of KIR-mediated tolerogenic responses and HLA-G*01:05N correlates with NK cells activation, results herein indicate that an immune
activating milieu during pregnancy is more likely observed in association with the development of
ASD, similarly to what occurs in women with recurrent miscarriages