title: An HLA-G(∗)14bp insertion/deletion polymorphism associates with the development of autistic spectrum disorders.
abstract: HLA-G expressed by the trophoblast ligates KIR molecules expressed by maternal NK cells at the uterine fetal/maternal interface: this interaction is involved in generating immune tolerance during pregnancy. A 14-bp insertion in the HLA-G 3'-UTR associates with significantly reduced levels of both HLA-G mRNA and soluble HLA-G, thus hampering the efficacy of HLA-G-mediated immune tolerance during pregnancy. Because prenatal immune activation is suggested to play an important role in the onset of autistic spectrum disorders (ASD) we performed an in-depth evaluation of HLA-G polymorphisms in a well-characterized cohort of Italian families of ASD children. Results showed that frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls (p<0.05 in all cases); analysis of the frequency of transmission of the 14bp+ allele from parents to ASD children and their non-ASD siblings showed that the 14bp+ allele was more frequently transmitted (T) to ASD children, whereas it was preferentially not transmitted (NT) to the non-ASD siblings (overall discrepancy: p=0.02; OR: 2.6, 95% CI: 1.1-6.4). Results herein suggest that HLA-G polymorphisms are associated with ASD development, possibly as a consequence of prenatal immune activation. These data infer that the immune alterations seen in ASD are associated with the maternal-fetal interaction alone, and reinforce the observation that different genetic backgrounds characterize ASD children and their non-ASD siblings.
authors.affiliation: Don C. Gnocchi Foundation IRCCS, Milan, Italy. Electronic address: fguerini@dongnocchi.it.
authors.forename: Franca R
authors.initials: FR
authors.lastname: Guerini
authors.affiliation: Don C. Gnocchi Foundation IRCCS, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bolognesi
authors.affiliation: Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Chiappedi
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna and Associazione Nazionale Famiglie di Persone con Disabilitá Intellettiva e/o Relazionale (ANFFAS), Macerata, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ghezzo
authors.affiliation: Department of Health Sciences, University of Milano, Milan, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Canevini
authors.affiliation: Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Martina M
authors.initials: MM
authors.lastname: Mensi
authors.affiliation: Department of Health Sciences, University of Milano, Milan, Italy.
authors.forename: Aglaia
authors.initials: A
authors.lastname: Vignoli
authors.affiliation: Don C. Gnocchi Foundation IRCCS, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Agliardi
authors.affiliation: Don C. Gnocchi Foundation IRCCS, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Zanette
authors.affiliation: Don C. Gnocchi Foundation IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milano, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D059951:HLA-G Antigens / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D007558:Italy; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
chemical_list: D020413:3' Untranslated Regions; D059951:HLA-G Antigens
keywords: Autistic spectrum disorder; Genetic polymorphism; HLA; HLA-G; Immune activation; Immune system; In utero immunology; KIR; NK cells