Gene Variant May Increase Autism Risk

Megan Brooks

October 21, 2011

October 21, 2011 — Pregnant women who carry a particular variation in the MET gene are more likely to produce autoantibodies to the brains of their developing fetus, increasing their risk of having a child with autism, new research shows.

Dr. Judy Van de Water

"While the notion that maternal antibodies to fetal brain proteins are specifically associated with autism is not new, the fact that we have identified a potential risk factor for producing those antibodies is novel," Judy Van de Water, PhD, an immunologist and co–principal investigator from the University of California, Davis, MIND Institute, told Medscape Medical News.

"This is the first study to link a genetic susceptibility factor previously identified to be associated with autism risk and a known immune risk factor specifically associated with autism. Further, it defines a mechanistic pathway to explore further regarding how the autoantibodies are generated," Dr. Van de Water explained.

Harvey S. Singer, MD, from the Johns Hopkins University School of Medicine in Baltimore, Maryland, who was not involved in the research, noted that research from several laboratories, including his own, has suggested a role for maternal antibodies as a cause for autism in some individuals.

"One question that follows is why mothers would produce antibodies that cross-react against fetal brain. Suggestions have included microchimerism, and now in the Van de Water paper a possible genetic alteration," Dr. Singer said.

The Culprit

For the study, Dr. Van de Water and colleagues examined the action of the MET receptor tyrosine kinase, previously linked to risk for autism spectrum disorder (ASD), in 202 mothers of children with autism and 163 mothers of typically developing children. The participants are enrolled in the Northern California–based Childhood Autism Risks from Genetics and the Environment study.

In a report published online October 18 in Translational Psychiatry, the investigators report that the functional MET promotor variant rs1858830 C allele was strongly associated with the presence of an ASD-specific 37+73-kDa band pattern of maternal autoantibodies to fetal brain proteins (P = .003).

This particular band pattern was present in 9% of the mothers (19/202) of children with an ASD and none of the 163 mothers of typically developing children.

The MET C allele was also associated with decreased expression of MET protein in the immune system (peripheral blood mononuclear cells). This could lead to more intense and prolonged immune response when cells are activated as a result of bacteria or virus exposure, the researchers say.

The study also provides evidence, they add, that women harboring the MET C allele are deficient in interleukin 10, a crucial immunoregulatory protein, and that this may leave them more susceptible to prolonged inflammatory conditions.

Screening Test?

"Our future studies will include expansion of this study to better understand all of the immunologic pathways involved, and to better understand what the triggering factors are that lead to maternal antibody–associated autism," said Dr. Van de Water.

"The most obvious clinical implications for us," she added, "are the identification of risk factors that we can test for prior to pregnancy. The second implication is development of a treatment that can be administered when faced with this risk factor. Can we someday use immune therapeutics to prevent autism? We will fully explore this possibility."

The authors have disclosed no relevant financial relationships.

Transl Psychiatry. Published online October 18, 2011. Full text

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