Published online August 1, 2008
PEDIATRICS Vol. 122 No. 2 August 2008, pp. e438-e445 (doi:10.1542/peds.2007-3604)

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ARTICLE

Macrophage Migration Inhibitory Factor and Autism Spectrum Disorders

Elena L. Grigorenko, PhD^a,b,c,d, Summer S. Han, MPhil^e, Carolyn M. Yrigollen, BS^a, Lin Leng, PhD^c,f, Yuka Mizue, PhD^g, George M. Anderson, PhD^a, Erik J. Mulder, MD, PhD^h, Annelies de Bildt, MD^h, Ruud B. Minderaa, MD, PhD^h, Fred R. Volkmar, MD^a,b, Joseph T. Chang, PhD^e, Richard Bucala, MD, PhD^c,f

^a Child Study Center and Departments of
^b Psychology
^c Epidemiology and Public Health
^e Statistics
^f Internal Medicine and Pathology, Yale University, New Haven, Connecticut
^d Department of Psychology, Moscow State University, Moscow, Russia
^g Sapporo Immuno Diagnostic Laboratory, Sapporo, Japan
^h Accare/University Medical Center Groningen, University Center for Child and Adolescent Psychiatry, Groningen, Netherlands

OBJECTIVE. Autistic spectrum disorders are childhood neurodevelopmental disorders characterized by social and communicative impairment and repetitive and stereotypical behavior. Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity that promotes monocyte/macrophage-activation responses by increasing the expression of Toll-like receptors and inhibiting activation-induced apoptosis. On the basis of results of previous genetic linkage studies and reported altered innate immune response in autism spectrum disorder, we hypothesized that MIF could represent a candidate gene for autism spectrum disorder or its diagnostic components.

METHODS. Genetic association between autism spectrum disorder and MIF was investigated in 2 independent sets of families of probands with autism spectrum disorder, from the United States (527 participants from 152 families) and Holland (532 participants from 183 families). Probands and their siblings, when available, were evaluated with clinical instruments used for autism spectrum disorder diagnoses. Genotyping was performed for 2 polymorphisms in the promoter region of the MIF gene in both samples sequentially. In addition, MIF plasma analyses were conducted in a subset of Dutch patients from whom plasma was available.

RESULTS. There were genetic associations between known functional polymorphisms in the promoter for MIF and autism spectrum disorder–related behaviors. Also, probands with autism spectrum disorder exhibited higher circulating MIF levels than did their unaffected siblings, and plasma MIF concentrations correlated with the severity of multiple autism spectrum disorder symptoms.

CONCLUSIONS. These results identify MIF as a possible susceptibility gene for autism spectrum disorder. Additional research is warranted on the precise relationship between MIF and the behavioral components of autism spectrum disorder, the mechanism by which MIF contributes to autism spectrum disorder pathogenesis, and the clinical use of MIF genotyping.

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Key Words: autism spectrum disorder • ASD • MIF • neurodevelopmental disorders • genetic association • genetic polymorphisms • immunologic insult

Abbreviations: ASD—autism spectrum disorder • CNS—central nervous system • MIF—macrophage migration inhibitory factor • SNP—single-nucleotide polymorphism • ADI—Autism Diagnostic Interview • ADOS—Autism Diagnostic Observational Schedule

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Accepted Mar 27, 2008.

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