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Macrophage migration inhibitory factor and autism spectrum disorders.

ABSTRACT: 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.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.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.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.

SUBMITTER: Grigorenko EL

PROVIDER: S-EPMC3816765 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Macrophage migration inhibitory factor and autism spectrum disorders.

Grigorenko Elena L EL Han Summer S SS Yrigollen Carolyn M CM Leng Lin L Mizue Yuka Y Anderson George M GM Mulder Erik J EJ de Bildt Annelies A Minderaa Ruud B RB Volkmar Fred R FR Chang Joseph T JT Bucala Richard R

Pediatrics 20080801 2

<h4>Objective</h4>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 a ...[more]

PMID: 18676531

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Project description:Human macrophage migration inhibitory factor (MIF) is a cytokine that plays a role in several metabolic and inflammatory processes. Single nucleotide polymorphism (SNP) -173 G/C (rs755622) on MIF gene has been associated with numerous diseases, such as arthritis and cancer. However, most of the reports concerning the association of MIF with these and other pathologies are inconsistent and remain quite controversial. Therefore, we performed a meta-analysis from 96 case-control studies on -173 G/C MIF SNP and stratified the data according to the subjects geographic localization or the disease pathophysiology, in order to determine a more meaningful significance to this SNP. The polymorphism was strongly associated with an increased risk in autoimmune-inflammatory, infectious and age-related diseases on the dominant (OR: 0.74 [0.58-0.93], P < 0.01; OR: 0.81 [0.74-0.89], P < 0.0001; and OR: 0.81 [0.76-0.87], P < 0.0001, respectively) and the recessive models (OR: 0.74 [0.57-0.095], P < 0.01; OR: 0.66 [0.48-0.92], P < 0.0154; and OR: 0.70 [0.60-0.82], P < 0.0001, respectively). Also, significant association was found in the geographic localization setting for Asia, Europe and Latin America subdivisions in the dominant (OR: 0.76 [0.69-0.84], P < 0.0001; OR: 0.77 [0.72-0.83], P < 0.0001; OR: 0.61 [0.44-0.83], P-value: 0.0017, respectively) and overdominant models (OR: 0.85 [0.77-0.94], P < 0.0001; OR: 0.80 [0.75-0.86], P < 0.0001; OR: 0.73 [0.63-0.85], P-value: 0.0017, respectively). Afterwards, we implemented a network meta-analysis to compare the association of the polymorphism for two different subdivisions. We found a stronger association for autoimmune than for age-related or autoimmune-inflammatory diseases, and stronger association for infectious than for autoimmune-inflammatory diseases. We report for the first time a meta-analysis of rs755622 polymorphism with a variety of stratified diseases and populations. The study reveals a strong association of the polymorphism with autoimmune and infectious diseases. These results may help direct future research on MIF-173 G/C in diseases in which the relation is clearer and thus assist the search for more plausible applications.

Dataset Information

Macrophage migration inhibitory factor and autism spectrum disorders.

Publications

Macrophage migration inhibitory factor and autism spectrum disorders.

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