Macrophage migration inhibitory factor and autism spectrum disorders.
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.
Grigorenko
Elena L
EL
Child Study Center, Department ofPsychology, Yale University, New Haven, Connecticut 06519, USA. elena.grigorenko@yale.edu
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
D000483:Alleles; D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics*; D008297:Male; D015999:Multivariate Analysis; D009426:Netherlands; D010375:Pedigree; D011110:Polymorphism, Genetic; D011379:Prognosis; D014481:United States
D008263:Macrophage Migration-Inhibitory Factors