Original articleTachykinin 1 (TAC1) gene SNPs and haplotypes with autism: A case-control study
Introduction
Autism is a neurodevelopmental disorder characterized by early onset of the three cardinal symptoms: disturbance of social interaction, atypical language development, and restricted, repetitive, stereotyped patterns of behavior and interests [1]. The genetic involvement of autism has been supported by its higher concordance rates for monozygotic twins than for dizygotic [2], [3] and the several chromosomal loci possibly linked to autism, including 7q22-q31 [1].
Glutamate is one of the neurochemicals speculated to contribute to the pathogenesis of autism, because (1) there are many similarities between the symptoms evoked by glutamate antagonist treatment and the symptoms of autism found in several human and animal studies [4]; (2) several neuropathological and brain-imaging studies of autistic patients have shown involvement of the cerebral regions where glutamatergic neurons originate [4]; (3) the mRNA levels of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor increases in autistic subjects [5]; (4) the aspartate/glutamate carrier SLC25A12 gene and metabotropic glutamate receptor 8 gene have been reported to be associated with autism [6], [7].
In this study, we focused on the Tachykinin 1 gene (TAC1; MIM162320) because it is located in 7q21-q22 and encodes a precursor containing substance P and other neurokinins (Neurokinin A, Neurokinin K, and Neuropeptide γ) [8], some of which are implicated in the modulation of glutamate-driven neurotransmission and excitotoxicity in the basal forebrain and other CNS regions [9]. Moreover, TAC1 mutant mice are less sensitive to nociceptive stimulation, which reminds us of some autistic patients ignorant of pain [4], [11]. An increase in proinflammatory cytokines and the activation of microglia and astrocytes in the brain of autistic patients may be also associated with the inflammatory responses of TAC1 products [12].
Based on TAC1 biological information and its chromosomal location, we considered the gene worth analyzing as one of the autism candidate genes. In the present study, we tested for the presence of an association of three single nucleotide polymorphisms (SNPs) of TAC1, and haplotypes consisting of the SNPs, with autism, using case-control design.
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Subjects and methods
The patients comprised 170 unrelated Japanese with autism (147 males and 23 females, mean age = 20.8 years within a range of 3–41 years). The patients were recruited from the outpatient clinics of the departments of psychiatry, Tokyo University Hospital and Tokai University Hospital, and seven daycare facilities for subjects with developmental disorders. All the hospitals and facilities were located around Tokyo. All the subjects met the DSM-IV criteria for autistic disorder. The diagnoses were
Results
The allele frequencies of the SNPs of the TAC1 gene are summarized in Table 1. No significant difference was observed in genotypic distributions (not shown in the tables) or allele frequencies of the three markers of the TAC1 gene between patients and controls. The minor allele frequencies of the SNPs were higher than 19% in all three SNPs. For all assayed SNPs, none of the SNPs deviated from Hardy–Weinberg equilibrium.
The pair-wise D′ and r2 values of the SNPs within the TAC1 gene are
Discussion
We genotyped three SNPs within the TAC1 gene. No association was found in the allele and haplotype distributions between autistic patients and normal controls.
The 95% confidence intervals of the odds ratios were within 0.66 and 1.49 in all three SNPs of the gene. Considering the sample size and minor allele frequencies in the present study, our results might have adequate statistical power (>0.8) to contradict the effects of the gene with odds ratios of approximately 1.7 or more.
The TAC1 gene
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