The human leukocyte antigen (HLA) genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases. Interestingly, it has been reported that autism subjects often have associations with HLA genes/haplotypes, suggesting an underlying dysregulation of the immune system mediated by HLA genes. Genetic studies have only succeeded in identifying autism-causing genes in a small number of subjects suggesting that the genome has not been adequately interrogated. Close examination of the HLA region in autism has been relatively ignored, largely due to extraordinary genetic complexity. It is our proposition that genetic polymorphisms in the HLA region, especially in the non-antigen-presenting regions, may be important in the etiology of autism in certain subjects.

Studies suggest genetic polymorphisms may increase an individual’s susceptibility to CP. Most findings have yet to be corroborated in an independent cohort. This case-control study is nested within all 334,333 infants ≥ 36 weeks gestation born at Kaiser Permanente Medical Care Program, 1991–2002. We included only non-Hispanic whites who had a neonatal blood sample available. Case patients (N=138) were identified from medical records to have spastic or dyskinetic CP. Controls (N=165) were randomly selected from the population. We genotyped polymorphisms previously associated with CP: inducible nitric oxide synthase (iNOS) -231, apolipoprotein E (apoE) ε2 and ε4 alleles, tumor necrosis factor-α -308, interleukin-8 -251, lymphotoxin 60, endothelial nitric oxide synthase -922, endothelial protein C receptor 219, mannose binding lectin 54 and 52, factor V Leiden, methyltetrahydrofolate reductase 1298 and 667, prothrombin 20210, and platelet activator inhibitor 11053. Similar to previous reports, the iNOS -231 T allele (25.7% vs. 18.9%, P=0.04) and the apoE ε4 allele (19.3% vs. 13.2%, P=0.04) were more common in patients with CP than in controls. However, there was no statistically significant association between any genetic polymorphism and CP after correction for multiple comparisons.

Background

Research indicates that the etiology of autism has a strong genetic component, yet so far the search for genes that contribute to the disorder, including several whole genome scans, has led to few consistent findings. However, three studies indicate that the complement C4B gene null allele (i.e. the missing or nonfunctional C4B gene) is significantly more frequent in individuals with autism. Due to the close proximity of the CYP21A2 gene to the C4B locus (3 kb) it was decided to examine samples from autistic subjects, including many with known C4B null alleles for common CYP21A2 mutations.

Methods

Samples from subjects diagnosed with autism and non-autistic controls (controls) previously typed for C4B null alleles were studied. Allele specific polymerase chain reaction (PCR) methods were used to determine 8 of the most common CYP21A2 genetic mutations, known to completely or partially inhibit 21-hydroxylase, the enzyme encoded by the CYP21A2 gene.

Results

Although the combined autism and control study subjects had 50 C4B null alleles only 15 CYP21A2 mutations were detected in over 2250 genotypes. Eight mutations were detected in the autistic samples and 7 in the controls. The frequency of CYP21A2 mutations was similar between the autism and control samples. Only one individual (autistic) carried a chromosome containing both C4B null allele and CYP21A2 mutations.

Background

There appears to be a significant increase in the prevalence rate of autism. Reasons for the increase are unknown, however, there is a substantial body of evidence that suggests the etiology involves infections of the pregnant mother or of a young child. Most infections result in fever that is routinely controlled with antipyretics such as acetaminophen. The blocking of fever inhibits processes that evolved over millions of years to protect against microbial attack. Immune mechanisms in the central nervous system are part of this protective process.

Hypothesis

The blockage of fever with antipyretics interferes with normal immunological development in the brain leading to neurodevelopmental disorders such as autism in certain genetically and immunologically disposed individuals.

Testing the hypothesis

Epidemiological studies to determine associations between the use of antipyretics and neurodevelopmental disorders should be undertaken. Biochemical tests will involve the examination of fluids/serum by mass spectrometry and the determination of cytokine/chemokine levels in serum and cell culture fluids after stimulation with fever-inducing molecules from bacteria, viruses and yeast. Postmortem brain can be examined by immunohistochemistry or other methods such as fluorescent in situ hybridization (FISH) to determine altered expression levels of chemokines/cytokines and other molecules.

Implications of the hypothesis

1) The use of antipyretics during pregnancy or in young children may be reserved for more severe fevers. 2) The perplexing genetic findings in autism may be better understood by categorizing genes along functional pathways. 3) New treatments based on immune, cell, pharmacological or even heat therapies may be developed.