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1.  HLA Immune Function Genes in Autism 
Autism Research and Treatment  2012;2012:959073.
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.
doi:10.1155/2012/959073
PMCID: PMC3420779  PMID: 22928105
2.  Activating killer-cell immunoglobulin-like receptors (KIR) and their cognate HLA ligands are significantly increased in autism 
Brain, behavior, and immunity  2012;26(7):1122-1127.
Killer-cell immunoglobulin-like receptor (KIR) proteins are expressed on natural killer (NK) cells and appear important in innate and adaptive immunity. There are about 14 KIR genes on chromosome 19q13.4, composed of those that inhibit and those that activate NK cell killing. Haplotypes have different combinations of these genes meaning that not all genes are present in a subject. There are two main classes of cognate human leukocyte antigen (HLA) ligands (HLA-Bw4 and HLA-C1/C2) that bind to the inhibitory/activating receptors. As a general rule, the inhibitory state is maintained except when virally infected or tumor cells are encountered; however, both increased activation and inhibition states have been associated with susceptibility and protection against numerous disease states including cancer, arthritis, and psoriasis.
Utilizing DNA from 158 Caucasian subjects with autism and 176 KIR control subjects we show for the first time a highly significant increase in four activating KIR genes (2DS5, 3DS1, 2DS1 and 2DS4) as measured by chi square values and odds ratios. In addition, our data suggests a highly significant increase in the activating KIR gene 2DS1 and its cognate HLA-C2 ligand (2DS1+C2; p=0.00003 [Odds Ratio=2.87]). This information ties together two major immune gene complexes, the Human Leukocyte Complex and the Leukocyte Receptor Complex, and may partially explain immune abnormalities observed in many subjects with autism.
doi:10.1016/j.bbi.2012.07.014
PMCID: PMC3469320  PMID: 22884899
killer-cell immunoglobulin-like receptor; KIR genes; KIR haplotypes; human leukocyte antigen; HLA ligands; leukocyte receptor complex; autism; immune dysfunction; natural killer cells
3.  Genetic Risk Factors for Perinatal Arterial Ischemic Stroke 
Pediatric neurology  2013;48(1):36-41.
The cause of perinatal arterial ischemic stroke is unknown in most cases. We explored whether genetic polymorphisms modify the risk of perinatal arterial ischemic stroke. In a population-based case-control study of 1997–2002 births at Kaiser Permanente Northern California, we identified 13 white infants with perinatal arterial ischemic stroke. Controls included 86 randomly selected white infants. We genotyped polymorphisms in 9 genes involved in inflammation, thrombosis or lipid metabolism that have been previously linked with stroke, and compared genotype frequencies in case and control individuals. We tested the following polymorphisms: TNF-α-308, IL-6, lymphotoxin A, factor V Leiden, MTHFR 1298 and 667, prothrombin 20210, and apolipoprotein E ε2 and ε4 alleles. Patients with perinatal arterial ischemic stroke were more likely than controls to have at least one apolipoprotein E ε4 allele (54% vs. 25%, p=0.03). More patients with perinatal arterial ischemic stroke carried two ε4 alleles than did controls (15% vs. 2%, p=0.09), though this finding was not statistically significant. Proinflammatory and prothrombotic polymorphisms were not associated with perinatal arterial ischemic stroke in this small study. The apolipoprotein E polymorphism may confer genetic susceptibility for perinatal arterial ischemic stroke. Larger population-based studies are needed to confirm this finding.
doi:10.1016/j.pediatrneurol.2012.09.016
PMCID: PMC3539155  PMID: 23290018
perinatal stroke; Apolipoprotein E
4.  A Genome-Wide Survey of Transgenerational Genetic Effects in Autism 
PLoS ONE  2013;8(10):e76978.
Effects of parental genotype or parent-offspring genetic interaction are well established in model organisms for a variety of traits. However, these transgenerational genetic models are rarely studied in humans. We have utilized an autism case-control study with 735 mother-child pairs to perform genome-wide screening for maternal genetic effects and maternal-offspring genetic interaction. We used simple models of single locus parent-child interaction and identified suggestive results (P<10−4) that cannot be explained by main effects, but no genome-wide significant signals. Some of these maternal and maternal-child associations were in or adjacent to autism candidate genes including: PCDH9, FOXP1, GABRB3, NRXN1, RELN, MACROD2, FHIT, RORA, CNTN4, CNTNAP2, FAM135B, LAMA1, NFIA, NLGN4X, RAPGEF4, and SDK1. We attempted validation of potential autism association under maternal-specific models using maternal-paternal comparison in family-based GWAS datasets. Our results suggest that further study of parental genetic effects and parent-child interaction in autism is warranted.
doi:10.1371/journal.pone.0076978
PMCID: PMC3811986  PMID: 24204716
5.  California Very Preterm Birth Study: design and characteristics of the population- and biospecimen bank-based nested case-control study 
Very preterm birth (VPTB) is a leading cause of infant mortality, morbidity and racial disparity in the U.S. The underlying causes of VPTB are multiple and poorly understood. The California Very Preterm Birth Study was conducted to discover maternal and infant genetic and environmental factors associated with VPTB. This paper describes the study design, population, data and specimen collection, laboratory methods and characteristics of the study population. Using a large, population-based cohort created through record linkage of livebirths delivered from 2000 to 2007 in five counties of southern California, and existing data and banked specimens from state-wide prenatal and newborn screening, 1100 VPTB cases and 796 control mother-infant pairs were selected for study (385/200 White, 385/253 Hispanic and 330/343 Black cases/controls, respectively). Medical record abstraction of cases was conducted at over 50 hospitals to identify spontaneous VPTB, improve accuracy of gestational age, obtain relevant clinical data and exclude cases that did not meet eligibility criteria. VPTB was defined as birth at <32 weeks in Whites and Hispanics and <34 weeks in Blacks. Approximately 55% of all VPTBs were spontaneous and 45% had medical indications or other exclusions. Of the spontaneous VPTBs, approximately 41% were reported to have chorioamnionitis. While the current focus of the California Very Preterm Birth Study is to assess the role of candidate genetic markers on spontaneous VPTB, its design enables the pursuit of other research opportunities to identify social, clinical and biological determinants of different types of VPTB with the ultimate aim of reducing infant mortality, morbidity and racial disparities in these health outcomes in the US and elsewhere.
doi:10.1111/j.1365-3016.2011.01252.x
PMCID: PMC3536480  PMID: 22471684
Study design; California Very Preterm Birth Study
6.  Candidate Genes and Risk for Cerebral Palsy: a Population-Based Study 
Pediatric research  2011;70(6):642-646.
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.
doi:10.1203/PDR.0b013e31823240dd
PMCID: PMC3210921  PMID: 21857382
7.  C4B null alleles are not associated with genetic polymorphisms in the adjacent gene CYP21A2 in autism 
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.
doi:10.1186/1471-2350-9-1
PMCID: PMC2265260  PMID: 18179706
8.  Is fever suppression involved in the etiology of autism and neurodevelopmental disorders? 
BMC Pediatrics  2003;3:9.
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.
doi:10.1186/1471-2431-3-9
PMCID: PMC194752  PMID: 12952554

Results 1-8 (8)