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. Control subjects included 86 randomly selected white infants. We genotyped polymorphisms in nine genes involved in inflammation, thrombosis, or lipid metabolism previously linked with stroke, and compared genotype frequencies in case and control individuals. We tested several polymorphisms: tumor necrosis factor-? -308, interleukin-6, lymphotoxin A, factor V Leiden, methyltetrahydrofolate reductase 1298 and 667, prothrombin 20210, and apolipoprotein E ?2 and ?4 alleles. Patients with perinatal arterial ischemic stroke were more likely than control subjects to demonstrate at least one apolipoprotein E ?4 allele (54% vs 25%, P = 0.03). More patients with perinatal arterial ischemic stroke carried two ?4 alleles than did control subjects (15% vs 2%, P = 0.09), although this finding lacked statistical significance. Proinflammatory and prothrombotic polymorphisms were not associated with perinatal arterial ischemic stroke. The apolipoprotein E polymorphism may confer genetic susceptibility for perinatal arterial ischemic stroke. Larger population-based studies are required to confirm this finding.
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.
Studies suggest that genetic polymorphisms may increase an individuals 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 wk 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 NOS (iNOS)-231, apolipoprotein E (apoE) ?2 and ?4 alleles, TNF-?-308, IL-8 -251, lymphotoxin 60, endothelial NOS -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 versus 18.9%, p = 0.04) and the apoE ?4 allele (19.3 versus 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.
We report that a significant number of autistic children have serum levels of IgA antibodies above normal to the enzyme tissue transglutaminase II (TG2), and that expression of these antibodies to TG2 is linked to the (HLA)-DR3, DQ2 and DR7, DQ2 haplotypes. TG2 is expressed in the brain, where it has been shown to be important in cell adhesion and synaptic stabilization. Thus, these children appear to constitute a subpopulation of autistic children who fall within the autism disease spectrum, and for whom autoimmunity may represent a significant etiological component of their autism.
Chorioamnionitis is associated with increased risk for cerebral palsy (CP) in term infants. A functional polymorphism in the interleukin-6 (IL-6) gene has been implicated in newborn brain injury. We studied whether the IL-6 -174 G/C polymorphism confers increased risk for CP in term infants.
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.
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.
The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP(3) production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis.
Very preterm birth (VPTB) is a leading cause of infant mortality, morbidity and racial disparity in the US. 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 statewide 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.
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