Detection of functional single-nucleotide polymorphisms that affect apoptosis

Harris, Sandra; Gil, Germán A.; Robins, Harlan; Hu, Wenwei; Hirshfield, Kim M.; Bond, Elisabeth E.; Bond, Gareth L.; Levine, Arnold J.

doi:10.1073/pnas.0508390102

Cited by 78 publications

(102 citation statements)

References 24 publications

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“…However, lymphocytes from normal Caucasians homozygous for the C-G portion of the haplotype T-C-G have higher levels of AKT1 protein, and lowered reponse to apoptotic stimuli, than those harbouring the T-A haplotype (48). As we found no clear relationship between haplotype and AKT1 transcription in the SBS, further studies are required to elucidate any differential effect in schizophrenic patients (associated with AKT1 or not) versus controls.…”

Section: Discussioncontrasting

confidence: 38%

AKT1 Is Associated with Schizophrenia Across Multiple Symptom Dimensions in the Irish Study of High Density Schizophrenia Families

Thiselton

Vladimirov²,

Kuo³

et al. 2008

Biological Psychiatry

148

111

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Background-The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients.

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Section: Discussioncontrasting

confidence: 38%

AKT1 Is Associated with Schizophrenia Across Multiple Symptom Dimensions in the Irish Study of High Density Schizophrenia Families

Thiselton

Vladimirov²,

Kuo³

et al. 2008

Biological Psychiatry

148

111

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“…Previously reported SNP309 G allele frequencies in Northern European Caucasians were Ϸ33%, but in African Americans they have been noted to be significantly lower, Ϸ11% (14,24,25). A salient feature of the African Americans and Caucasians figures is that, in both populations, the G allele of SNP309 is highly correlated with all of the other SNPs across the entire region of MDM2 covered by the Celera Diagnostic SNP set, resulting in only one G haplotype in both populations.…”

Section: Resultsmentioning

confidence: 97%

“…For that reason, the haplotype structure of 14 different SNPs in the MDM-2 gene was determined by employing three different racial and ethnic populations: one African American population, one Caucasian not selected for ethnicity, and one Caucasian of the Ashkenazi Jewish ethnic group. These populations were chosen for further haplotype analysis, as it had been previously observed that African Americans have a low G allele frequency, non-Jewish Caucasians an intermediate G allele frequency, and Ashkenazi Jewish groups a high G allele frequency (14,24).The results presented in this report indicate that there are only a few common (Ն1%) G allele haplotypes in all three populations studied, one in the African American and Caucasian data sets and two in the Ashkenazi Jewish data set. The SNPs in the G allele haplotype are thus highly correlated.…”

mentioning

confidence: 99%

Haplotype structure and selection of the MDM2 oncogene in humans

Atwal

Bond

Metsuyanim³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The MDM2 protein is an ubiquitin ligase that plays a critical role in regulating the levels and activity of the p53 protein, which is a central tumor suppressor. A SNP in the human MDM2 gene (SNP309 T/G) occurs at frequencies dependent on demographic history and has been shown to have important differential effects on the activity of the MDM2 and p53 proteins and to associate with altered risk for the development of several cancers. In this report, the haplotype structure of the MDM2 gene is determined by using 14 different SNPs across the gene from three different population samples: Caucasians, African Americans, and the Ashkenazi Jewish ethnic group. The results presented in this report indicate that there is a substantially reduced variability of the deleterious SNP309 G allele haplotype in all three populations studied, whereas multiple common T allele haplotypes were found in all three populations. This observation, coupled with the relatively high frequency of the G allele haplotype in both and Caucasian and Ashkenazi Jewish population data sets, suggests that this haplotype could have undergone a recent positive selection sweep. An entropy-based selection test is presented that explicitly takes into account the correlations between different SNPs, and the analysis of MDM2 reveals a significant departure from the standard assumptions of selective neutrality.cancer ͉ p53 ͉ population genetics ͉ SNP ͉ entropy I n response to a wide variety of stresses, such as DNA damage or oncogene activation, the p53 tumor suppressor protein is activated and initiates a transcriptional program leading to cell cycle arrest, cell senescence or apoptosis (1). This eliminates clones of cells that have acquired mutations, which arise at a high frequency when DNA replication or the cell cycle proceeds under stress. When the p53 gene is mutated in either the germ line or in a somatic cell, many types of cancers can arise (2). The p53 protein is regulated by a ubiquitin ligase, the MDM2 protein, which binds to p53, blocking its function as a transcription factor, and polyubiquitinates the p53 protein sending it to the proteiosome for degradation (3). The MDM2 gene in turn is positively regulated by p53-mediated transcription, setting up an autoregulatory loop that keeps both proteins at moderate levels. Stress responses perturb this feedback loop, which leads to the initiation of p53-dependent apoptosis.Functional SNPs in the human genome have been identified in both the p53 and the MDM2 genes (4). In the p53 gene, a SNP (codon 72) results in the change of a proline residue to an arginine at codon 72 of the p53 protein (p53-Pro and p53-Arg, respectively). Multiple groups have shown that p53-Pro is weaker than p53-Arg in its ability to both suppress cellular transformation and induce apoptosis in cell culture (5-8), and can associate with an earlier onset of tumor formation and a poorer tumor response to chemotherapy in humans (7, 9, 10). In the MDM2 gene, a SNP (SNP309) results in a nucleotide change from the wild-type thymine (T...

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“…It is interesting to note that of the SNPs showing significant interaction with OCs defined as OC greater than three and OC greater than four, the minor allele of rs1130233 in AKT1 has been shown to render cells more sensitive to radiation-induced apoptosis, suggesting a functional role for that SNP in AKT1-mediated signaling. 29 Differential maternal recall between cases and controls is not of concern because we used a family-based study design; however, non-directional maternal recall could result in misclassification by serious OC status, which would bias estimates toward the null. The ability of mothers to correctly report obstetric complications decades after birth has been shown to be accurate, 30,31 especially for severe complications or major medical events, although other studies have shown that maternal recall is not always reliable.…”

Section: Discussionmentioning

confidence: 99%

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk

et al. 2008

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The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-a) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia.

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Detection of functional single-nucleotide polymorphisms that affect apoptosis

Cited by 78 publications

References 24 publications

AKT1 Is Associated with Schizophrenia Across Multiple Symptom Dimensions in the Irish Study of High Density Schizophrenia Families

AKT1 Is Associated with Schizophrenia Across Multiple Symptom Dimensions in the Irish Study of High Density Schizophrenia Families

Haplotype structure and selection of the MDM2 oncogene in humans

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk

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