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Aberrant expression of the platelet-derived growth factor alpha-receptor (PDGFRA) gene has been associated with various diseases, including neural tube defects and gliomas. We have previously identified 5 distinct haplotypes for the PDGFRA promoter region, designated H1, H2alpha, H2beta, H2gamma and H2delta. Of these haplotypes H1 and H2alpha are the most common, whereby H1 drives low and H2alpha high transcriptional activity in transient transfection assays. Here we have investigated the role of these PDGFRA promoter haplotypes in gliomagenesis at both the genetic and cellular level. In a case-control study on 71 glioblastoma patients, we observed a clear underrepresentation of H1 alleles, with pH1 = 0.141 in patients and pH1 = 0.211 in a combined Western European control group (n = 998, p < 0.05). Furthermore, in 3 out of 4 available H1/H2alpha heterozygous human glioblastoma cell lines, H1-derived mRNA levels were more than 10-fold lower than from H2alpha, resulting at least in part from haplotype-specific epigenetic differences such as DNA methylation and histone acetylation. Together, these results indicate that PDGFRA promoter haplotypes may predispose to gliomas. We propose a model in which PDGFRA is upregulated in a haplotype-specific manner during neural stem cell differentiation, which affects the pool size of cells that can later undergo gliomagenesis., ((c) 2008 Wiley-Liss, Inc.)

Previous studies found that allergies are inversely related to risk of glioma. In an earlier publication, using data from a Swedish case-control study, Schwartzbaum et al. report an inverse relation between risk of glioblastoma and four single nucleotide polymorphisms (SNP) on two genes [interleukin (IL)-4Ralpha, IL-13] that are associated with allergies. In addition, recent studies suggest that IL-4 and IL-13 induce cyclooxygenase-2 (COX-2) to resolve brain inflammation. To see whether previous Swedish results (110 cases, 430 controls) would be replicated, we estimated the association between glioblastoma and two IL-4Ralpha (rs1805015, rs1801275) and two IL-13 (rs20541, rs1800925) SNPs and their haplotypes and one COX-2 SNP (-765GC) using additional English, Danish, and Finnish data (217 cases, 1,171 controls). Among general population controls, we evaluated associations between these haplotypes, the COX-2 SNP, and self-reported allergies. Our data did not support our original observations relating individual IL-4Ralpha, IL-13, or COX-2 SNPs to glioblastoma risk. However, the T-G IL-4Ralpha haplotype was associated with glioblastoma risk (odds ratio, 2.26; 95% confidence interval, 1.13-4.52) and there was a suggestion of an inverse relation between this haplotype and hayfever prevalence among controls (odds ratio, 0.38; 95% confidence interval, 0.14-1.03). The lack of support for a link between four IL-4Ralpha and IL-13 SNPs and glioblastoma may reflect the absence of associations or may result from uncontrolled confounding by haplotypes related both to those that we examined and glioblastoma. Nonetheless, the association between the T-G IL-4Ralpha haplotype and glioblastoma risk may indicate a role of immune factors in glioblastoma development.

In 17 years we have performed 6,505 neurosurgical procedures in the neurosurgical unit of the Salisbury Hospital Group. Only 62% were performed on Africanpatients and 38% on European patients, despite the fact that the African population exceeds the European population by 20 times. This is partly due to the tolerance of rural people towards disease and partly to a number of social factors. The European group has a greater percentage of elderly people than the African group and, although we could not estimate the incidence of tumors among the African group, we would expect their overall incidence per capita to be lower because malignant tumors tend to occur in older people. We do not suspect the existence of a genetic factor in tumor incidence. There were 205 primary intracranial neoplasms in Africans and 244 in Europeans. Histological study shows that 33% of all tumors were meningiomas in the African group compared to 19% in the European group. Gliomas comprised 61.3% of the European series and 48.8% of the African series but the distribution by Kernohan's grading of astrocytomas was the same in both groups. If age was a factor, Grades I and II should have predominated in the African group, but did not. The incidence for each tumor among our European patients followed the patterns reported in various European and USA series. Likewise the pattern emerging from our African series closely paralleled the reports of other workers in Africa. Acoustic neuromas appear to be rather rare among Africans. The average age of all adults with tumors was 15 years lower in the African group than in the European group. However, this is entirely related to the age structure of the population, and not to an earlier age of occurrence. The average ages of medulloblastoma cases were identical. In our European series the occurrence according to age was much the same as that reported by overseas workers. The sex incidence of tumors in the European group seems to be a fair reflection of the situation elsewhere; in the African group it is questionable because men go into the towns to work and leave their families in the country. There was no significant difference in the location of tumors in the two groups. Results of treatment were uniformly inferior in the African group, partly due to the lateness of arrival at the hospital so that the growth was already far advanced and also because many patients suffered poor health from concomitant disease.