No association between the PTGS2/PLA2G4A locus and schizophrenia in a Chinese population.

The present study was undertaken to replicate an association between the PTGS2/PLA2G4A locus and schizophrenia among a Chinese population. We recruited 168 Chinese parent-offspring trios of Han descent, consisting of fathers, mothers and affected offspring with schizophrenia. Of 3 informative SNPs genotyped, no one showed allelic association with schizophrenia; the haplotype analysis also failed to capture a haplotypic association with the illness. Because the frequencies of alleles and genotypes of SNPs analyzed differ in the Chinese population as compared with a British population that initially showed the genetic association between the PTGS2/PLA2G4A locus and schizophrenia, the ethnic background may be a major reason for poor replication of the initial finding.

The CLDN5 locus may be involved in the vulnerability to schizophrenia.

The present study was designed to detect three single nucleotide polymorphisms (SNPs) located on 22q11 that was thought as being of particularly importance for genetic research into schizophrenia. We recruited a total of 176 Chinese family trios of Han descent, consisting of mothers, fathers and affected offspring with schizophrenia for the genetic analysis. The transmission disequilibrium test (TDT) showed that of three SNPs, rs10314 in the 3'-untranslated region of the CLDN5 locus was associated with schizophrenia (chi(2) = 4.75, P = 0.029). The other two SNPs, rs1548359 present in the CDC45L locus centromeric of rs10314 and rs739371 in the 5'-flanking region of the CLDN5 locus, did not show such an association. The global chi-square (chi(2)) test showed that the 3-SNP haplotype system was not associated with schizophrenia although the 1-df test for individual haplotypes showed that the rs1548359(C)-rs10314(G)-rs739371(C) haplotype was excessively non-transmitted (chi(2) = 5.32, P = 0.02). Because the claudin proteins are a major component for barrier-forming tight junctions that could play a crucial role in response to changing natural, physiological and pathological conditions, the CLDN5 association with schizophrenia may be an important clue leading to look into a meeting point of genetic and environmental factors.

Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders.

Schizophrenia is a common mental disorder with a complex pattern of inheritance. Despite a large number of studies in the past decades, its molecular etiology remains unknown. In this study, we proposed a 'system-thinking' strategy in seeking the combined effect of susceptibility genes for a complex disorder by using paranoid schizophrenia as an example. We genotyped 85 reported single-nucleotide polymorphisms (SNPs) present in 23 genes for the dopamine (DA) metabolism pathway among 83 paranoid schizophrenics and 108 normal controls with detailed clinical and genetic information. We developed two novel multilocus approaches-the potential effective SNP combination pattern and potential effective dynamic effects analysis, by which three susceptibility genotype combinations were found to be associated with schizophrenia. These results were also validated in a family-based cohort consisting of 95 family trios of paranoid schizophrenia. The present findings suggest that the COMT and ALDH3 combination may be the most common type involved in predisposing to schizophrenia. Since the combination blocks the whole pathways for the breakdown of DA and noradrenaline, it is very likely to play a central role in developing paranoid schizophrenia.

Association study of neuregulin 1 gene with schizophrenia.

A number of studies have indicated that 8p22-p12 is likely to harbor schizophrenia susceptibility loci. In this region, the candidate gene of interest, neuregulin 1 (NRG1), may play a role in the pathogenesis of schizophrenia. Then in the present study, we performed the linkage disequilibrium to determine the association between three genetic variants (SNPs: rs3924999, rs2954041, SNP8NRG221533) on NRG1 gene and schizophrenia in 246 Chinese Han schizophrenic family trios using PCR-based restriction fragment length polymorphism method and denaturing high-performance liquid chromatography. The transmission disequilibrium test analysis for each variant showed a significant difference between two transmitted alleles even after Bonferroni correction (rs3924999, P=0.007752; rs2954041, P=0.0009309; SNP8NRG221533, P=0.012606). The global chi(2) test for haplotype transmission also revealed a strong association (chi(2)=46.068, df=7, P&<0.000001). Our results suggest that the NRG1 gene may play a role in conferring susceptibility to the disease.

G1 arrest and relative protein expressions in mouse thymocytes induced by whole body X-ray irradiation.

OBJECTIVE: To investigate the molecular regulation of G1 arrest of mouse thymocytes induced by ionizing radiation. METHODS: Cell cycle was analyzed by flow cytometry (FCM) following staining of cells with propidium iodide. Fluorescent staining and flow cytometry analysis were employed for measurement of protein expression. RESULTS: It was demonstrated that G1 phase of mouse thymocytes increased significantly at 12 h after whole body irradiation (WBI) with the doses of 0.5, 1.0 and 2.0 Gy, and at 24 h following 2.0 Gy exposure, measured by FCM. In the time course experiment, it was found that G1 phase of thymocytes increased significantly at 4 h, reached a peak level at 24 h and came down toward 48 h after WBI with 2.0 Gy X-rays. The results also showed that after 2.0 Gy exposure, the expression of proteins in mouse thymocytes increased significantly from 1 h to 8 h for p53, for p21 from 4 h to 48 h, and for MDM2 at 4 h and 8 h, measured by FCM. But no change was found for GADD45 protein expression. CONCLUSION: These results suggest that G1 arrest could be induced by a single dose of 0.5 Gy, 1.0 Gy or 2.0 Gy, and its molecular control might be established through the p53-p21 pathway.

Ionizing radiation-induced IL-1 alpha, IL-6 and GM-CSF production by human lung cancer cells.

A cell line derived from human lung cancer (AOI) was employed in the present study. A panel of cytokines were quantified by ELISA technique following cellular exposure to X-irradiation. Tremendous increase in the levels of both IL-1 alpha and IL-6 were observed, GM-CSF was also detected. A comparison of time kinetics of IL-1 alpha and IL-6 production was made with that of cell cycle progression which was determined by FCM BrdU/DNA bivariate analysis. No cell cycle specific changes were found. The biological implication of radiation-induced cytokine production was discussed.

Experimental radiotherapy and metastasis of human lung cancer xenografts in nude mice.

Using a cell line derived from human lung cancer (AOI), we successfully established human xenografts in KSN nude mice, which showed high incidence of multiple spontaneous metastases. The highest incidence of metastasis in untreated hosts was observed in the spleen followed by the lungs and lymph nodes. The rate of metastasis reached 100% in the mice bearing large sized tumors, when metastasis to any organ or tissue was counted. Experimental radiotherapy caused remarkable redistribution of metastatic foci among different organs. Lung metastasis tended to decrease, while metastasis to the liver and the kidney was increased after radiotherapy. Radiation-induced production of cytokines was speculated to be responsible for such an alteration of metastasis pattern.

EPR study of mouse tissues in search for adaptive responses to low level whole-body X-irradiation.

Effect of a low dose of whole-body X-irradiation (D1 = 0.075 Gy) of mice on some biochemical changes induced in the spleen and thymus by a subsequent challenge dose (D2 = 1.5 Gy) was studied by electron paramagnetic resonance (EPR). Kunming and SHK mice were used. Concentration of ribonucleotide reductase (RR) in the spleen and thymus of unirradiated Kunming mice was 0.70 and 0.46 microM respectively, and of unirradiated SKH mice--0.37 and 0.21 microM respectively (systematic error 45%). For mice exposed only to the low dose (D1 group), a stimulating effect on RR activity in spleen and thymus was found, while in mice subjected only to the D2 dose (D2 group) activity of the enzyme in the organs decreased considerably 18 h after irradiation. The group of mice irradiated with D1 and D2 doses, given at a 6-h interval (D1 plus D2 group), showed a RR activity in the organs lower than D1 and higher than D2 groups. This finding indicates that there exists an adaptation-like response to a low-dose whole-body irradiation in murine spleen and thymus. This low 'inductive' dose makes the organs' RR less susceptible to inhibition induced by a subsequent challenge dose. Preliminary results showed that the same kind of response is probably a characteristic of the RR content of splenocytes as well as of the rate of thymidine incorporation into splenocytes. 5-Thyml radicals of DNA (TH radicals) induced in whole tissues by gamma-irradiation in vitro at 77 K were also studied. Radiochemical yield of these radicals (4.0 and 5.3 nmol j-1), for spleen and thymus respectively of unirradiated Kunming mice, and 2.3 and 2.6 nmol J-1, for spleen and thymus respectively of unirradiated SHK mice (systematic error 30%), decreased significantly in both organs upon D2 irradiation. This decrease, however, was the consequence of DNA content diminishing upon D2 irradiation rather than change of DNA radiosensitivity: the beta value of TH radicals, i.e. yield of radicals per unit mass of DNA in each organ was equal for the mice from all D1, D1 plus D2, D2 and control groups. The beta values of TH radicals in mouse spleen and thymus were of the same order of magnitude compared with the yield of the single-strand breaks of DNA measured previously in rat organs just after whole-body irradiation, i.e. about 1 x 10(2) (Gy x 10(12) Da)-1.