Genetic Susceptibility To Glioma In Chinese Han Population

Part?Validation of Association of Sequence Variants of GWAS with Glioma Susceptibility in a Chinese Han PopulationA genome-wide association study is defined as a genetic association study in which the density of genetic markers and the extent of linkage disequilibrium is sufficient to capture a large proportion of the common variation in the human genome in the population under study, and the number of specimens genotyped provides sufficient power to detect variants of modest effect. For the first time in the history of biomedicine. GWAS provide us with a powerful and accurate tool to tackle the complete genome for disease gene search entirely without segregation information.Two glioma genome-wide association studies in European populations identified 15 genetic variants in 5 gene regions (TERT, CCDC26, CCDKN2A/B, PHLDB1, RTEL1) strongly associated with risk of glioma. but it is unknown whether these variants associate with glioma risk in Asian populations.Using retrospective hospital-based case-control study, we genotyped these 14 variants in 976 glioma patients and 1,057 control subjects to evaluate their associations with risk of glioma, particularly high-grade glioma glioblastoma (n=312), in a Chinese population. We recruited 976 patients with histopathologically confirmed glioma and 1.057 healthy controls between October 2004 and July 2009 from the Department of Neurosurgery at Huashan Hospital. Fudan University (Shanghai, China). There were no restrictions on age. sex, or histologic type, but patients with a self-reported history of cancer and patients with previous radiotherapy or chemotherapy for unknown disease conditions were excluded. Genotyping was performed with the MassARRAY iPLEX platform (Sequenom, San Diego, California) through the use of an allele-specific matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.Overall, we identified five susceptibility SNP on 20q13.33 RTEL1 rs6010620 (P=2.79×10-6). 11q23.3 PHLDB1 rs498872 (P=3.8×10-6) and 5p15.33 TERT rs2736100 (P=0.0002) rs2853676 (P=0.0067), rs2736098 (P=0.0046) for glioma risk in this study population:also for glioblastoma risk on 20q13.33 RTEL1 rs6010620 (P=3.57×10-7), 11q23.3 PHLDB1 rs498872 (P= 3.8×10-6), and 5p15.33 TERT rs2736100 and rs2736098 (P=1.21×10-4. 2.84×10-4, respectively). This study provides further evidence of the three glioma susceptibility regions in 20q13.33,11q23.3 and 5p15.33 in Chinese populations. Part?Fine Mapping Association Study with Glioma Susceptibility in a Chinese Han PopulationBy enhancing the detection dense of genetic susceptibility loci with diseases, fine mapping study can find the most strongly associated marker with disease and identify susceptibility gene or decrease the susceptibility regions, and investigate the deseases passway better. New susceptibility SNPs has been previously reported to be associated with prostal cancer using fine mapping association study.Two recent genome-wide association studies have independently identified 15 glioma susceptibility varations on five chromosome regions. And our previous study we identified five susceptibility varations on chromosome regions 20q13.33,11q23.3 and 5p15.33 for glioma risk in Chinese Han population.In this study, a fine-mapping analysis using HapMap SNPs was conducted across?86kb (chr5:1236212-1324121).-96kb(chr20:62291008-62387830) and?151kb(chr11:118404804-118576463) regions with 43 tag SNPs in 983 glioma cases and 1024 controls of Chinese Han. The result implicated that rs6089953, rs6062484, rs3787098, rs2297440, rs2257885 rs3761121, rs1058319, rs5019252, rs6011076 on RTEL1 (rs6089953, P=9.02E-05; rs6062484, P=2.16E-05; rs3787098, P=4.02E-04; rs2297440, P=5.11E-06; rs2257885,P=1.40E-09;rs3761121, P=4.45E-07; rs1058319, P=1.29E-11; rs5019252, P=4.31E-08; rs6011076, P=6.88E-35) and rs7115634, rs2236661, rs494560, rs1774 on PHLDB1 (rs7115634, P=2.85E-04; rs2236661, P=1.81E-05;rs494560, P= 4.32E-05; rs17748, P=2.87E-05) are the strongly associated markers with glioma.Three TERT SNPs (rs4635969, rs401681 and rs414965), six RTEL1 SNPs (rs6089953 and rs2738780; rs6062484 and rs2297437:rs5019252 and rs4809224) and eight PHLDB1 SNPs (rs12289253 and rs3741324; rs494560 and rs17748; rs10892251 and rsl 1216943; rs4639966 and rs496547) were in significant linkage disequilibrium. Haplotype-specific analysis revealed frequency differences between cases and controls (P sim=0.0105,2.91E-04,1.81E-05, 8.75E-09,0.0541,2.50E-06,1.20E-05 and 0.0141).Further investigation is warranted to determine whether these SNP alone or in combination with additional variants contributes to glioma susceptibility. This study provides evidence of glioma risk valiation and prevention, significance of screening the high risk group and early diagnoses for glioma in China, and help decreasing the incidence of glioma.