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DNA methylation contributes to natural human variation

ABSTRACT: DNA methylation analysis using the Infinium HumanMethylation450 BeadChip platform (Illumina) of 96 Caucasian American, 96 Han Chinese American and 96 African American LCL samples determined differences in terms of differentially methylated sites. Importantly, the observed differences were confirmed in primary blood samples of 10 healthy Caucasian, 10 African American (GSE36064) and 10 Asian individuals. Genes associated to differentially methylated site suggest an influence of DNA methylation on phenotype differences. Interestingly, methylation differences could be partially traced back to genetic polymorphisms.

ORGANISM(S): Pan troglodytes schweinfurthii Pan troglodytes troglodytes Homo sapiens Pan troglodytes Pan troglodytes verus

PROVIDER: GSE36369 | GEO | 2013/07/22

SECONDARY ACCESSION(S): PRJNA153243

REPOSITORIES: GEO

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Project description:We used microarrays to identify the variation of basal gene expression level among 287 lymphoblastoid cell lines. Radiation therapy is used to treat half of all cancer patients. Response to radiation therapy varies widely among patients. Therefore, we performed a genome-wide association study (GWAS) to identify biomarkers to help predict radiation response using 277 ethnically defined human lymphoblastoid cell lines (LCLs). Basal gene expression levels and 1.3 million genome-wide SNP markers from both Affymetrix and Illumina platforms were assayed for all 277 human LCLs. MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays for radiation cytotoxicity were also performed to obtain area under the curve (AUC) as a radiation response phenotype for use in the association studies. Functional validation of candidate genes, selected from an integrated analysis that used SNP, expression and AUC data, was performed with multiple cancer cell lines using specific siRNA knockdown, followed by MTS and colony-forming assays. 27 loci, each containing at least 2 SNPs within 50kb with p-values <10-4, were associated with radiation AUC. 270 expression probe sets were associated with radiation AUC with p<10-3. The integrated analysis identified 50 SNPs in 14 of the 27 loci that were associated with both AUC and the expression of 39 genes that were also associated with radiation AUC (p<10-3). Functional validation using siRNA knockdown in multiple tumor cell lines showed that C13orf34, MAD2L1, PLK4, TPD52 and DEPDC1B each significantly altered radiation sensitivity in at least 2 cancer cell lines. Studies performed with LCLs can help to identify novel biomarkers that might contribute to variation in response to radiation therapy and enhance our understanding of mechanisms underlying that variation. EBV-transformed LCLs from 95 African-American (AA), 96 Caucasian-American (CA), and 96 Han Chinese-American (HCA) unrelated healthy subjects (sample sets HD100AA, HD100CAU, HD100CHI) were purchased from the Coriell Cell Repository (Camden, NJ).

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DNA methylation contributes to natural human variation

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