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CDH13 Is Associated with Cellular Viability After Exposure to Ionizing Radiation Using Genome-Wide Screening
Hannah-Lena Schmidt1, Olena Ohlei2, Sarah Herwest1
1Biology of Aging Working Group, Department of Endocrinology and Metabolism, Charité-University Medical Center Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Genetic variants influence cellular sensitivity to chemotherapy and radiation. This study identified specific single nucleotide polymorphisms (SNPs) and genes, including CDH13, associated with ionizing radiation (IR) and mitomycin C (MMC) sensitivity in lymphoblastoid cell lines.
Area of Science:
- Genetics and Molecular Biology
- Cancer Research
- Radiation Biology
Background:
- Genetic variations are known to impact cellular responses to genotoxic agents like chemotherapy and ionizing radiation (IR).
- Understanding these genetic underpinnings is crucial for personalized medicine and predicting treatment outcomes.
- Lymphoblastoid cell lines (LCLs) provide a valuable model for studying inter-individual differences in cellular sensitivity.
Purpose of the Study:
- To identify single nucleotide polymorphisms (SNPs) and genes associated with normal cellular sensitivity to ionizing radiation (IR) and mitomycin C (MMC).
- To investigate the potential role of CDH13 in regulating cellular sensitivity to IR.
- To assess the predictive power of polygenic risk scores (PGS) for cancer-related phenotypes on IR and MMC sensitivity.
Main Methods:
- Determined LCL viability after exposure to increasing doses of IR or MMC using the alamarBlue assay.
- Conducted genome-wide association studies (GWASs) using LCL sensitivity data as quantitative traits.
- Calculated polygenic risk scores (PGS) from UK Biobank GWAS data for cancer-related phenotypes.
Main Results:
- A genome-wide significant association was found between SNP rs74728080 in the CDH13 gene and cellular viability following IR treatment (p < 5 × 10⁻⁸).
- The most significant SNP for MMC sensitivity was rs113978558 in the PLD5 gene (p = 9.232 × 10⁻⁸).
- Polygenic risk scores explained approximately 5% and 3% of the phenotypic variance in IR and MMC sensitivity, respectively.
Conclusions:
- The study identified CDH13 as a potential key regulator of cellular sensitivity to ionizing radiation.
- The findings highlight the utility of GWAS and PGS in dissecting the genetic architecture of cellular responses to genotoxic agents.
- Further functional studies are warranted to elucidate the precise mechanisms by which CDH13 influences IR sensitivity.
