Wang TM, et al. - Researchers evaluated genetic variants that contribute to radiation-induced brain injury, since genome-wide association studies (GWASs) have effectively recognized single nucleotide polymorphisms (SNPs) related to radiation toxicity. This three-stage study is the first GWAS of radiation-induced brain injury that implicates the genetic susceptibility gene CEP128 involved in temporal lobe injury (TLI) development and offers insight into the underlying mechanisms of radiation-induced brain injury. They discovered that rs162171 in the intron of CEP128 was statistically significantly related to TLI development.

Methods

• Using magnetic resonance imaging for TLI diagnosis, researchers followed-up a prospective observational cohort, Genetic Architecture of Radiotherapy Toxicity and Prognosis.
• Genome-wide association analysis was conducted in 1,082 subjects and validated the top associations in two independent cohorts of 1,119 and 741 patients, respectively.
• In this analysis, all statistical tests were two-sided.

Results

• According to the findings, a promoter variant rs17111237 (A > G, minor allele frequency [MAF] = 0.14) was identified in CEP128 related to TLI risk (hazard ratio = 1.45, 95% confidence interval = 1.26 to 1.66, P_combined=3.18 × 10^–7) which is in moderate linkage disequilibrium (LD) with rs162171 (MAF = 0.18, R² = 0.69), the top signal in CEP128 (hazard ratio = 1.46, 95% confidence interval = 1.29–1.66, P_combined= 6.17 × 10^–9).
• Patients were divided into different subgroups with varying risk with 5-year TLI-free rates ranging from 33.7% to 95.5%, combining the clinical variables with the top SNP.
• Researchers found that CEP128, a key component of mother centriole, tightly interacts with multiple radiation-resistant genes and plays a vital role in maintaining the functional cilia, which otherwise will lead to a malfunction of the neural network.
• It was noted that A > G alteration at rs17111237 impaired the promoter activity of CEP128 and knockdown of CEP128 decreased the clonogenic cell survival of U87 cells under radiation.
• They observed that 12.7% (27/212) of the GWAS-based associated genes (P < .001) were enriched in the neurogenesis pathway.