Computational protocol: TNFSF10/TRAIL regulates human T4 effector memory lymphocyte radiosensitivity and predicts radiation induced acute and subacute dermatitis

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Protocol publication

[…] The FBAT method and software [, ] was used to perform a single marker analysis between the frequent SNPs and the quantitative trait while taking into account the family structure (command fbat -o). Two methods have been used to obtain a p-value for the global association of TNFSF10 with the trait : a) The Fisher product [] of the p-values obtained from the single point association analysis was taken, and its significance was assessed using 10,000 permutations, b) The FBAT Multi-Marker statistic [, ] was computed, and its significance was assessed using 10,000 permutations. [...] Acute and subacute dermatitis, acute erythema, acute hyperpigmentation and late fibrosis were assessed prospectively using the CTCAE v3 grading system in the CO-HO-RT trial []. Toxicity was treated as a binary outcome and was determined by taking the highest CTCAE grade occurrence during radiotherapy to 6 weeks after radiotherapy for acute toxicities and from 3 months after radiotherapy to the end of follow-up (minimum 2 years, maximum 8 years) for late toxicities. For each toxicity endpoint, patients were considered cases if they had CTCAE grade ≥ 2 and controls if they had CTCAE grade ≤ 1. The percentage of CD8+ lymphocytes undergoing radiation-induced apoptosis was treated as a continuous outcome.Genomic DNA was isolated from blood, genotyped using a commercial genome-wide SNP array (Affymetrix SNP6.0, Affymetrix, San Diego, CA)]. Because rs1131532, and rs3815496 were not directly genotyped on the array, the surrounding region of chromosome 3 (position 100,000,001 to 200,000,000, hg build 19) was imputed to the 1000 Genomes reference data using IMPUTE2 software (]. Following imputation, the SNPs of interest were confirmed to be in Hardy-Weinberg equilibrium (p-value > 10−6) and showed good imputation quality (info score > 0.3). SNPTEST software [] was used to analyze SNP-phenotype association with the frequentist test and expected method, which uses expected genotype counts (i.e. genotype dosages) obtained from imputation. An additive genetic inheritance model was assumed in all analyses. […]

Pipeline specifications

Software tools FBAT, IMPUTE, SNPTEST
Application GWAS
Diseases Breast Neoplasms, Dermatitis