title: A genetic variant near the PMAIP1/Noxa gene is associated with increased bleomycin sensitivity.
abstract: Mutagen sensitivity, a measurement of chromatid breaks induced by various mutagens in short-term cultures of peripheral blood lymphocytes, is an established risk factor for a number of cancers and is highly heritable. The purpose of this study is to identify genetic predictors of mutagen sensitivity. Therefore, we conducted a multi-stage genome-wide association study. The primary scan analyzed 539,437 autosomal SNPs in 673 healthy individuals, followed by validations in two independent sets of 575 and 259 healthy individuals, respectively. One SNP, rs8093763, on chromosome 18q21 showed significant association with bleomycin (BLM) sensitivity (combined P = 2.64 × 10⁻⁸). We observed significantly lower BLM-induced chromotid breaks for genotypes containing wild-type allele compared with the homozygous variant genotype in the discovery set (0.71 versus 0.90, P= 3.77 × 10⁻⁵) and in replication phase 1 (0.61 versus 0.84, P= 7.00 × 10⁻⁵). The result of replication phase 2 was not statistically significant (0.65 versus 0.68, P= 0.44). This SNP is approximately 64 kb from PMAIP1/Noxa, which is a radiation-inducible gene and exhibits higher expression in BLM-sensitive lymphoblastoid cell lines than insensitive cell lines upon BLM treatment. In conclusion, we identified a biologically plausible genetic variant on 18q21 near the PMAIP1/Noxa gene that is associated with BLM sensitivity.
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Jingliang
authors.initials: J
authors.lastname: Xing
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrandt
authors.forename: Waun
authors.initials: W
authors.lastname: Ki Hong
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001761:Bleomycin / Q000378:metabolism* / Q000633:toxicity*; D016022:Case-Control Studies; D002843:Chromatin / Q000187:drug effects*; D002869:Chromosome Aberrations / Q000187:drug effects; D002887:Chromosomes, Human, Pair 18; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity; D020641:Polymorphism, Single Nucleotide; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D044465:White People; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D002843:Chromatin; D009153:Mutagens; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D001761:Bleomycin