TY - JOUR
T1 - A genetic variant near the PMAIP1/Noxa gene is associated with increased bleomycin sensitivity
AU - Gu, Jian
AU - Ye, Yuanqing
AU - Spitz, Margaret R.
AU - Lin, Jie
AU - Kiemeney, Lambertus A.
AU - Xing, Jingliang
AU - Hildebrandt, Michelle A.T.
AU - Ki Hong, Waun
AU - Amos, Christopher I.
AU - Wu, Xifeng
N1 - Funding Information:
This work was supported by the National Institutes of Health (CA127615 and CA74880 to X.W., CA133996 to C.I.A. and CA055769 to M.R.S.).
PY - 2011/2
Y1 - 2011/2
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddq509
DO - 10.1093/hmg/ddq509
M3 - Article
C2 - 21106707
AN - SCOPUS:78751697971
SN - 0964-6906
VL - 20
SP - 820
EP - 826
JO - Human molecular genetics
JF - Human molecular genetics
IS - 4
M1 - ddq509
ER -