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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??). 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??) and in replication phase 1 (0.61 versus 0.84, P= 7.00 × 10??). 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.

SUBMITTER: Gu J

PROVIDER: S-EPMC3024041 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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A genetic variant near the PMAIP1/Noxa gene is associated with increased bleomycin sensitivity.

Gu Jian J Ye Yuanqing Y Spitz Margaret R MR Lin Jie J Kiemeney Lambertus A LA Xing Jingliang J Hildebrandt Michelle A T MA Ki Hong Waun W Amos Christopher I CI Wu Xifeng X

Human molecular genetics 20101124 4

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 5 ...[more]

PMID: 21106707

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Project description:BackgroundAdaptor-related protein complex 2 alpha 2 subunit (AP2A2) gene encodes a protein-a subunit of the AP-2 adaptor protein complex. Evidence has revealed that benzodiazepine receptor-associated protein 1 (BZRAP1) is abundant in the hippocampus with potential effects on brain diseases. Recently, an epidemiological study reported that two variants (rs7396366 and rs2526378) closest to the AP2A2 and BZRAP1 genes are associated with higher plasma lipids and Alzheimer's disease. Whether the two single nucleotide polymorphisms (SNPs) are actually relevant to coronary artery disease (CAD) and CAD severity remains elusive. Our aim was to assess whether these two SNPs are relevant to CAD and its severity in a Chinese population.MethodsThree hundred and thirty-five patients with documented CAD (282 stable CAD, 28 non-ST-segment elevation myocardial infarction, 25 ST-segment elevation myocardial infarction), and 372 non-CAD controls were included in the study. The participants were divided into two groups according to coronary angiography results. CAD patients were further demarcated into subgroups with one-, two-, or three-vessel stenosis. Genotypes at rs7396366 and rs2526378 were examined using polymerase chain reaction-ligase detection reaction. The association between these two SNPs with CAD and its severity were analyzed.ResultsThe frequency of the rs7396366 TT genotype was significantly higher in CAD patients than in controls (13.7% vs. 7.8%, 95% CI: 1.15-3.07, P = 0.014). Subjects with a variant genotype T allele had an increased risk of CAD compared with G allele carriers (additive model: 95% CI: 1.21-3.35, P = 0.008). After adjustment for traditional cardiovascular risk factors, analysis of the dominant models involving rs7396366 also showed that T allele carriers had a significantly higher risk for CAD than G allele carriers had (dominant model: OR 1.48, 95% CI: 1.03-2.14, P = 0.035). Age, sex, type 2 diabetes mellitus, fasting plasma glucose, and the TT genotype in rs7396366 were significantly associated with three-vessel lesions. Despite these significant outcomes of rs7396366, information on rs2526378 showed no significant difference between CAD patients and non-CAD controls.ConclusionOur results show that the T allele and TT genotype in rs7396366, closest to the AP2A2 gene, are linked to an increased risk of CAD and its severity in a Chinese population.

Dataset Information

A genetic variant near the PMAIP1/Noxa gene is associated with increased bleomycin sensitivity.

Publications

A genetic variant near the PMAIP1/Noxa gene is associated with increased bleomycin sensitivity.

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