TY - JOUR
T1 - A single nucleotide polymorphism tags variation in the arylamine N-acetyltransferase 2 phenotype in populations of European background
AU - García-Closas, Montserrat
AU - Heind, David W.
AU - Silvermana, Debra
AU - Malatsk, Núria
AU - Yeager, Meredith
AU - Jacobs, Kevin
AU - Doll, Mark A.
AU - Figueroa, Jonine D.
AU - Baris, Dalsu
AU - Schwenn, Molly
AU - Kogevinas, Manolis
AU - Johnson, Alison
AU - Chatterjee, Nilanjan
AU - Moore, Lee E.
AU - Moeller, Timothy
AU - Real, Francisco X.
AU - Chanock, Stephen
AU - Rothman, Nathaniel
PY - 2011/4
Y1 - 2011/4
N2 - The arylamine N-acetyltransferase 2 (NAT2) slow acetylation phenotype is an established risk factor for urinary bladder cancer. We reported earlier on this risk association using NAT2 phenotypic categories inferred from NAT2 haplotypes based on seven single nucleotide polymorphisms (SNPs) in a study in Spain. In a subsequent genome-wide scan, we have identified a single common tag SNP (rs1495741) located in the 30 end of NAT2 that is also associated with bladder cancer risk. The aim of this report is to evaluate the agreement between the common tag SNP and the 7-SNP NAT2 inferred phenotype. The agreement between the 7-SNP NAT2 inferred phenotype and the tag SNP, rs1495741, was initially assessed in 2174 individuals from the Spanish Bladder Cancer Study (SBCS), and confirmed in a subset of individuals from the Main and Vermont component the New England Bladder Cancer Study (NEBCS).We also investigated the association of rs1495741 genotypes with NAT2catalytic activity in cryopreserved hepatocytes from 154 individuals of European background. We observed very strong agreement between rs1495741 and the 7-SNP inferred NAT2 phenotype: sensitivity and specificity for the NAT2 slow phenotype was 99 and 95%, respectively. Our findings were replicated in an independent population from the NEBCS. Estimates for the association between NAT2 slow phenotype and bladder cancer risk in the SBCS and its interaction with cigarette smoking were comparable for the 7-SNP inferred NAT2 phenotype and rs1495741. In addition, rs1495741 genotypes were strongly related to NAT2 activity measured in hepatocytes (P < 0.0001). A novel NAT2 tag SNP (rs1495741) predicts with high accuracy the 7-SNP inferred NAT2 phenotype, and thus can be used as a sole marker in pharmacogenetic or epidemiological studies of populations of European background. These findings illustrate the utility of tag SNPs, often used in genome-wide association studies (GWAS), to identify novel phenotypic markers. Further studies are required to determine the functional implications of rs1495741 and the structure and evolution of the haplotype on which it resides. Pharmacogenetics and Genomics 21:231-236
AB - The arylamine N-acetyltransferase 2 (NAT2) slow acetylation phenotype is an established risk factor for urinary bladder cancer. We reported earlier on this risk association using NAT2 phenotypic categories inferred from NAT2 haplotypes based on seven single nucleotide polymorphisms (SNPs) in a study in Spain. In a subsequent genome-wide scan, we have identified a single common tag SNP (rs1495741) located in the 30 end of NAT2 that is also associated with bladder cancer risk. The aim of this report is to evaluate the agreement between the common tag SNP and the 7-SNP NAT2 inferred phenotype. The agreement between the 7-SNP NAT2 inferred phenotype and the tag SNP, rs1495741, was initially assessed in 2174 individuals from the Spanish Bladder Cancer Study (SBCS), and confirmed in a subset of individuals from the Main and Vermont component the New England Bladder Cancer Study (NEBCS).We also investigated the association of rs1495741 genotypes with NAT2catalytic activity in cryopreserved hepatocytes from 154 individuals of European background. We observed very strong agreement between rs1495741 and the 7-SNP inferred NAT2 phenotype: sensitivity and specificity for the NAT2 slow phenotype was 99 and 95%, respectively. Our findings were replicated in an independent population from the NEBCS. Estimates for the association between NAT2 slow phenotype and bladder cancer risk in the SBCS and its interaction with cigarette smoking were comparable for the 7-SNP inferred NAT2 phenotype and rs1495741. In addition, rs1495741 genotypes were strongly related to NAT2 activity measured in hepatocytes (P < 0.0001). A novel NAT2 tag SNP (rs1495741) predicts with high accuracy the 7-SNP inferred NAT2 phenotype, and thus can be used as a sole marker in pharmacogenetic or epidemiological studies of populations of European background. These findings illustrate the utility of tag SNPs, often used in genome-wide association studies (GWAS), to identify novel phenotypic markers. Further studies are required to determine the functional implications of rs1495741 and the structure and evolution of the haplotype on which it resides. Pharmacogenetics and Genomics 21:231-236
KW - Bladder cancer
KW - Genome-wide scan
KW - NAT2 phenotype
KW - Single nucleotide polymorphism
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U2 - 10.1097/FPC.0b013e32833e1b54
DO - 10.1097/FPC.0b013e32833e1b54
M3 - Article
C2 - 20739907
AN - SCOPUS:79955484827
SN - 1744-6872
VL - 21
SP - 231
EP - 236
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
IS - 4
ER -