Abstract A62: Tobacco exposure, risk for bladder cancer, and modification by NAT2 in different ethnic populations
Authors: Divan Hozefa A. , Van Den Berg David , Cortessis Victoria K. , Joshi Amit D. , Gago-Dominguez Manuela , Stern Mariana C. , Conti David V. , Pike Malcolm C. , Gao Yu-Tang , Xiang Yong-Bing , Yuan Jian-Min 
Published: June 2012

Introduction: Occupational exposure to arylamine compounds is a well-established risk factor for bladder cancer. With greater regulation, industrial arylamine exposure in the United States has reduced, thus making tobacco smoke the predominant source of arylamine exposure. Though exposure is greater in China than in the US, bladder cancer rates are higher in the US. These circumstances, together with evidence of familial aggregation of bladder cancer, have long suggested a role of inherited genetic factors in disease etiology. Previous studies indicate that slow variants of polymorphic N-acetyltranseferase, an arylamine-metabolizing enzyme encoded by the NAT2 locus, is a risk factor. Differences in distribution of slow acetylation may underlie demonstrated ethnic differences in bladder cancer risk. Thus cases of transitional cell carcinoma of the urinary bladder were studied to understand the role of the NAT2 gene and arylamine exposure differences between Caucasians and Chinese.

Methods: A population-based case-control study of bladder cancer conducted in Los Angeles County (LA), California and Shanghai, China. Cases were diagnosed with urothelial carcinoma from 1987 to 1996 and from 1995 to 1998 in Shanghai. Controls were matched on gender, age in both populations, with further matching on neighborhood in Los Angeles. Participants completed in-person interviews providing information on several risk factors including smoking. All Shanghai participants and those LA participants interviewed from 1992 onward provided peripheral blood samples. Participants also provided samples of urine following timed ingestion of caffeine from which urinary metabolite ratios were assessed as a phenotypic measure of NAT2 activity. Genotypic analysis of 30 Tag SNPs within the NAT2 locus was conducted, and inferred phenotype assigned by haplotype analysis (SAS/Genetics, Proc Haplotype) followed by assignment of “slow” and “rapid” alleles according to consensus NAT2 gene nomenclature (http://louisville.edu/medschool/pharmacology/consensus-human-arylamine-n-acetyltransferase-gene-nomenclature/nat_pdf_files/Human_NAT2_alleles.pdf) was done. Gene-disease associations were estimated in subsequent statistical analysis employing logistic regression using N:M matching and an additive model for genetic effect.

Results: 786 (LA) and 1026 (Shanghai) participants contributed to the analysis. As previously reported (Carcinogenesis 29:1386, 2008), bladder cancer risk was associated with “slow” measured phenotype among the LA participants who reported smoking 30 or more pack-years. Among LA participants, we further observed that rs1495741A (OR=1.47, 95% CI: 1.08–1.99) to be associated with risk, as reported for a separate study population of European origin (Pharmacogenetics and Genomics 21:231,2011). Among Shanghai participants, “slow” measured phenotype was also associated with risk (OR=1.44, 95% CI: 1.08–1.92). Unexpectedly, among Shanghai participants, both the “slow” inferred phenotype and rs1495741A allele were associated with risk in the direction opposite to that observed among LA participants (OR=0.65, 95% CI: 0.44–0.94; OR=0.70, 95% CI: 0.50–0.97). Based upon consensus NAT2 gene nomenclature, nearly 29% of Shanghai participants had at least one haplotype defined as a “slow substrate dependent” allele, whereas such alleles were observed in fewer than 3% of LA participants.

Conclusions: Lower bladder cancer occurrence among Chinese compared with non-Hispanic whites may be related in part to differences in genetic susceptibility. Additional studies are ongoing to clarify whether ethnic differences in associations to inferred phenotype and to rs1495741A arise from differences in organization of the NAT2 locus between populations of European and Chinese descent as well as differential exposure of these populations to mono-versus diarylamines (Int J Cancer 118:161, 2006), or perhaps to both of these factors.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A62.