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Carcinogenesis Advance Access originally published online on March 20, 2007
Carcinogenesis 2007 28(7):1520-1525; doi:10.1093/carcin/bgm063
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Susceptibility to arsenic-induced skin lesions from polymorphisms in base excision repair genes

Carrie V. Breton1,*, Wei Zhou2, Molly L. Kile2, E.A. Houseman3, Quazi Quamruzzaman4, Mahmuder Rahman4, Golam Mahiuddin4 and David C. Christiani1,2

1 Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA
2 Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA
3 Department of Work Environment, University of Massachusetts Lowell, Kitson Hall, 202E, One University Avenue Lowell, MA 01854, USA
4 Dhaka Community Hospital, 190/1 Baro Moghbazar, Wireless Railgate, 1217, Dhaka, Bangladesh

* To whom correspondence should be addressed. Tel: +617 416 9897; Fax: +617 432 3441; Email: cbreton{at}hsph.harvard.edu

Genetic polymorphisms in the base excision DNA repair pathway may influence individual susceptibility to arsenic and the development of arsenic-induced skin lesions. Data from a case–control study of 792 cases and 792 matched controls conducted in Bangladesh from 2001 to 2003 were analyzed using conditional logistic regression to assess the associations between four common base excision repair (BER) genetic polymorphisms X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln, XRCC1 Arg194Trp, human 8-oxoguanine DNA glycosylase (hOGG1) Ser326Cys and apurinic/apyrimidinic endonuclease (APE1) Asp148Glu and arsenic-induced skin lesions including melanosis and keratosis. Adjusted for toenail arsenic, body mass index, education, smoking and betel nut use, individuals with the APE1 148Glu/Glu polymorphism had a 2-fold increased odds of skin lesions compared with individuals with the 148Asp/Asp genotype (1.93; 95% confidence interval 1.15, 3.19). Gene–environment interactions between toenail arsenic and XRCC1 Arg194Trp and APE1 Asp148Glu were observed. Within the lowest arsenic tertile, APE1 148Glu/Glu had 2.5 times the odds ratio compared with wild-type, whereas within the highest tertile of arsenic the odds ratios for skin lesions did not differ. In contrast, at low arsenic levels, the odds ratios for skin lesions did not differ much by XRCC1 Arg194Trp genotype. However, at the highest tertile of arsenic, the XRCC1 194Arg/Arg polymorphism conferred a 3-fold larger odds ratio for skin lesions compared with XRCC1 194Trp/Trp. Individuals may have different odds for developing skin lesions based in part on their genetic profile for BER and their arsenic exposure history. Future research on arsenic-induced skin lesions should consider the impact of genetic variation to individual susceptibility to arsenic toxicity.

Abbreviations: APE1, apurinic/apyrimidinic endonuclease; BER, base excision repair; BMI, body mass index; CIs, confidence intervals; hOGG1, human 8-oxoguanine DNA glycosylase; HWE, Hardy–Weinberg equilibrium; POL ß, polymerase ß; RORint, ratio of odds ratios for the interaction; RRint, interaction risk ratio; XRCC1, X-ray repair cross-complementing group 1

Received November 28, 2006; revised January 23, 2007; accepted March 15, 2007.


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