TY - JOUR
T1 - Comprehensive analysis of 5-Aminolevulinic acid dehydrogenase (ALAD) variants and renal cell carcinoma risk among individuals exposed to lead
AU - van Bemmel, Dana M.
AU - Boffetta, Paolo
AU - Liao, Linda M.
AU - Berndt, Sonja I.
AU - Menashe, Idan
AU - Yeager, Meredith
AU - Chanock, Stephen
AU - Karami, Sara
AU - Zaridze, David
AU - Matteev, Vsevolod
AU - Janout, Vladimir
AU - Kollarova, Hellena
AU - Bencko, Vladimir
AU - Navratilova, Marie
AU - Szeszenia-Dabrowska, Neonilia
AU - Mates, Dana
AU - Slamova, Alena
AU - Rothman, Nathaniel
AU - Han, Summer S.
AU - Rosenberg, Philip S.
AU - Brennan, Paul
AU - Chow, Wong Ho
AU - Moore, Lee E.
PY - 2011/7/26
Y1 - 2011/7/26
N2 - Background: Epidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead. Methods: The objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. Results: The adjusted risk associated with the ALAD variant rs8177796 CT/TT was increased (OR = 1.35, 95%CI = 1.05-1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles ( GGOR = 2.68, 95%CI = 1.17-6.12, p = 0.01; GAOR = 1.79, 95%CI = 1.06-3.04 with an interaction approaching significance (p int = 0.06). No significant modification in RCC risk was observed for the functional variant rs1800435 (K68N). Haplotype analysis identified a region associated with risk supporting tagging SNP results. Conclusion: A common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure.
AB - Background: Epidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead. Methods: The objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. Results: The adjusted risk associated with the ALAD variant rs8177796 CT/TT was increased (OR = 1.35, 95%CI = 1.05-1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles ( GGOR = 2.68, 95%CI = 1.17-6.12, p = 0.01; GAOR = 1.79, 95%CI = 1.06-3.04 with an interaction approaching significance (p int = 0.06). No significant modification in RCC risk was observed for the functional variant rs1800435 (K68N). Haplotype analysis identified a region associated with risk supporting tagging SNP results. Conclusion: A common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure.
UR - http://www.scopus.com/inward/record.url?scp=79960576472&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0020432
DO - 10.1371/journal.pone.0020432
M3 - Article
C2 - 21799727
AN - SCOPUS:79960576472
SN - 1932-6203
VL - 6
JO - PLoS ONE
JF - PLoS ONE
IS - 7
M1 - e20432
ER -
