Comprehensive analysis of 5-Aminolevulinic acid dehydrogenase (ALAD) variants and renal cell carcinoma risk among individuals exposed to lead

Dana M. van Bemmel, Paolo Boffetta, Linda M. Liao, Sonja I. Berndt, Idan Menashe, Meredith Yeager, Stephen Chanock, Sara Karami, David Zaridze, Vsevolod Matteev, Vladimir Janout, Hellena Kollarova, Vladimir Bencko, Marie Navratilova, Neonilia Szeszenia-Dabrowska, Dana Mates, Alena Slamova, Nathaniel Rothman, Summer S. Han, Philip S. RosenbergPaul Brennan, Wong Ho Chow, Lee E. Moore

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere20432
JournalPloS one
Volume6
Issue number7
DOIs
StatePublished - 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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