title: Comprehensive analysis of 5-aminolevulinic acid dehydrogenase (ALAD) variants and renal cell carcinoma risk among individuals exposed to lead.
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 ((GG)OR = 2.68, 95%CI = 1.17-6.12, p = 0.01; (GA)OR = 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer Prevention Fellowship Program, Office of the Director, National Cancer Institute, Bethesda, Maryland, United States of America. vanbemmeld@mail.nih.gov
authors.forename: Dana M
authors.initials: DM
authors.lastname: van Bemmel
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liao
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.forename: Idan
authors.initials: I
authors.lastname: Menashe
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Sara
authors.initials: S
authors.lastname: Karami
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Matteev
authors.forename: Vladimir
authors.initials: V
authors.lastname: Janout
authors.forename: Hellena
authors.initials: H
authors.lastname: Kollarova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bencko
authors.forename: Marie
authors.initials: M
authors.lastname: Navratilova
authors.forename: Neonilia
authors.initials: N
authors.lastname: Szeszenia-Dabrowska
authors.forename: Dana
authors.initials: D
authors.lastname: Mates
authors.forename: Alena
authors.initials: A
authors.lastname: Slamova
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Summer S
authors.initials: SS
authors.lastname: Han
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rosenberg
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.forename: Lee E
authors.initials: LE
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics*; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics*; D007854:Lead / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000623:Porphobilinogen Synthase / Q000235:genetics*
chemical_list: D007854:Lead; D000623:Porphobilinogen Synthase