Abstract
BackgroundEpidemiologic 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.MethodsThe 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.ResultsThe adjusted risk associated with the ALAD variant rs8177796CT/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 (pint = 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.ConclusionA 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.
Highlights
Lead is a naturally occurring heavy metal used in the manufacturing of consumer products including; batteries, paints, metal products, cable covering, and ceramic glaze
We first explored the association between lead exposure and renal cell carcinoma (RCC) risk
After adjusting for age, gender, and center, the overall risk of RCC was increased among participants exposed to any lead (OR = 1.70, 95%confidence intervals (CI) = 1.21–2.38; p-value = 0.002) when compared to those with no reported lead exposure
Summary
Lead is a naturally occurring heavy metal used in the manufacturing of consumer products including; batteries, paints, metal products (such as sheet metal), cable covering, and ceramic glaze. The wide-spread use of lead in manufacturing results in a continued occupational exposure to lead world-wide. The toxic effects of acute lead exposure are well-established. Lead exposure results in adverse effects on hematopoietic, gastrointestinal, urinary, cardiovascular, and nervous systems [1]. Chronic lead exposure has been associated with aberrant cognitive development in children, anemia, hypertension, and the development of neurological disorders [2,3,4,5]. The International Agency for Research on Cancer (IARC) classifies inorganic lead as a probable human carcinogen (Group 2A), based on sufficient evidence from animal studies and limited epidemiologic research [6]. 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
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