Lead and δ-Aminolevulinic Acid Dehydratase Polymorphism: Where Does It Lead? A Meta-Analysis Original paper

What was reviewed?

This meta-analysis examined ALAD polymorphism and lead, specifically whether the δ-aminolevulinic acid dehydratase (ALAD) gene variant (ALAD2 vs ALAD1) modifies blood and bone lead levels and clinical toxicity markers. The authors pooled observational studies reporting genotype-stratified data for blood lead (BLL), cortical and trabecular bone lead, zinc protoporphyrin (ZPP), hemoglobin, serum creatinine, dimercaptosuccinic acid (DMSA)–chelatable lead, and blood pressure. Random-effects models produced weighted mean differences or standardized mean differences; heterogeneity, Hardy–Weinberg equilibrium (HWE) violations, and publication bias were assessed. The biological rationale is that ALAD2 alters enzyme charge and binds more lead at the active site, potentially increasing measured BLL while decreasing bioavailable lead to downstream heme-pathway targets.

Who was reviewed?

Twenty-four studies met inclusion criteria; fourteen contributed to the BLL analysis (n=6,672: 5,861 ALAD1/1 and 811 ALAD2 carriers). Populations spanned occupationally exposed lead workers, environmentally exposed adults, and children. Allele frequencies varied by ancestry and setting, and two studies deviated from HWE, which the authors handled by sensitivity analyses (pooled results with and without those studies). Outcome coverage differed across papers (e.g., bone lead subsets; renal indices; DMSA testing), but overall the dataset enabled genotype-stratified synthesis across exposure tiers—from high occupational exposures to low environmental background—providing a framework to interpret genotype as an exposure/toxicity modifier.

Most important findings

ALAD2 carriage was associated with higher BLLs in lead workers, null differences in environmentally exposed adults, and larger, but design-limited differences in children; bone lead did not differ by genotype. For hematologic endpoints, ALAD2 carriers had slightly higher hemoglobin and lower (nonsignificant) ZPP, consistent with less heme-pathway inhibition despite higher BLL. DMSA-chelatable lead was lower in ALAD2, indicating reduced bioavailable/chelatable lead. Renal and blood-pressure findings were mixed overall, with small, setting-dependent effects. Mechanistically, stronger binding of lead to ALAD2 raises measured BLL yet reduces lead available to inhibit ferrochelatase, aligning with lower ZPP and slightly higher hemoglobin.

Key implications

Clinically, ALAD2 is a susceptibility modifier: in high-exposure workplaces, ALAD2 carriers may present with higher BLLs but fewer heme-pathway perturbations, whereas at low environmental exposures, genotype has little influence on BLL. Interpreting BLL without genotype may overestimatethe effective toxic burden in ALAD2 carriers or underestimate it in ALAD1/1 individuals when using ZPP/hemoglobin as effect markers. For microbiome research and databases, record exposure tier (occupational vs environmental), genotype (ALAD), and, where feasible, other modifiers (e.g., VDR, eNOS) when linking lead to taxa/pathways; this improves comparability of signatures and reduces misclassification when BLL is used as the sole exposure variable.