Genetic variation and urine cadmium levels: ABCC1 effects in the Strong Heart Family Study

Environ Pollut. 2021 May 1;276:116717. doi: 10.1016/j.envpol.2021.116717. Epub 2021 Feb 11.

Abstract

Genetic effects are suspected to influence cadmium internal dose. Our objective was to assess genetic determinants of urine cadmium in American Indian adults participating in the Strong Heart Family Study (SHFS). Urine cadmium levels and genotyped short tandem repeat (STR) markers were available on 1936 SHFS participants. We investigated heritability, including gene-by-sex and smoking interactions, and STR-based quantitative trait locus (QTL) linkage, using a variance-component decomposition approach, which incorporates the genetic information contained in the pedigrees. We also used available single nucleotide polymorphisms (SNPs) from Illumina's Metabochip and custom panel to assess whether promising QTLs associated regions could be attributed to SNPs annotated to specific genes. Median urine cadmium levels were 0.44 μg/g creatinine. The heritability of urine cadmium concentrations was 28%, with no evidence of gene-by-sex or -smoking interaction. We found strong statistical evidence for a genetic locus at chromosome 16 determining urine cadmium concentrations (Logarithm of odds score [LOD] = 3.8). Among the top 20 associated SNPs in this locus, 17 were annotated to ABCC1 (p-values from 0.0002 to 0.02), and attenuated the maximum linkage peak by a ∼40%. Suggestive QTL signals (LOD>1.9) in chromosomes 2, 6, 11, 14, and 19, showed associated SNPs in the genes NDUFA10, PDE10A, PLEKHA7, BAZ1A and CHAF1A, respectively. Our findings support that urinary cadmium levels are heritable and influenced by a QTL on chromosome 16, which was explained by genetic variation in ABCC1. Studies with extended sets of genome-wide markers are needed to confirm these findings and to identify additional metabolism and toxicity pathways for cadmium.

Keywords: American Indians; Association study; Cadmium; Heritability; Quantitative trait locus linkage.

MeSH terms

  • Adult
  • Cadmium* / urine
  • Chromosomal Proteins, Non-Histone
  • Genetic Linkage
  • Genotype
  • Humans
  • Multidrug Resistance-Associated Proteins / genetics
  • Phosphoric Diester Hydrolases
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci*

Substances

  • BAZ1A protein, human
  • Chromosomal Proteins, Non-Histone
  • Multidrug Resistance-Associated Proteins
  • Cadmium
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases
  • multidrug resistance-associated protein 1