A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh

PLoS Genet. 2019 Mar 20;15(3):e1007984. doi: 10.1371/journal.pgen.1007984. eCollection 2019 Mar.


Inorganic arsenic (iAs) is a carcinogen, and exposure to iAs via food and water is a global public health problem. iAs-contaminated drinking water alone affects >100 million people worldwide, including ~50 million in Bangladesh. Once absorbed into the blood stream, most iAs is converted to mono-methylated (MMA) and then di-methylated (DMA) forms, facilitating excretion in urine. Arsenic metabolism efficiency varies among individuals, in part due to genetic variation near AS3MT (arsenite methyltransferase; 10q24.32). To identify additional arsenic metabolism loci, we measured protein-coding variants across the human exome for 1,660 Bangladeshi individuals participating in the Health Effects of Arsenic Longitudinal Study (HEALS). Among the 19,992 coding variants analyzed exome-wide, the minor allele (A) of rs61735836 (p.Val101Met) in exon 3 of FTCD (formiminotransferase cyclodeaminase) was associated with increased urinary iAs% (P = 8x10-13), increased MMA% (P = 2x10-16) and decreased DMA% (P = 6x10-23). Among 2,401 individuals with arsenic-induced skin lesions (an indicator of arsenic toxicity and cancer risk) and 2,472 controls, carrying the low-efficiency A allele (frequency = 7%) was associated with increased skin lesion risk (odds ratio = 1.35; P = 1x10-5). rs61735836 is in weak linkage disequilibrium with all nearby variants. The high-efficiency/major allele (G/Valine) is human-specific and eliminates a start codon at the first 5´-proximal Kozak sequence in FTCD, suggesting selection against an alternative translation start site. FTCD is critical for catabolism of histidine, a process that generates one-carbon units that can enter the one-carbon/folate cycle, which provides methyl groups for arsenic metabolism. In our study population, FTCD and AS3MT SNPs together explain ~10% of the variation in DMA% and support a causal effect of arsenic metabolism efficiency on arsenic toxicity (i.e., skin lesions). In summary, this work identifies a coding variant in FTCD associated with arsenic metabolism efficiency, providing new evidence supporting the established link between one-carbon/folate metabolism and arsenic toxicity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Alleles
  • Ammonia-Lyases / genetics*
  • Ammonia-Lyases / physiology
  • Arsenic / metabolism
  • Arsenic / toxicity*
  • Arsenic Poisoning
  • Bangladesh
  • Environmental Exposure
  • Female
  • Folic Acid / metabolism
  • Gene Frequency / genetics
  • Glutamate Formimidoyltransferase / genetics*
  • Glutamate Formimidoyltransferase / physiology
  • Humans
  • Male
  • Methylation
  • Methyltransferases / genetics*
  • Methyltransferases / metabolism
  • Multifunctional Enzymes
  • Mutation, Missense
  • Odds Ratio
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors
  • Skin Diseases / chemically induced
  • Skin Diseases / genetics
  • Water Pollutants, Chemical


  • Multifunctional Enzymes
  • Water Pollutants, Chemical
  • Folic Acid
  • Methyltransferases
  • AS3MT protein, human
  • FTCD protein, human
  • Glutamate Formimidoyltransferase
  • Ammonia-Lyases
  • Arsenic