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

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

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Department of Public Health Sciences, The University of Chicago, Chicago, IL, United States of America.
Department of Human Genetics, The University of Chicago, Chicago, IL, United States of America.
Comprehensive Cancer Center, The University of Chicago, Chicago, IL United States of America.
Division of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, IL, United States of America.
UChicago Research Bangladesh, Mohakhali, Dhaka, Bangladesh.
Research and Evaluation Division, BRAC, Dhaka, Bangladesh.
International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh.
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, United States of America.
Department of Medicine, The University of Chicago, Chicago, IL, United States of America.
Institute for Population and Precision Health, The University of Chicago, Chicago, IL, United States of America.


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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

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