Abstract
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.
Highlights
Exposure to inorganic arsenic through consumption of contaminated drinking water is a major global health problem
Ingested arsenic absorbed into the blood stream is metabolized in order to facilitate excretion in urine and removal from the body
The only region of the genome known to contain variation that impacts arsenic metabolism efficiency is 10q24.32, and these variants likely alter the function of the nearby gene AS3MT
Summary
Chronic exposure to arsenic through food and drinking water is a serious global health issue, as arsenic can increase risk for cancer, cardiorespiratory diseases, and other chronic conditions. In order to identify new genetic variants that affect arsenic metabolism, we measured variation in proteincoding regions across the entire genome for >4,800 individuals with varying levels of exposure to arsenic through naturally-contaminated drinking water in Bangladesh. Using this data, we identified a variant in the FTCD gene (formiminotransferase cyclodeaminase) that is associated with arsenic metabolism efficiency and risk for arsenic-induced skin lesions. We identified a variant in the FTCD gene (formiminotransferase cyclodeaminase) that is associated with arsenic metabolism efficiency and risk for arsenic-induced skin lesions This genetic variant alters the FTCD amino acid sequence, potentially disrupting a cryptic protein translation start site in exon 3. FTCD codes for an enzyme involved in histidine catabolism and one-carbon/folate metabolism; our result provides new evidence supporting the well-established hypothesis that the folate/one-carbon cycle plays an important role in arsenic-related disease
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