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A missense variant in FTCD affects arsenic metabolism and toxicity phenotypes in Bangladesh.
- Source :
- PLoS Genetics; 3/22/2019, Vol. 15 Issue 3, p1-18, 18p
- Publication Year :
- 2019
-
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<superscript>-13</superscript>), increased MMA% (P = 2x10<superscript>-16</superscript>) and decreased DMA% (P = 6x10<superscript>-23</superscript>). 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<superscript>-5</superscript>). 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15537390
- Volume :
- 15
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- PLoS Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 135634194
- Full Text :
- https://doi.org/10.1371/journal.pgen.1007984