A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh.
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-m...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-03-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1007984 |
| _version_ | 1797995847425720320 |
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| author | Brandon L Pierce Lin Tong Samantha Dean Maria Argos Farzana Jasmine Muhammad Rakibuz-Zaman Golam Sarwar Md Tariqul Islam Hasan Shahriar Tariqul Islam Mahfuzar Rahman Md Yunus Vincent J Lynch Devin Oglesbee Joseph H Graziano Muhammad G Kibriya Mary V Gamble Habibul Ahsan |
| author_facet | Brandon L Pierce Lin Tong Samantha Dean Maria Argos Farzana Jasmine Muhammad Rakibuz-Zaman Golam Sarwar Md Tariqul Islam Hasan Shahriar Tariqul Islam Mahfuzar Rahman Md Yunus Vincent J Lynch Devin Oglesbee Joseph H Graziano Muhammad G Kibriya Mary V Gamble Habibul Ahsan |
| author_sort | Brandon L Pierce |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T10:08:07Z |
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| id | doaj.art-1aba6777696e4dfa8e8bc0e75e54c65b |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-11T10:08:07Z |
| publishDate | 2019-03-01 |
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| series | PLoS Genetics |
| spelling | doaj.art-1aba6777696e4dfa8e8bc0e75e54c65b2022-12-22T04:30:10ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042019-03-01153e100798410.1371/journal.pgen.1007984A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh.Brandon L PierceLin TongSamantha DeanMaria ArgosFarzana JasmineMuhammad Rakibuz-ZamanGolam SarwarMd Tariqul IslamHasan ShahriarTariqul IslamMahfuzar RahmanMd YunusVincent J LynchDevin OglesbeeJoseph H GrazianoMuhammad G KibriyaMary V GambleHabibul AhsanInorganic 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.https://doi.org/10.1371/journal.pgen.1007984 |
| spellingShingle | Brandon L Pierce Lin Tong Samantha Dean Maria Argos Farzana Jasmine Muhammad Rakibuz-Zaman Golam Sarwar Md Tariqul Islam Hasan Shahriar Tariqul Islam Mahfuzar Rahman Md Yunus Vincent J Lynch Devin Oglesbee Joseph H Graziano Muhammad G Kibriya Mary V Gamble Habibul Ahsan A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh. PLoS Genetics |
| title | A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh. |
| title_full | A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh. |
| title_fullStr | A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh. |
| title_full_unstemmed | A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh. |
| title_short | A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh. |
| title_sort | missense variant in ftcd is associated with arsenic metabolism and toxicity phenotypes in bangladesh |
| url | https://doi.org/10.1371/journal.pgen.1007984 |
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