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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)e1007984
JournalPLoS genetics
Volume15
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

hydroxymethyltransferases and formyltransferases
Bangladesh
Arsenic
arsenic
phenotype
metabolism
toxicity
Phenotype
skin lesions
lesion
Exome
skin
allele
formiminotetrahydrofolate cyclodeaminase
Folic Acid
folic acid
Skin
carbon
Carbon
Alleles

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Pierce, B. L., Tong, L., Dean, S., Argos, M., Jasmine, F., Rakibuz-Zaman, M., ... Ahsan, H. (2019). A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh. PLoS genetics, 15(3), e1007984. https://doi.org/10.1371/journal.pgen.1007984

A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh. / Pierce, Brandon L.; Tong, Lin; Dean, Samantha; Argos, Maria; Jasmine, Farzana; Rakibuz-Zaman, Muhammad; Sarwar, Golam; Islam, Md Tariqul; Shahriar, Hasan; Islam, Tariqul; Rahman, Mahfuzar; Yunus, Md; Lynch, Vincent J.; Oglesbee, Devin; Graziano, Joseph H.; Kibriya, Muhammad G.; Gamble, Mary V.; Ahsan, Habibul.

In: PLoS genetics, Vol. 15, No. 3, 01.03.2019, p. e1007984.

Research output: Contribution to journalArticle

Pierce, BL, Tong, L, Dean, S, Argos, M, Jasmine, F, Rakibuz-Zaman, M, Sarwar, G, Islam, MT, Shahriar, H, Islam, T, Rahman, M, Yunus, M, Lynch, VJ, Oglesbee, D, Graziano, JH, Kibriya, MG, Gamble, MV & Ahsan, H 2019, 'A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh', PLoS genetics, vol. 15, no. 3, pp. e1007984. https://doi.org/10.1371/journal.pgen.1007984
Pierce, Brandon L. ; Tong, Lin ; Dean, Samantha ; Argos, Maria ; Jasmine, Farzana ; Rakibuz-Zaman, Muhammad ; Sarwar, Golam ; Islam, Md Tariqul ; Shahriar, Hasan ; Islam, Tariqul ; Rahman, Mahfuzar ; Yunus, Md ; Lynch, Vincent J. ; Oglesbee, Devin ; Graziano, Joseph H. ; Kibriya, Muhammad G. ; Gamble, Mary V. ; Ahsan, Habibul. / A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh. In: PLoS genetics. 2019 ; Vol. 15, No. 3. pp. e1007984.
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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.",
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AU - Pierce, Brandon L.

AU - Tong, Lin

AU - Dean, Samantha

AU - Argos, Maria

AU - Jasmine, Farzana

AU - Rakibuz-Zaman, Muhammad

AU - Sarwar, Golam

AU - Islam, Md Tariqul

AU - Shahriar, Hasan

AU - Islam, Tariqul

AU - Rahman, Mahfuzar

AU - Yunus, Md

AU - Lynch, Vincent J.

AU - Oglesbee, Devin

AU - Graziano, Joseph H.

AU - Kibriya, Muhammad G.

AU - Gamble, Mary V.

AU - Ahsan, Habibul

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N2 - 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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