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

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.

Rare, Protein-Altering Variants in AS3MT and Arsenic Metabolism Efficiency: A Multi-Population Association Study

“…This is the same pattern of association observed among the HEALS study participants by Pierce et al. ( 2012 , 2013 , 2019 ) for common variants that are associated with AME, namely, the risk allele decreases DMA% and increases MMA% and iAs%. This study represents one of the first attempts to assess the effects of rare inherited variation on AME in humans, and we address this question in multiple population groups of different ancestries and arsenic exposure levels.…”

“…We used previously reported association estimates and SEs (from the HEALS cohort) for the a ) of AS3MT SNPs and FTCD SNP with DMA%; and b ) associations of AS3MT SNPs and FTCD SNP with skin lesions (Table S8) ( Pierce et al. 2013 , 2019 ). Given an estimated logOR of 0.069 for a 1-unit decrease in DMA% and an 8.7% reduction in DMA% among carriers (from meta-analysis, Table 3 ), the estimated the risk of developing skin lesions for carriers in the HEALS cohort was 82% higher ( ) compared with noncarriers of AS3MT rare variants (Table S9).…”

Research Participants’ Attitudes towards Receiving Information on Genetic Susceptibility to Arsenic Toxicity in Rural Bangladesh

“…Within HEALS, we have the opportunity to study the impact of returning information on genetic susceptibility to arsenic toxicity. Using genetic variation in the AS3MT (arsenic methyltransferase) and FTCD (formiminotransferase cyclodeaminase) regions known to impact arsenic metabolism efficiency and arsenic-induced skin lesion risk [13,26,27], we can identify participants at high risk for arsenic toxicities. In the context of an exposure reduction intervention (i.e., Chen et al [22] and Huhmann et al [28]), informing high-risk individuals of their increased genetic risk may provide additional motivation to change behavior and reduce exposure, potentially increasing the effectiveness of an intervention among those most susceptible to the effects of exposure.…”

Arsenic and gallbladder cancer risk: Mendelian randomization analysis of European prospective data

“…Statistics on the association between the percentages of arsenic species and the instrumental variables rs9527 and rs11191527 near AS3MT, and rs61735836 in exon 3 of FTCD were retrieved from two publications. 4,9 Additive mixed linear regression models were used for association testing in two study populations comprising 2,060 (AS3MT) and 1,660 (FTCD) arsenic-exposed Bangladeshi individuals. The variance in relative abundance of arsenic species explained by the considered genetic variants (for example,~10% for DMA%) and the available sample size (103 prospective cases and 168 controls) translated into a detectable OR of around 0.39 per standard deviation (SD; type I error rate of 5%).…”

“…Ethics approval was obtained for all studies and informed consent was provided by all participants. Statistics on the association between the percentages of arsenic species and the instrumental variables rs9527 and rs11191527 near AS3MT , and rs61735836 in exon 3 of FTCD were retrieved from two publications . Additive mixed linear regression models were used for association testing in two study populations comprising 2,060 ( AS3MT ) and 1,660 ( FTCD ) arsenic‐exposed Bangladeshi individuals.…”