Abstract LB-159: A missense variant in FTCD is associated with arsenic metabolism efficiency and arsenic toxicity in Bangladesh

Abstract

Abstract Exposure to drinking water contaminated with inorganic arsenic (iAs), a known human carcinogen, affects over 100 million people worldwide. Arsenic-induced skin lesions are an early sign of arsenic toxicity and a risk factor for subsequent cancer. Once absorbed into the blood, iAs can be converted to mono-methylated (MMA) and then di-methylated (DMA) forms of arsenic, with methylation facilitating the excretion of arsenic in urine. The relative abundance of these arsenic species in urine (iAs%, MMA%, DMA%) represents the efficiency with which an individual metabolizes arsenic. The AS3MT region is the only locus known to harbor variants that influence arsenic metabolism efficiency in humans. In order to identify additional variants that impact arsenic metabolism, we measured protein-coding variants across the human exome using Illumina’s Exome Chip for 1,660 Bangladeshi individuals participating in the Health Effects of Arsenic Longitudinal Study. Among 20,265 exonic variants with a minor allele frequency greater than 1%, only rs61735836 showed associations of experiment-wide significance for all three arsenic metabolite percentages (P=8x10-22, P=7x10-16, and P=2x10-12 for DMA%, MMA%, and iAs%, respectively). The minor allele (A) has a frequency of ~7% in our study (consistent with 1,000 Genomes data) and is associated with decreased DMA% and increased MMA% and iAs%. In subsequent analyses of 2,401 skin lesions cases and 2,472 controls, the low-efficiency allele (A) was associated with increased skin lesion risk (OR=1.25; P=5x10-4), suggesting this variant impacts arsenic toxicity through its impact on metabolism and internal dose of arsenic. rs61735836 is a missense variant (p.Val101Met) in exon 3 of FTCD, which codes for forminidoyltransferase cyclodeaminase. This enzyme is involved in one-carbon metabolism and is critical for production of methenyltetrahydrofolate, a donor of one-carbon groups to the methionine cycle. Methionine provides methyl groups for arsenic metabolism, and variation in folate status and one-carbon metabolism have long been hypothesized to influence arsenic metabolism, with folate supplementation resulting in increased arsenic metabolism efficiency in a randomized trial. FTCD expression in liver (the primary site of arsenic metabolism) is higher than in any other human tissue, but rs614735826 is not associated with gene expression in any tissue (based on GTEx). Furthermore, rs61735836 is not in LD (r2<0.1) with any nearby variant in South Asian populations, suggesting its effect on arsenic metabolism is likely through an amino acid substitution that alters FTCD function. This work implicates FTCD as a novel locus influencing arsenic metabolism efficiency, with potential implications for arsenic-induced cancer risk, and establishes an additional link between one-carbon metabolism and the methylation/metabolism of inorganic arsenic. Citation Format: Brandon L. Pierce, Lin Tong, Maria Argos, Farzana Jasmine, Mary V. Gamble, Joseph Graziano, Muhammad G. Kibriya, Habibul Ahsan. A missense variant in FTCD is associated with arsenic metabolism efficiency and arsenic toxicity in Bangladesh [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-159. doi:10.1158/1538-7445.AM2017-LB-159