A missense variant in the FTCD gene (other than the AS3MT gene)) affects arsenic metabolism and toxicity phenotypes in Bangladesh

This topic is very central to gene-environment interactions (i.e. if everyone in a population is exposed to the same undesirable levels of arsenic — why isn’t the toxic response similar) Exposure to inorganic arsenic forms (iAs) in contaminated drinking water is a major global health problem; more than 130 million individuals worldwide are exposed at levels of >10 μg/L, including ~50 million in Bangladesh, where contamination of ground water is a well-known public health issue. Arsenic is a human carcinogen, and chronic exposure to iAs levels through drinking water at levels exceeding 50–100 μg/L is associated with various types of cancer in many populations, including the United States. Arsenic exposure has also been linked to increased risk of type-2 diabetes, cardiovascular disease, non-malignant lung disease, and decreased longevity.

Arsenic-induced skin lesions are an early sign of arsenic exposure and toxicity, which indicates a risk factor for subsequent cancer. Once absorbed into the blood stream, iAs can be converted to mono-methylated (MMA), and then di-methylated (DMA) forms of arsenic, with methylation facilitating excretion of arsenic in the urine (this metabolism is believed to occur primarily in the liver). The relative abundance of these forms of arsenic in urine (percent iAs versus percent MMA versus percent DMA) — varies across individuals and represents the efficiency with which an individual metabolizes arsenic.

Arsenic metabolism is influenced by lifestyle (e.g. occupation, cigarette smoking) and demographic (e.g. ethnicity, climate) factors, as well as genetic variation. Prior genome-wide association studies (GWAS), linkage, and candidate gene studies have shown that variation in the chromosomal 10q24.32 region near the AS3MT gene (arsenite methyltransferase) influences arsenic metabolism efficiency; two independent association signals have been observed in the AS3MT gene region among exposed Bangladeshi individuals. These metabolism-related single-nucleotide variants (SNVs) appear to impact DMA production (not the conversion of iAs to MMA), and “DMA-increasing alleles” have also been shown to be associated with reduced risk for arsenic-induced skin lesions via a SNV-arsenic (i.e. gene-environment, GxE) interaction.

Other than the AS3MT gene region located at chromosome 10q24.32, no other regions of the human genome had been known (until now) that contain variants that show robust and replicable evidence of association with arsenic metabolism efficiency — although studies of heritability suggest that additional variants are likely to exist. In order to identify additional genetic variants that influence arsenic metabolism efficiency, authors [see attached article] conducted a whole-exome sequencing (WES) study; 1,660 Bangladeshi individuals participating in the Health Effects of Arsenic Longitudinal Study (HEALS) were studied. Among almost 20,000 SNVs analyzed exome-wide, the minor allele (A; adenosine, which changed amino-acid-101 from valine to methionine) in exon 3 of the FTCD gene (formiminotransferase cyclodeaminase) was associated with: increased urinary iAs levels (P = 8 x 10–13); increased MMA levels (P =P = 2 x 10–16); and decreased DMA levels (P = 6 x 10–23).

Among 2,401 individuals with arsenic-induced skin lesions (i.e. an indicator of toxicity and cancer risk), compared with 2,472 controls, those carrying the low-metabolism allele [minor allele frequency (MAF) = 7%] were associated with increased skin lesion risk (odds ratio = 1.35; P = 1 x 10–5). The FTCD enzyme is critical for breakdown of histidine, a process that participates in the one-carbon/folate cycle, which ultimately provides methyl groups for arsenic metabolism (methylation). In this study population, therefore, the FTCD and AS3MT SNVs, together, explain ~10% of the heritable variation in DMA metabolite levels — thus supporting a causal effect of arsenic metabolism efficiency on arsenic toxicity (i.e. skin lesions). In summary, these data identify a coding variant in FTCD associated with arsenic metabolism efficiency, providing new evidence of a link between one-carbon/folate metabolism and arsenic toxicity. 😊


PLoS Genet Mar 2o19; 15: e1007984

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