Correction: A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh.
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ABSTRACT:
SUBMITTER: Pierce BL
PROVIDER: S-EPMC6527204 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
Publications
Correction: A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh.
Pierce Brandon L BL Tong Lin L Dean Samantha S Argos Maria M Jasmine Farzana F Rakibuz-Zaman Muhammad M Sarwar Golam G Islam Md Tariqul MT Shahriar Hasan H Islam Tariqul T Rahman Mahfuzar M Yunus Md M Lynch Vincent J VJ Oglesbee Devin D Graziano Joseph H JH Kibriya Muhammad G MG Gamble Mary V MV Ahsan Habibul H
PLoS genetics 20190520 5
[This corrects the article DOI: 10.1371/journal.pgen.1007984.]. ...[more]
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Project 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.
| S-EPMC6443193 | biostudies-literature
Project description:Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10(-8)) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P?=?0.0005). Using a subset of individuals with prospectively measured arsenic (n?=?769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P?=?0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P?=?10(-12)) and neighboring gene C10orf32 (P?=?10(-44)), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide.
| S-EPMC3285587 | biostudies-literature
Project description:Large individual differences in susceptibility to arsenic-induced diseases are well-documented and frequently associated with different patterns of arsenic metabolism. In this context, the role of the gut microbiome in directly metabolizing arsenic and triggering systemic responses in diverse organs raises the possibility that gut microbiome phenotypes affect the spectrum of metabolized arsenic species. However, it remains unclear how host genetics and the gut microbiome interact to affect the biotransformation of arsenic. Using an integrated approach combining 16S rRNA gene sequencing and HPLC-ICP-MS arsenic speciation, we demonstrate that IL-10 gene knockout leads to a significant taxonomic change of the gut microbiome, which in turn substantially affects arsenic metabolism.
| S-EPMC3997221 | biostudies-literature
Project description:BackgroundArsenic exposure through drinking water is a serious global health issue. Observational studies suggest that individuals who metabolize arsenic efficiently are at lower risk for toxicities such as arsenical skin lesions. Using two single nucleotide polymorphisms(SNPs) in the 10q24.32 region (near AS3MT) that show independent associations with metabolism efficiency, Mendelian randomization can be used to assess whether the association between metabolism efficiency and skin lesions is likely to be causal.MethodsUsing data on 2060 arsenic-exposed Bangladeshi individuals, we estimated associations for two 10q24.32 SNPs with relative concentrations of three urinary arsenic species (representing metabolism efficiency): inorganic arsenic (iAs), monomethylarsonic acid(MMA) and dimethylarsinic acid (DMA). SNP-based predictions of iAs%, MMA% and DMA% were tested for association with skin lesion status among 2483 cases and 2857 controls.ResultsCausal odds ratios for skin lesions were 0.90 (95% confidence interval[CI]: 0.87, 0.95), 1.19 (CI: 1.10, 1.28) and 1.23 (CI: 1.12, 1.36)for a one standard deviation increase in DMA%, MMA% and iAs%,respectively. We demonstrated genotype-arsenic interaction, with metabolism-related variants showing stronger associations with skin lesion risk among individuals with high arsenic exposure (synergy index: 1.37; CI: 1.11, 1.62).ConclusionsWe provide strong evidence for a causal relationship between arsenic metabolism efficiency and skin lesion risk. Mendelian randomization can be used to assess the causal role of arsenic exposure and metabolism in a wide array of health conditions.exposure and metabolism in a wide array of health conditions.Developing interventions that increase arsenic metabolism efficiency are likely to reduce the impact of arsenic exposure on health.
| S-EPMC3887566 | biostudies-literature
Project description:BackgroundMillions of households throughout Bangladesh have been exposed to high levels of arsenic (As) causing various deadly diseases by drinking groundwater from shallow tubewells for the past 30 years. Well testing has been the most effective form of mitigation because it has induced massive switching from tubewells that are high (>50 µg/L) in As to neighboring wells that are low in As. A recent study has shown, however, that shallow low-As wells are more likely to be contaminated with the fecal indicator E. coli than shallow high-As wells, suggesting that well switching might lead to an increase in diarrheal disease.MethodsApproximately 60,000 episodes of childhood diarrhea were collected monthly by community health workers between 2000 and 2006 in 142 villages of Matlab, Bangladesh. In this cross-sectional study, associations between childhood diarrhea and As levels in tubewell water were evaluated using logistic regression models.ResultsAdjusting for wealth, population density, and flood control by multivariate logistic regression, the model indicates an 11% (95% confidence intervals (CIs) of 4-19%) increase in the likelihood of diarrhea in children drinking from shallow wells with 10-50 µg/L As compared to shallow wells with >50 µg/L As. The same model indicates a 26% (95%CI: 9-42%) increase in diarrhea for children drinking from shallow wells with ?10 µg/L As compared to shallow wells with >50 µg/L As.ConclusionChildren drinking water from shallow low As wells had a higher prevalence of diarrhea than children drinking water from high As wells. This suggests that the health benefits of reducing As exposure may to some extent be countered by an increase in childhood diarrhea.
| S-EPMC3247276 | biostudies-literature
Project description:BackgroundIn human genetics research, it has become common practice for researchers to consider returning genetic information to participants who wish to receive it. Research participants in lower-resource settings may have barriers or competing interests that reduce the benefit or relevance of such information. Thus, the decision to return genetic information in these settings may involve special considerations of participants' interests and preferences. In this project, our goal was to assess Bangladeshi research participants' attitudes towards receiving information regarding genetic susceptibility to the effects of consuming arsenic-contaminated drinking water, a serious environmental health concern in Bangladesh and other countries.MethodsWe administered a short questionnaire to 200 individuals participating in the Health Effects of Arsenic Longitudinal Study. Associations between survey responses and participant characteristics were estimated using logistic regression.ResultsOverall, 100% of our participants were interested in receiving information regarding their genetic susceptibility to arsenic toxicities, and 91% indicated that being at increased genetic risk would motivate them to make efforts to reduce their exposure. Lower levels of education showed evidence of association with less concern regarding the health effects of arsenic and lower levels of motivation to reduce exposure in response to genetic information.ConclusionsResearch participants in this low-resource setting appeared interested in receiving information on their genetic susceptibility to arsenic toxicity and motivated to reduce exposure in response to such information. Additional research is needed to understand how best to communicate genetic information in this population and to assess the impact of such information on individuals' behaviors and health.
| S-EPMC7605079 | biostudies-literature
Project description:BackgroundInorganic arsenic (As) is methylated via one carbon metabolism (OCM) to mono- and dimethylated arsenicals (MMA and DMA), facilitating urinary excretion. Hyperhomocysteinemia (HHcys), a marker of impaired OCM, is a risk factor for As-induced skin lesions, but the influences of single nucleotide polymorphisms (SNPs) in OCM genes on Hcys, As metabolism and skin lesion risk is unclear.ObjectivesTo (i) explore genetic sources of Hcys and the causal role of HHcys in As-induced skin lesion development using OCM genetic proxies for HHcys and (ii) identify OCM SNPs associated with urinary As metabolite proportions and/or skin lesion incidence.MethodsWe conducted a case-control study nested in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh which 876 incident skin lesion cases were matched to controls on sex, age, and follow-up time. We measured serum Hcys, urinary As metabolites, and 26 SNPs in 13 OCM genes.ResultsSerum Hcys and urinary %DMA were independently associated with increased and decreased odds of skin lesions, respectively. The T allele of MTHFR 677 C ➔ T (rs1801133) was associated with HHcys, higher %MMA, and lower %DMA, but not with skin lesions. Interactions between SNPs and water As on skin lesion risk were suggestive for three variants: the G allele of MTRR rs1801394 and T allele of FOLR1 rs1540087 were associated with lower odds of skin lesions with lower As (≤50 μg/L), and the T allele of TYMS rs1001761 was associated with higher odds of skin lesions with higher As.ConclusionsWhile HHcys and decreased %DMA were associated with increased risk for skin lesions, and MTHFR 677 C ➔ T was a strong predictor of HHcys, MTHFR 677 C ➔ T was not associated with skin lesion risk. Future studies should explore (i) non-OCM and non-genetic determinants of Hcys and (ii) if genetic findings are replicated in other As-exposed populations, mechanisms by which OCM SNPs may influence the dose-dependent effects of As on skin lesion risk.
| S-EPMC5873983 | biostudies-literature
Project description:Exposure to inorganic arsenic (InAs) via drinking water and/or food is a considerable worldwide problem. Methylation of InAs generates monomethyl (MMAsIII+V)- and dimethyl (DMAsIII+V)-arsenical species in a process that facilitates urinary As elimination; however, MMAs is considerably more toxic than either InAs or DMAs. Emerging evidence suggests that incomplete methylation of As to DMAs, resulting in increased MMAs, is associated with increased risk for a host of As-related health outcomes. The biochemical pathway that provides methyl groups for As methylation, one-carbon metabolism (OCM), is influenced by folate and other micronutrients, including choline and betaine. Individuals and species differ widely in their ability to methylate As. A growing body of research, including cell-culture, animal-model, and epidemiological studies, has demonstrated the role of OCM-related micronutrients in As methylation. This review examines the evidence that nutritional status and nutritional interventions can influence the metabolism and toxicity of As, with a primary focus on folate.
| S-EPMC6441546 | biostudies-literature
Project description:[This corrects the article DOI: 10.1371/journal.pgen.1008922.].
| S-EPMC7842877 | biostudies-literature
Project description:Axillary osmidrosis (AO) is a common condition characterized by an offensive odor arising from apocrine gland secretions in the axillae that socially and psychologically impairs affected individuals. The exact aetiology of AO is still not fully understood, but genetic factors have been suggested to play an important role. Recently, a single nucleotide polymorphism (SNP) rs17822931 in the ABCC11 gene located on human chromosome 16q12.1 has been shown to be associated with AO. In this study, we genotyped rs17822931 in two independent samples of Chinese Hans including 93 AO individuals vs 95 controls and 81 AO individuals vs 106 controls by using SNaPshot Multiplex Kit. We confirmed the association for ABCC11 gene, showing that rs17822931-G was significantly associated with increased risk for AO (Pcombined = 1.42E-21, OR = 83.94, 95% CI = 83.03-84.85). We also found rs17822931 was associated with subphenotypes of AO. AO individuals carrying the risk allele G are more likely to show wet earwax (P = 2.40E-05), higher frequency of family history (P = 1.04E-02) and early age of onset (P = 3.81E-02). Our study concluded that the association of rs17822931 in the ABCC11 gene with AO was replicated in Chinese Han population.
| S-EPMC5423033 | biostudies-literature