Tamayo Lizeth I, Tong Lin, Davydiuk Tetiana, Vander Griend Donald, Haque Syed Emdadul, Islam Tariqul, Jasmine Farzana, Kibriya Muhammad G, Graziano Joseph, Chen Lin, Le X Chris, Ahsan Habibul, Gamble Mary V, Pierce Brandon L
Department of Public Health Sciences, University of Chicago, Chicago, Illinois, United States of America.
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.
PLoS Genet. 2025 Sep 2;21(9):e1011826. doi: 10.1371/journal.pgen.1011826. eCollection 2025 Sep.
In Bangladesh, > 50 million individuals are chronically exposed to inorganic arsenic (iAs) through drinking water, increasing risk for cancer and other iAs-related diseases. Previous studies show that individuals' ability to metabolize and eliminate iAs, and their risk of toxicity, is influenced by genetic variation in the AS3MT and FTCD gene regions.
To identify additional loci influencing arsenic metabolism, we used data from Bangladeshi individuals to conduct genome-wide association analyses of the relative abundances of arsenic species measured in both urine (n = 6,540) and blood (n = 976). These species include iAs, monomethylated arsenic (MMA) and dimethylated arsenic (DMA) species.
In analyses of urine arsenic species, we identified a novel association signal in the FMO gene cluster (1q24.3), with the lead SNP residing in FMO3 (MMA% P = 4.2x10-16). In analyses of blood arsenic species, we identified an additional signal in the FMO cluster, with the lead SNP residing in FMO4 (DMA% P = 2.3x10-22) and a novel signal at 10q25.1, with the lead SNP in GSTO1 (DMA% P = 5.3x10-13). Lead SNPs at FMO3 and GSTO1 are associated with the splicing of FMO3 and GSTO1, respectively, in multiple tissue types, but also contain missense variants. The lead SNPs at FMO4 are associated with FMO4 expression level in multiple tissue types. These newly identified SNPs did not show a clear association with risk for arsenic-induced skin lesions (P > 0.05), based on 3,448 cases and 5,207 controls.
We identified novel loci influencing arsenic metabolites measured in both urine and blood. FMOs are involved in the oxidation of xenobiotics but have no known direct role in arsenic metabolism, while GSTO1 has a well-established role in catalyzing the reduction of arsenic species. The novel associations we report appear specific to blood or urine, with no detectable impact on skin toxicity risk, pointing to complexities in arsenic metabolism and its genetic contributors that require further study.
在孟加拉国，超过5000万人通过饮用水长期接触无机砷（iAs），这增加了患癌症和其他与iAs相关疾病的风险。先前的研究表明，个体代谢和消除iAs的能力及其中毒风险受AS3MT和FTCD基因区域的基因变异影响。
为了确定影响砷代谢的其他基因座，我们使用来自孟加拉国个体的数据，对尿液（n = 6540）和血液（n = 976）中测量的砷物种相对丰度进行全基因组关联分析。这些物种包括iAs、一甲基砷（MMA）和二甲基砷（DMA）物种。
在尿液砷物种分析中，我们在FMO基因簇（1q24.3）中发现了一个新的关联信号，主要单核苷酸多态性（SNP）位于FMO3（MMA% P = 4.2×10-16）。在血液砷物种分析中，我们在FMO簇中发现了另一个信号，主要SNP位于FMO4（DMA% P = 2.3×10-22），并在10q25.1发现了一个新信号，主要SNP位于GSTO1（DMA% P = 5.3×10-13）。FMO3和GSTO1的主要SNP分别与多种组织类型中FMO3和GSTO1的剪接相关，但也包含错义变异。FMO4的主要SNP与多种组织类型中FMO4的表达水平相关。基于3448例病例和5207例对照，这些新发现的SNP与砷诱导的皮肤病变风险没有明显关联（P > 0.05）。
我们确定了影响尿液和血液中测量的砷代谢物的新基因座。FMO参与外源性物质的氧化，但在砷代谢中没有已知的直接作用，而GSTO1在催化砷物种的还原方面有明确作用。我们报告的新关联似乎特定于血液或尿液，对皮肤毒性风险没有可检测到的影响，这表明砷代谢及其遗传因素存在复杂性，需要进一步研究。
