Department of Public Health Sciences, University of Chicago (UChicago), Chicago, Illinois, USA.
Center for Research Informatics, UChicago, Chicago, Illinois, USA.
Environ Health Perspect. 2021 Apr;129(4):47007. doi: 10.1289/EHP8152. Epub 2021 Apr 7.
Common genetic variation in the arsenic methyltransferase () gene region is known to be associated with arsenic metabolism efficiency (AME), measured as the percentage of dimethylarsinic acid (DMA%) in the urine. Rare, protein-altering variants in could have even larger effects on AME, but their contribution to AME has not been investigated.
We estimated the impact of rare, protein-coding variation in on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants.
We generated targeted DNA sequencing data for the coding regions of for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, ), Strong Heart Study (SHS, ), and New Hampshire Skin Cancer Study (NHSCS, ). We assessed the collective effects of rare (allele frequency ), protein-altering variants on DMA%, using multiple approaches, including a test of the association between rare allele carrier status (yes/no) and DMA% using linear regression (adjusted for common variants in 10q24.32 region, age, sex, and population structure).
We identified 23 carriers of rare-protein-altering variant across all cohorts (13 in HEALS and 5 in both SHS and NHSCS), including 6 carriers of predicted loss-of-function variants. DMA% was 6-10% lower in carriers compared with noncarriers in HEALS [ (95% CI: , )], SHS [ (95% CI: , )], and NHSCS [ (95% CI: , )]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ (95% CI: , )].
Rare, protein-altering variants in were associated with lower mean DMA%, an indicator of reduced AME. Although a small percentage of the population (0.5-0.7%) carry these variants, they are associated with a 6-10% decrease in DMA% that is consistent across multiple ancestral and environmental backgrounds. https://doi.org/10.1289/EHP8152.
已知砷甲基转移酶（）基因区域的常见遗传变异与砷代谢效率（AME）有关，AME 以尿液中二甲基砷酸（DMA%）的百分比来衡量。可能存在更能影响 AME 的罕见、改变蛋白质的变体，但尚未研究它们对 AME 的贡献。
我们使用多人群方法估计罕见、编码的变体对 AME 的影响，以促进发现特定人群和共享因果罕见变体。
我们为三个砷暴露队列生成了编码区域的靶向 DNA 测序数据，这些队列具有尿液中砷物种测量的现有数据：砷纵向研究（HEALS，）、强心研究（SHS，）和新罕布什尔皮肤癌研究（NHSCS，）。我们使用多种方法评估了罕见（等位基因频率）、改变蛋白质的变体对 DMA%的综合影响，包括使用线性回归测试罕见等位基因携带者状态（是/否）与 DMA%之间的关联（调整 10q24.32 区域的常见变体、年龄、性别和人口结构）。
我们在所有队列中发现了 23 名罕见蛋白改变的携带者（HEALS 中有 13 名，SHS 和 NHSCS 各有 5 名），包括 6 名预测的功能丧失变异携带者。与非携带者相比，HEALS [（95% CI：，）]、SHS [（95% CI：，）]和 NHSCS [（95% CI：，）]中的 DMA%低 6-10%。在跨队列的荟萃分析中，DMA%在携带者中低 8.7% [（95% CI：，）]。
在中发现的罕见、改变蛋白质的变体与平均 DMA%降低有关，DMA% 是 AME 降低的指标。尽管只有 0.5-0.7%的人群携带这些变体，但它们与 DMA%降低 6-10%有关，这种降低在多个祖先和环境背景下是一致的。https://doi.org/10.1289/EHP8152。
