Pierce Brandon L, Tong Lin, Argos Maria, Gao Jianjun, Farzana Jasmine, Roy Shantanu, Paul-Brutus Rachelle, Rahaman Ronald, Rakibuz-Zaman Muhammad, Parvez Faruque, Ahmed Alauddin, Quasem Iftekhar, Hore Samar K, Alam Shafiul, Islam Tariqul, Harjes Judith, Sarwar Golam, Slavkovich Vesna, Gamble Mary V, Chen Yu, Yunus Mohammad, Rahman Mahfuzar, Baron John A, Graziano Joseph H, Ahsan Habibul
Int J Epidemiol. 2013 Dec;42(6):1862-71. doi: 10.1093/ije/dyt182.
Arsenic 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.
Using 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.
Causal 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).
We 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.
通过饮用水接触砷是一个严重的全球健康问题。观察性研究表明，能够有效代谢砷的个体发生诸如砷性皮肤损害等毒性反应的风险较低。利用位于10q24.32区域（靠近AS3MT）的两个单核苷酸多态性（SNP），它们与代谢效率呈现独立关联，孟德尔随机化可用于评估代谢效率与皮肤损害之间的关联是否可能具有因果关系。
利用2060名接触砷的孟加拉国个体的数据，我们估计了两个10q24.32 SNP与三种尿砷形态（代表代谢效率）的相对浓度之间的关联：无机砷（iAs）、一甲基胂酸（MMA）和二甲基胂酸（DMA）。在2483例病例和2857例对照中，对基于SNP的iAs%、MMA%和DMA%预测值与皮肤损害状态进行关联检验。
DMA%、MMA%和iAs%每增加一个标准差，皮肤损害的因果比值比分别为0.90（95%置信区间[CI]：0.87，0.95）、1.19（CI：1.10，1.28）和1.23（CI：1.12，1.36）。我们证明了基因型-砷相互作用，在高砷暴露个体中，与代谢相关的变异与皮肤损害风险的关联更强（协同指数：1.37；CI：1.11，1.62）。
我们为砷代谢效率与皮肤损害风险之间的因果关系提供了有力证据。孟德尔随机化可用于评估砷暴露和代谢在多种健康状况中的因果作用。开发提高砷代谢效率的干预措施可能会降低砷暴露对健康的影响。
