Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America.
PLoS One. 2013 Aug 14;8(8):e70792. doi: 10.1371/journal.pone.0070792. eCollection 2013.
Chronic exposure to arsenic in drinking water is associated with increased risk of type 2 diabetes mellitus (T2DM) but the underlying molecular mechanism remains unclear.
This study evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes associated with diabetes and arsenic exposure in drinking water on the risk of developing T2DM.
In 2009-2011, we conducted a follow up study of 957 Bangladeshi adults who participated in a case-control study of arsenic-induced skin lesions in 2001-2003. Logistic regression models were used to evaluate the association between 38 SNPs in 18 genes and risk of T2DM measured at follow up. T2DM was defined as having a blood hemoglobin A1C level greater than or equal to 6.5% at follow-up. Arsenic exposure was characterized by drinking water samples collected from participants' tubewells. False discovery rates were applied in the analysis to control for multiple comparisons.
Median arsenic levels in 2001-2003 were higher among diabetic participants compared with non-diabetic ones (71.6 µg/L vs. 12.5 µg/L, p-value <0.001). Three SNPs in ADAMTS9 were nominally associated with increased risk of T2DM (rs17070905, Odds Ratio (OR) = 2.30, 95% confidence interval (CI) 1.17-4.50; rs17070967, OR = 2.02, 95%CI 1.00-4.06; rs6766801, OR = 2.33, 95%CI 1.18-4.60), but these associations did not reach the statistical significance after adjusting for multiple comparisons. A significant interaction between arsenic and NOTCH2 (rs699780) was observed which significantly increased the risk of T2DM (p for interaction = 0.003; q-value = 0.021). Further restricted analysis among participants exposed to water arsenic of less than 148 µg/L showed consistent results for interaction between the NOTCH2 variant and arsenic exposure on T2DM (p for interaction = 0.048; q-value = 0.004).
These findings suggest that genetic variation in NOTCH2 increased susceptibility to T2DM among people exposed to inorganic arsenic. Additionally, genetic variants in ADAMTS9 may increase the risk of T2DM.
长期饮用含砷饮用水会增加患 2 型糖尿病（T2DM）的风险，但其中的分子机制尚不清楚。
本研究旨在评估与糖尿病相关的基因中单核苷酸多态性（SNP）与饮用水中砷暴露之间的相互作用对 T2DM 发病风险的影响。
在 2009-2011 年，我们对 957 名孟加拉国成年人进行了随访研究，这些成年人曾参加 2001-2003 年的一项与砷诱导皮肤损伤相关的病例对照研究。采用 logistic 回归模型评估了 18 个基因中的 38 个 SNP 与随访时 T2DM 风险之间的关联。T2DM 定义为随访时的血液血红蛋白 A1C 水平大于或等于 6.5%。砷暴露情况通过收集参与者自备井中的水样来描述。分析中应用了假发现率来控制多重比较。
与非糖尿病患者相比，糖尿病患者在 2001-2003 年的中位砷水平更高（71.6μg/L 比 12.5μg/L，p 值＜0.001）。ADAMTS9 中的三个 SNP 与 T2DM 风险的增加呈名义关联（rs17070905，比值比（OR）=2.30，95%置信区间（CI）1.17-4.50；rs17070967，OR=2.02，95%CI 1.00-4.06；rs6766801，OR=2.33，95%CI 1.18-4.60），但这些关联在调整多重比较后并未达到统计学意义。观察到砷与 NOTCH2（rs699780）之间存在显著的交互作用，这显著增加了 T2DM 的发病风险（交互作用的 p 值=0.003；q 值=0.021）。在暴露于砷浓度低于 148μg/L 的水的参与者中进行的进一步限制分析显示，NOTCH2 变异与砷暴露对 T2DM 之间的交互作用具有一致性（交互作用的 p 值=0.048；q 值=0.004）。
这些发现表明，NOTCH2 中的遗传变异增加了暴露于无机砷人群中患 T2DM 的易感性。此外，ADAMTS9 中的遗传变异可能会增加 T2DM 的发病风险。
