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. 2013 Aug 14;8(8):e70792.
doi: 10.1371/journal.pone.0070792. eCollection 2013.

Genetic susceptible locus in NOTCH2 interacts with arsenic in drinking water on risk of type 2 diabetes

Wen-Chi Pan  1 , Molly L Kile, Wei Jie Seow, Xihong Lin, Quazi Quamruzzaman, Mahmuder Rahman, Golam Mahiuddin, Golam Mostofa, Quan Lu, David C Christiani
Affiliations

Genetic susceptible locus in NOTCH2 interacts with arsenic in drinking water on risk of type 2 diabetes

Wen-Chi Pan et al. PLoS One. .

Abstract

Background: 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.

Objectives: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Exposure-response relationship between arsenic in drinking water and diabetes by NOTCH2 in Dhaka, Bangladesh, 2001–2011.
Restricted analyses were performed among people exposed to water arsenic below 148 μg/L adjusting for age, sex, BMI, smoking, skin lesion, and arsenic in drinking water using cubic polynomial models. P for interaction was 0.012. Sample sizes were 316 for TT carriers and 325 for TC/CC carriers of rs699780. The solid line indicated the estimated odds ratio using lowest exposure levels of water arsenic as the reference. Water arsenic was natural logarithm- transformed.
See this image and copyright information in PMC

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