Article Publish Status: FREE
Abstract Title:

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

Abstract Source:

PLoS One. 2013 ;8(8):e70792. Epub 2013 Aug 14. PMID: 23967108

Abstract Author(s):

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

Article Affiliation:

Wen-Chi Pan


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 (71.6µg/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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