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Title: Genetic Susceptible Locus in NOTCH2 Interacts with Arsenic in Drinking Water on Risk of Type 2 Diabetes
Authors: Pan W.-C.
Kile M.L.
Seow W.J. 
Lin X.
Quamruzzaman Q.
Rahman M.
Mahiuddin G.
Mostofa G.
Lu Q.
Christiani D.C.
Keywords: arsenic
drinking water
hemoglobin A1c
Adamts9 gene
case control study
controlled study
disease association
drug induced disease
follow up
gene locus
genetic susceptibility
genetic variability
genotype environment interaction
hemoglobin blood level
logistic regression analysis
major clinical study
marker gene
molecular mechanics
non insulin dependent diabetes mellitus
Notch2 gene
risk assessment
single nucleotide polymorphism
skin defect
water contamination
Diabetes Mellitus, Type 2
Drinking Water
Environmental Exposure
Gene-Environment Interaction
Genetic Loci
Genetic Predisposition to Disease
Polymorphism, Single Nucleotide
Receptor, Notch2
Water Pollutants, Chemical
Issue Date: 2013
Citation: Pan W.-C., Kile M.L., Seow W.J., Lin X., Quamruzzaman Q., Rahman M., Mahiuddin G., Mostofa G., Lu Q., Christiani D.C. (2013). Genetic Susceptible Locus in NOTCH2 Interacts with Arsenic in Drinking Water on Risk of Type 2 Diabetes. PLoS ONE 8 (8) : e70792. ScholarBank@NUS Repository.
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 ?g/L vs. 12.5 ?g/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 ?g/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. © 2013 Pan et al.
Source Title: PLoS ONE
ISSN: 19326203
DOI: 10.1371/journal.pone.0070792
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