title: Genetic susceptible locus in NOTCH2 interacts with arsenic in drinking water on risk of type 2 diabetes.
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.
  
  
  OBJECTIVE
  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.
authors: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors: Wen-Chi
authors: WC
authors: Pan
authors: Molly L
authors: ML
authors: Kile
authors: Wei Jie
authors: WJ
authors: Seow
authors: Xihong
authors: X
authors: Lin
authors: Quazi
authors: Q
authors: Quamruzzaman
authors: Mahmuder
authors: M
authors: Rahman
authors: Golam
authors: G
authors: Mahiuddin
authors: Golam
authors: G
authors: Mostofa
authors: Quan
authors: Q
authors: Lu
authors: David C
authors: DC
authors: Christiani
mesh_terms: D000328:Adult; D001151:Arsenic / Q000633:toxicity*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics*; D060766:Drinking Water / Q000737:chemistry*; D004781:Environmental Exposure / Q000009:adverse effects; D005260:Female; D059647:Gene-Environment Interaction; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D051883:Receptor, Notch2 / Q000235:genetics*; D014874:Water Pollutants, Chemical / Q000633:toxicity
chemical_list: D060766:Drinking Water; D051883:Receptor, Notch2; D014874:Water Pollutants, Chemical; D001151:Arsenic
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