Gene-gene interactions lead to higher risk for development of type 2 diabetes in an Ashkenazi Jewish population

Rosalind J. Neuman, Jon Wasson, Gil Atzmon, Julio Wainstein, Yair Yerushalmi, Joseph Cohen, Nir Barzilai, Ilana Blech, Benjamin Glaser, M. Alan Permutt

Research output: Contribution to journalArticle

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Abstract

Background: Evidence has accumulated that multiple genetic and environmental factors play important roles in determining susceptibility to type 2 diabetes (T2D). Although variants from candidate genes have become prime targets for genetic analysis, few studies have considered their interplay. Our goal was to evaluate interactions among SNPs within genes frequently identified as associated with T2D. Methods/Principal Findings: Logistic regression was used to study interactions among 4 SNPs, one each from HNF4A[rs1884613], TCF7L2[rs12255372], WFS1[rs10010131], and KCNJ11[rs5219] in a case-control Ashkenazi sample of 974 diabetic subjects and 896 controls. Nonparametric multifactor dimensionality reduction (MDR) and generalized MDR (GMDR) were used to confirm findings from the logistic regression analysis. HNF4A and WFS1 SNPs were associated with T2D in logistic regression analyses [P<0.0001, P<0.0002, respectively]. Interaction between these SNPs were also strong using parametric or nonparametric methods: the unadjusted odds of being affected with T2D was 3 times greater in subjects with the HNF4A and WFS1 risk alleles than those without either (95% CI = [1.7-5.3]; P≤0.0001). Although the univariate association between the TCF7L2 SNP and T2D was relatively modest [P = 0.02], when paired with the HNF4A SNP, the OR for subjects with risk alleles in both SNPs was 2.4 [95% CI = 1.7-3.4; P≤0.0001]. The KCNJ11 variant reached significance only when paired with either the HNF4A or WFSI SNPs: unadjusted ORs were 2.0 [95% CI = 1.4-2.8; P≤0.0001] and 2.3 [95% CI = 1.2-4.4; P≤0.0001], respectively. MDR and GMDR results were consistent with the parametric findings. Conclusions: These results provide evidence of strong independent associations between T2D and SNPs in HNF4A and WFS1 and their interaction in our Ashkenazi sample. We also observed an interaction in the nonparametric analysis between the HNF4A and KCNJ11 SNPs (P≤0.001), demonstrating that an independently non-significant variant may interact with another variant resulting in an increased disease risk.

Original languageEnglish (US)
Article numbere9903
JournalPLoS One
Volume5
Issue number3
DOIs
StatePublished - 2010

Fingerprint

gene interaction
Medical problems
noninsulin-dependent diabetes mellitus
Type 2 Diabetes Mellitus
Single Nucleotide Polymorphism
Genes
Multifactor Dimensionality Reduction
Population
Logistics
genes
Logistic Models
alleles
Regression analysis
Alleles
Regression Analysis
genetic techniques and protocols
regression analysis
Association reactions
sampling
environmental factors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Neuman, R. J., Wasson, J., Atzmon, G., Wainstein, J., Yerushalmi, Y., Cohen, J., ... Permutt, M. A. (2010). Gene-gene interactions lead to higher risk for development of type 2 diabetes in an Ashkenazi Jewish population. PLoS One, 5(3), [e9903]. https://doi.org/10.1371/journal.pone.0009903

Gene-gene interactions lead to higher risk for development of type 2 diabetes in an Ashkenazi Jewish population. / Neuman, Rosalind J.; Wasson, Jon; Atzmon, Gil; Wainstein, Julio; Yerushalmi, Yair; Cohen, Joseph; Barzilai, Nir; Blech, Ilana; Glaser, Benjamin; Permutt, M. Alan.

In: PLoS One, Vol. 5, No. 3, e9903, 2010.

Research output: Contribution to journalArticle

Neuman, RJ, Wasson, J, Atzmon, G, Wainstein, J, Yerushalmi, Y, Cohen, J, Barzilai, N, Blech, I, Glaser, B & Permutt, MA 2010, 'Gene-gene interactions lead to higher risk for development of type 2 diabetes in an Ashkenazi Jewish population', PLoS One, vol. 5, no. 3, e9903. https://doi.org/10.1371/journal.pone.0009903
Neuman, Rosalind J. ; Wasson, Jon ; Atzmon, Gil ; Wainstein, Julio ; Yerushalmi, Yair ; Cohen, Joseph ; Barzilai, Nir ; Blech, Ilana ; Glaser, Benjamin ; Permutt, M. Alan. / Gene-gene interactions lead to higher risk for development of type 2 diabetes in an Ashkenazi Jewish population. In: PLoS One. 2010 ; Vol. 5, No. 3.
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AU - Wasson, Jon

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AU - Yerushalmi, Yair

AU - Cohen, Joseph

AU - Barzilai, Nir

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AU - Permutt, M. Alan

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N2 - Background: Evidence has accumulated that multiple genetic and environmental factors play important roles in determining susceptibility to type 2 diabetes (T2D). Although variants from candidate genes have become prime targets for genetic analysis, few studies have considered their interplay. Our goal was to evaluate interactions among SNPs within genes frequently identified as associated with T2D. Methods/Principal Findings: Logistic regression was used to study interactions among 4 SNPs, one each from HNF4A[rs1884613], TCF7L2[rs12255372], WFS1[rs10010131], and KCNJ11[rs5219] in a case-control Ashkenazi sample of 974 diabetic subjects and 896 controls. Nonparametric multifactor dimensionality reduction (MDR) and generalized MDR (GMDR) were used to confirm findings from the logistic regression analysis. HNF4A and WFS1 SNPs were associated with T2D in logistic regression analyses [P<0.0001, P<0.0002, respectively]. Interaction between these SNPs were also strong using parametric or nonparametric methods: the unadjusted odds of being affected with T2D was 3 times greater in subjects with the HNF4A and WFS1 risk alleles than those without either (95% CI = [1.7-5.3]; P≤0.0001). Although the univariate association between the TCF7L2 SNP and T2D was relatively modest [P = 0.02], when paired with the HNF4A SNP, the OR for subjects with risk alleles in both SNPs was 2.4 [95% CI = 1.7-3.4; P≤0.0001]. The KCNJ11 variant reached significance only when paired with either the HNF4A or WFSI SNPs: unadjusted ORs were 2.0 [95% CI = 1.4-2.8; P≤0.0001] and 2.3 [95% CI = 1.2-4.4; P≤0.0001], respectively. MDR and GMDR results were consistent with the parametric findings. Conclusions: These results provide evidence of strong independent associations between T2D and SNPs in HNF4A and WFS1 and their interaction in our Ashkenazi sample. We also observed an interaction in the nonparametric analysis between the HNF4A and KCNJ11 SNPs (P≤0.001), demonstrating that an independently non-significant variant may interact with another variant resulting in an increased disease risk.

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