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


RESULTS
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<or=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<or=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<or=0.0001] and 2.3 [95% CI = 1.2-4.4; P<or=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<or=0.001), demonstrating that an independently non-significant variant may interact with another variant resulting in an increased disease risk.
Neuman
Rosalind J
RJ
Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States of America. rneuman@wustl.edu
Wasson
Jon
J
Atzmon
Gil
G
Wainstein
Julio
J
Yerushalmi
Yair
Y
Cohen
Joseph
J
Barzilai
Nir
N
Blech
Ilana
I
Glaser
Benjamin
B
Permutt
M Alan
MA
D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D007585:Jews; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk
C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D008565:Membrane Proteins; C114987:wolframin protein