J Korean Med Sci.  2017 Feb;32(2):264-271. 10.3346/jkms.2017.32.2.264.

The FOXO1 Gene-Obesity Interaction Increases the Risk of Type 2 Diabetes Mellitus in a Chinese Han Population

• Gong L
• Li R
• Ren W
• Wang Z
• Wang Z
• Yang M
• Zhang S

• KMID: 2364170
• DOI: http://doi.org/10.3346/jkms.2017.32.2.264

Abstract

Here, we aimed to study the effect of the forkhead box O1-insulin receptor substrate 2 (FOXO1-IRS2) gene interaction and the FOXO1 and IRS2 genes-environment interaction for the risk of type 2 diabetes mellitus (T2DM) in a Chinese Han population. We genotyped 7 polymorphism sites of FOXO1 gene and IRS2 gene in 780 unrelated Chinese Han people (474 cases of T2DM, 306 cases of healthy control). The risk of T2DM in individuals with AA genotype for rs7986407 and CC genotype for rs4581585 in FOXO1 gene was 2.092 and 2.57 times higher than that with GG genotype (odds ratio [OR] = 2.092; 95% confidence interval [CI] = 1.178-3.731; P = 0.011) and TT genotype (OR = 2.571; 95% CI = 1.404-4.695; P = 0.002), respectively. The risk of T2DM in individuals with GG genotype for Gly1057Asp in IRS2 gene was 1.42 times higher than that with AA genotype (OR = 1.422; 95% CI = 1.037-1.949; P = 0.029). The other 4 single nucleotide polymorphisms (SNPs) had no significant association with T2DM (P > 0.05). Multifactor dimensionality reduction (MDR) analysis showed that the interaction between SNPs rs7986407 and rs4325426 in FOXO1 gene and waist was the best model confirmed by interaction analysis, closely associating with T2DM. There was an increased risk for T2DM in the case of non-obesity with genotype combined AA/CC, AA/AC or AG/AA for rs7986407 and rs4325426, and obesity with genotype AA for rs7986407 or AA for rs4325426 (OR = 3.976; 95% CI = 1.156-13.675; P value from sign test [P(sign)] = 0.025; P value from permutation test [P(perm)] = 0.000-0.001). Together, this study indicates an association of FOXO1 and IRS2 gene polymorphisms with T2DM in Chinese Han population, supporting FOXO1-obesity interaction as a key factor for the risk of T2DM.

Keyword

Type 2 Diabetes; Gene and Environment; FOXO1; IRS2; Obesity

MeSH Terms

Asian Continental Ancestry Group*
Diabetes Mellitus, Type 2*
Genotype
Humans
Multifactor Dimensionality Reduction
Obesity
Polymorphism, Single Nucleotide

Figure

• 

  Fig. 1 LD maps for SNPs genotyped in FOXO 1 gene. Shades of gray show the strength of the pairwise LD based on D', and numbers indicate the value of r 2 expressed as a percentage. LD = linkage disequilibrium, SNP = single nucleotide polymorphism, FOXO1 = forkhead box O1, D' = standardized LD coefficient.

• 

  Fig. 2 Distribution of high-risk and low-risk genotypes in the best 3-factor model. High-risk genotypes are in dark gray and low-risk genotypes are in light gray. The number of T2DM patients (left bar in boxes) and control subjects (right bar in boxes) are shown for each 3-factor combination. rs7986407: 0 for AA genotype, 1 for AG genotype, 2 for GG genotype; rs4325426: 0 for AA genotype, 1 for AC genotype, 2 for CC genotype; Age: 0 for ≤ 40 years, 1 for > 40 years and ≤ 60 years, 2 for > 60 years; BMI: 0 for < 25 kg/m2, 1 for ≥ 25 kg/m2; Waist: 0 for < 90 cm (male) or 80 cm (female), 1 for ≥ 90 cm (male) or 80 cm (female); TG: 0 for < 1.7 mmol/L, 1 for ≥ 1.7 mmol/L. T2DM = type 2 diabetes mellitus, BMI = body mass index, TG = triglycerides.

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