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Gene-gene interactions lead to higher risk for development of type 2 diabetes in a Chinese Han population: a prospective nested case-control study.

ABSTRACT: BACKGROUND:The purpose of this study was to evaluate the effect of single-nucleotide polymorphisms (SNPs) of the GCKR and G6PC2 genes on risk for type 2 diabetes and the SNP-SNP and haplotype-based interactions between these genes. METHODS:Subjects of this nested case-control study were selected from a prospective cohort residing in the rural area of Luoyang city in China. Cases (n?=?538) were individually matched with controls. Six SNPs in the GCKR and G6PC2 genes were selected and genotyped using an SNPscan™ kit. Stratified Cox proportional hazards regression models were used to generate odds ratios (ORs) and 95% confidence intervals (CI) for different genotype models for the risk of T2DM. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the interactions between two genes with among six SNPs. The linkage disequilibrium (LD) analysis and the haplotype analysis were carried out by SHEsis online. RESULTS:We found that the C allele of rs780094 was associated with increased risk for T2DM in Han Chinese population. However, the rs492594-C allele in G6PC2 was associated with a decreased risk of T2DM. We also found a significant SNP-SNP interaction between rs2293572 and rs492594, and the CCCCGC and CGCCCA haplotypes significantly increased the risk of T2DM, however, the CCCCCA haplotype had lower susceptibility to T2DM. CONCLUSION:The results suggest that the GCKR and G6PC2 genes may contribute to the risk of T2DM independently and/or in an interactive manner in the Han Chinese population.

SUBMITTER: Zhou W

PROVIDER: S-EPMC6064617 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Gene-gene interactions lead to higher risk for development of type 2 diabetes in a Chinese Han population: a prospective nested case-control study.

Zhou Wen W Li Yuqian Y Zhang Lulu L Shi Yuanyuan Y Wang Chongjian C Zhang Dongdong D Liu Xuejiao X Mao Zhenxing Z Li Linlin L

Lipids in health and disease 20180728 1

<h4>Background</h4>The purpose of this study was to evaluate the effect of single-nucleotide polymorphisms (SNPs) of the GCKR and G6PC2 genes on risk for type 2 diabetes and the SNP-SNP and haplotype-based interactions between these genes.<h4>Methods</h4>Subjects of this nested case-control study were selected from a prospective cohort residing in the rural area of Luoyang city in China. Cases (n = 538) were individually matched with controls. Six SNPs in the GCKR and G6PC2 genes were selected a ...[more]

PMID: 30055620

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Project description: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.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.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.

Project description:BackgroundIL13, IL4, IL4RA, FCER1B and ADRB2 are susceptible genes of asthma and atopy. Our previous study has found gene-gene interactions on asthma between these genes in Chinese Han children. Whether the interactions begin in fetal stage, and whether these genes interact with prenatal environment to enhance cord blood IgE (CBIgE) levels and then cause subsequent allergic diseases have yet to be determined. This study aimed to determine whether there are gene-gene and gene-environment interactions on CBIgE elevation among the aforementioned five genes and prenatal environmental factors in Chinese Han population.Methods989 cord blood samples from a Chinese birth cohort were genotyped for nine single-nucleotide polymorphisms (SNPs) in the five genes, and measured for CBIgE levels. Prenatal environmental factors were collected using a questionnaire. Gene-gene and gene-environment interactions were analyzed with generalized multifactor dimensionality methods.ResultsA four-way gene-gene interaction model (IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713) was regarded as the optimal one for CBIgE elevation (testing balanced accuracy = 0.5805, P = 9.03 × 10-4). Among the four SNPs, only IL13 rs20541 was identified to have an independent effect on elevated CBIgE (odds ratio (OR) = 1.36, P = 3.57 × 10-3), while the other three had small but synergistic effects. Carriers of IL13 rs20541 TT, IL13 rs1800925 CT/TT, IL4 rs2243250 TT and ADRB2 rs1042713 AA were estimated to be at more than fourfold higher risk for CBIgE elevation (OR = 4.14, P = 2.69 × 10-2). Gene-environment interaction on elevated CBIgE was found between IL4 rs2243250 and maternal atopy (OR = 1.41, P = 2.65 × 10-2).ConclusionsGene-gene interaction between IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713, and gene-environment interaction between IL4 rs2243250 and maternal atopy begin in prenatal stage to augment IgE production in Chinese Han children.

Project description:BackgroundNoise-induced hearing loss (NIHL) is a complex, irreversible disease caused by the interaction of genetic and environmental factors. In recent years, a great many studies have been done to explore the NIHL susceptibility genes among humans. So far, high powerful detections have been founded that genes of potassium ion channel genes (KCNQ4 and KCNE1), catalase (CAT), protocadherin 15 (PCDH15), myosin 14 (MYH14) and heart shock protein (HSP70) which have been identified in more than one population may be associated with the susceptibility to NIHL. As for metabolic glutamate receptor7 gene (GRM7), a lot of researches mainly focus on age-related hearing loss (ARHL) and the results have shown that the polymorphisms of GRM7 are linked to the development of ARHL. However, little is known about the association of GRM7 and the susceptibility to NIHL. Therefore, the aim of this study was to explore the effect of GRM7 polymorphisms on the susceptibility to NIHL.MethodsA nested case-control study based on the cohort in a Chinese steel factory was implemented in 292 cases and 584 controls matched with the same sex, the age difference ≤ 5 years old, the same type of work, duration of occupational noise exposure ≤2 years. Five single nucleotide polymorphisms (SNPs) of GRM7 were gained through selecting and genotyping SNPs. Conditional logistic regression analysis was used to assess the main effect of GRM7 polymorphisms on the susceptibility to NIHL and the gene-by-environment interaction. Furthermore, the gene-by-gene interactions were analyzed by generalized multiple dimensionality reduction (GMDR).ResultsThis research discovered for the first time that the mutant allele C in rs1485175 of the GMR7 may decrease individuals' susceptibility to NIHL. The interaction between rs1485175 and cumulative noise exposure (CNE) at high level was found after the stratification according to CNE (p/p bon = 0.014/0.007, OR = 0.550, 95% CI: 0.340-0.891). Permutation test of GMDR suggested that rs1920109, rs1485175 and rs9826579 in GRM7 might interact with each other in the process of developing NIHL (p = 0.037).ConclusionsThe results suggest that the mutant allele C of rs1485175 in GRM7 may reduce the susceptibility to NIHL in Chinese Han population.

Dataset Information

Gene-gene interactions lead to higher risk for development of type 2 diabetes in a Chinese Han population: a prospective nested case-control study.

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Gene-gene interactions lead to higher risk for development of type 2 diabetes in a Chinese Han population: a prospective nested case-control study.

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