| BackgroundsType 2 diabetes (T2D) is a common multifactorial hereditary disease with both genetic and environmental determinants. The molecular genetic fundament of the monogenical diabetes was discovered at the beginning of the year 2007. After that the specific genes of T2D were determined. These genetic discoveries suggest that hereditary susceptibility of T2D can be speculated from hereditary factors, hence prognose, prevent and early diagnose for T2D. Up to now, there are 18 predisposing genes associated with T2D through genome-wide association study (GWAS) and other single nucleotide polymorphism (SNP) technique. Variations in rs7903146 of TCF7L2, rs5219 (E23K) of KCNJ11 and rs1801282 (Pro12Ala) of PPARG are most significant among the 18 genes. The candidate genes FOXO1 and HNF4A in the present study are both transcription factors involved in the transmission of PPARG insulin signals especially signals in liver and lipolysis. FOXO1 regulates the proliferation ofβ-cell in the situation of insulin resistance. Moreover, it is the coactivator of the promoter of gluconeogenesis genes. HNF4A can activate hundreds of genes especially those associated with glucose, fatty acid and cholesterol metabolisms. Therefore, both of them are selected as candidate genes for the risk of T2D. Additionally, evidence has recently indicated that the Alpha-2-adrenergic receptor (ADRA2A) genetic polymorphisms associated with T2D in Caucasians. Overexpression of ADRA2A inhibits insulin secretion. Catecholamines are associated with energy metabolism and gene-regulated catecholamine release may play an important role in obesity. ADRA2A is one such regulator. In the present study, we tested the association of genetic variation in FOXO1 and HNF4A based on case-control design. Moreover, we will explore whether they have interactive effect on the pathogenesis and development of T2D. The study also aimed at evaluating the association between ADRA2A polymorphisms and T2D and body weight in a Chinese Han population. MethodsWe make use of the non-matching case-control study. The subjects include 577 type 2 diabetic patients and 462 non-diabetic controls. With polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and TaqMan technology methods, single nucleotide polymorphisms (SNPs) of the FOXO1 and HNF4A genes were genotyped. Two SNPs (rs521674 and rs553668) in the ADRA2A gene were genotyped in 2094 Chinese subjects (1042 T2D patients and 1052 non-diabetic controls) by using TaqMan allelic discrimination technique.All statistical analyses were performed using the SPSS statistical package, version 16.0. We evaluated LD values (D'), r2 values and haplotypes by using the SHEsis online software (http://analysis.bio-x.cn/myAnalysis.php). Statistical powers were calculated using PS (Power and Sample Size Calculations Version 2.1.30). Analysis of gene-gene interaction on the risk of T2D was carried out by multifactor dimensionality reduction (MDR) version 2.0 beta 6 (http://www.epistasis.org). A P value of less than 0.05 was considered statistically significant.Results1. Association of polymorphisms in FOXO1 gene with T2DAs for the gene FOXO1, four SNPs (rs2701859, rs9549240, rs9549241, rs12585277) were observed in strong linkage (r2>0.90) and only four valid SNPs (rs17592236, rs2701859, rs3908773, rs4435111) were further genotyped. No statistically significant differences were observed between T2D cases and non-diabetic controls according either the genotype distributions or allele frequencies.2. Association of polymorphisms in HNF4A gene with T2DWe selected and genotyped six SNPs (rs6031558, rs4812831, rs717247, rs3212172, rs6031587 and rsl 1574736) from HNF4A. A SNP (rs11574736) in HNF4A is associated with T2D according both allele frequencies and genotype distributions (17.3%vs.22.2%, P=0.005, OR=0.74,95%CI=0.59-0.92; 3.3%vs.5.0%, P=0.02). Further analysis indicates that the frequencies of common haplotypes H7 (C-G-T-A-C-C), H8 (C-G-T-A-T-G) are significantly lower in T2D than in normal controls (2.8%vs.5.7%, P=0.001, OR=0.48,95%CI=0.31-0.76; 3.8%vs.6.4%, P=0.008, OR=0.58, 95%CI=0.39-0.87). 3. The interaction of FOXO1 gene and HNF4A gene on the pathogenesis of T2DThe analysis between FOXO1-HNF4A interactions on the risk of T2D was carried out by multifactor dimensionality reduction (MDR) version 2.0 beta 6. The rs717247/ rs6031587/rsl 1574736 model is the best one of the four models (testing accuracy= 0.58, CV consistency= 8/10). It means there maybe an interaction among the three SNPs in the gene HNF4A. The second optimum model is rs3908773/rs717247/rs6031587/ rs11574736 (testing accuracy= 0.55, CV consistency= 6/10). It contains a SNP (rs3908773) from FOXO1 and three SNPs (rs717247, rs6031587, rs1 1574736) from HNF4A. Therefore, we hold the opinion that FOXO1 and HNF4A may interact with each other. Moreover, positive results of association analyses about single SNP indicate HNF4A is the main factor during the interaction.4. Association of polymorphisms in ADRA2A gene with T2DA single-locus analysis implicated an association between SNP rs553668 and T2D (45.9%vs.47.4%, P=0.027, OR= 1.266,95%CI=1.028-1.560) in recessive model. No association of SNP rs521674 with T2D was found. Further analysis indicated that the association of SNP rs553668 was found in T2D patients with BMK25 kg/m2 (18.8%vs. 25.3%, P=0.011, OR= 1.464,95%CI= 1.091-1.963) but not with BMI≥25 kg/m2 (P= 0.612).ConclusionsThe present study shows no association between FOXOl genetic polymorphisms and T2D in Chinese Han population. However, we observed that HNF4A genetic polymorphisms were associated with T2D and HNF4A gene may be a susceptibility factor for T2D in Chinese Han population. Moreover, there may be an interaction between FOXO1 and HNF4A. Moreover, the present study provides evidence that the ADRA2A polymorphism rs553668 is associated with T2D and lean (BMI<25 kg/m2) but not with T2D with overweight (BMI≥25 kg/m2), and suggests that ADRA2A may play a role in the regulation of T2D with BMI25 kg/m2.
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