| Diabetes Mellitus(DM)is a metabolic disease characterized by chronic hyperglycemia due to insulin secretion defects and/or impaired insulin activity.With the aging of Chinese population and lifestyle changes,diabetes has become the main risk factor for atherosclerosis cardiovascular disease(ASCVD)and ASCVD death,and is also the leading cause of blindness,non-traumatic lower limb amputation,peripheral neuropathy and end-stage kidney disease.Diabetic kidney disease(DKD)which is previously known as diabetic nephropathy(DN),refers to the chronic kidney disease(CKD)caused by diabetes,is one of the major microvascular complications of diabetes.DKD which is the important cause of End-stage renal disease(ESRD)is a complex disease caused by both genetic and environmental factors.The prevalence of DKD in patients with type 2 diabetes(T2DM)in China was reported to be 10% to 40%.Many Risk factors have been found involved in the pathogenesis of DKD,including advanced age,gender,race,long-term illness,hyperglycemia,hypertension,obesity(especially abdominal obesity),high-salt diet,dyslipidemia,renal-toxic medicine,acute kidney injury,and excessive protein intake.Studies about the clinical indicators for diabetic kidney disease have been performed in China,while the the conclusions are inconsistent due to different research area.Forkhead box O1(Fox O1)is an important transcription factor belongs to the Fox O family.Fox O1 is primarily regulated by phosphinositide 3 kinase(PI3K)/Protein kinase B(AKT)and is involved in regulation of many genes expression.Fox O1 plays an important role in insulin resistance,islet beta cell proliferation,differentiation,apoptosis and glycolipid metabolism,contributing to the pathogenesis of T2 DM.So far,studies about Fox O1 and diabeticcomplications are limited.Basic studies have shown that Fox O1 may regulate antioxidant genes,and increasing Fox O1 expression in glomerular may improve DKD by reducing extracellular matrix accumulation and regulating cell autophagy.Therefore,Fox O1 might be served as a new marker for DKD.Single nucleotide polymorphism(SNP)is one of the most common human genetic variants,accounting for more than 90% of known genetic polymorphisms.SNP may cause diseases by altering genes expression.So far,it has been found that there are thousands of polymorphic sites on the Fox O1 gene,however,the effect of these polymorphic sites on Fox O1 function is not quite clear.In addition,the effects of polymorphic site reported on diabetes are not consistent.The data about the relationship between the Fox O1 gene SNPs and the development of DKD is even less.Therefore,the purpose of this study is to clarify the clinical characteristics of kidney disease in type 2 diabetes,and to explore the relationship between serum Fox O1 and diabetic kidney disease,and the relationship between Fox O1 gene SNP and the risk of DKD.These data may provide valuable information for the prediction,early diagnosis,individualized therapy and prognosis judgment for DKD.Part One Analysis of clinical risk factors of type 2 diabetic kidney diseaseObjective: To study the relationship between the clinical characteristics of type 2 diabetes and the occurrence of type 2 diabetic kidney disease.Methods: This study included 138 patients with type 2 diabetic kidney disease(T2DKD group)and 149 patients with type 2 diabetes(T2DM group).Clinical parameters were collected and statistical differences were analyzed by using single-factor logistic regression analysis.Risk factors for kidney disease in type 2 diabetes were screened,and the correlation between clinical characteristics of type 2 diabetes and the occurrence of kidney disease were assessed.Results:1.Gender and age were not statistically different between T2 DKD group and T2 DM group(P> 0.05).2.Drinking,total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C)had no statistical difference between the T2 DKD group and the T2 DM group(P>0.05);.3.Body mass index,smoking,duration of diabetes,history of hypertension,systolic blood pressure,diastolic blood pressure,reduced high-density lipoprotein cholesterol(HDL-C),triglycerides(TG),uric acid(UA),and hemoglobin A1c(Hb A1c)were statistically different between the T2 DKD and T2 DM groups(P<0.05).4.Logistic regression analysis showed that smoking,duration of diabetes,history of hypertension,systolic blood pressure,Hb A1 c,reduced HDL-C were associated with the occurrence of type 2 diabetic kidney disease(P<0.05),OR(95%CI)were 1.780(1.215-2.204),1.431(1.101-1.880),1.772(1.211-2.203),1.035(1.008-1.065),1.010(1.007-1.014),and 1.675(1.099-2.010).Conclusions: Smoking,duration of diabetes,history of hypertension,systolic blood pressure,Hb A1 c,reduced HDL-C were independent risk factors for type 2 diabetic kidney disease.Part Two The relationship between serum Fox O1 and the risk of type 2 diabetic kidney diseaseObjective: To study the relationship between serum Fox O1 levels and the risk of type 2 diabetic kidney disease.Methods: 138 patients with T2 DKD and 149 patients with T2 DM were included in this study.Clinical data was collected and serum Fox O1 levels were detected by using Enzyme-linked immunobent assay(ELISA).The correlation between serum Fox O1 levels and the occurrence of kidney disease in type 2 diabetes was assessed.Results: Serum Fox O1 levels in the T2 DKD group were significantly higher than those in the T2 DM group,with statistical differences(P<0.05),OR(95%CI)was 1.010(1.008-1.015).Conclusions:Serum FoxO1 was an independent risk factor for the development of kidney disease in type 2 diabetes.Part Three The relationship between Fox O1 gene polymorphism and the risk of type 2 diabetic kidney diseaseObjective: To study the relationship between Fox O1 genes rs17446614 and rs17592236 single nucleotide polymorphisms and the risk of type 2diabetic kidney disease.Methods:138 patients with T2 DKD and 149 patients with T2 DM were included in this study.The age and sex data were matched well.Single nucleotide polymorphism of Fox O1 gene were detected by polymerase chain reaction-restriction fragment length polymorphisms(PCR-RFLP).Haploview software was used to analyze the chain imbalance of Fox O1 gene polymorphism and the relationship between haplotype and relative risk of T2 DKD.The Odds ratio(OR)and the 95% confidence interval(95% CI)were used to assess the correlation between the SNP of the Fox O1 gene and the risk of T2 DKD.Logistic regression analysis was used for clinical characteristics correction and the subgroup analysis by gender was carried out.Results:1.The frequency of Fox O1 gene rs17446614 AA genotype distribution in the T2 DKD group was higher than that in the T2 DM group(P<0.05).The risk of diabetic kidney disease in AA genotype carriers was 4.412 times higher than that in GG genotype carriers(OR=5.412,95% CI: 1.013-26.559).2.Fox O1 gene rs17446614 A allele distribution frequency T2 DKD group was higher than T2 DM group(P<0.05).The risk of diabetic kidney disease in A allele carriers was 0.680 times higher than that in G allele carriers(OR=1.680,95%CI:1.060-2.662).3.Among women,the frequency of rs17446614 AA genotype distribution in the T2 DKD group was higher than that in the T2 DM group(P<0.05).Women with AA genotype had a 7.7 times increased risk of developing diabetic kidney disease than those with GG genotype(OR= 8.700,95%CI:1.008-75.062).4.Among women,the frequency of A allele distribution in the T2 DKD group was higher than that in the T2 DM group(P<0.05).Women with A allele had a 1.003 times increased risk of developing diabetic kidney disease than those with G allele(OR=2.003,95% CI:1.070-3.749).5.Among men,there were no correlations found between all genotypes and alleles in the genetic polymorphisms of the Fox O1 gene rs17446614 site and the risk of diabetic kidney disease.6.There were no correlations found between all genotypes and alleles in the genetic polymorphisms of the Fox O1 gene rs17592236 site and the risk of diabetic kidney disease.7.There was a linkage disequilibrium between Fox O1 gene rs17446614 and rs17592236 gene polymorphism,and the distribution frequency of A-C haplotype in T2 DKD group was higher than that in T2 DM group(P<0.05).A-C haplotype carriers were 0.850 times more likely to develop diabetic kidney disease than G-C haplotype carriers(OR=1.850,95%CI: 1.156-2.986).Conclusions:1.The Fox O1 gene rs17446614 site was correlated with the risk of type 2diabetic kidney disease.The Fox O1 gene rs17446614 AA genotype and A allele were susceptibility genes for type 2 diabetic kidney disease.2.The Fox O1 gene rs17446614 site AA genotype and A allele were susceptible factors for diabetic kidney disease in women.3.There were no correlations found between all genotypes and alleles in the genetic polymorphisms of the Fox O1 gene rs17592236 site and the risk of diabetic kidney disease.4.The Fox O1 gene rs17446614 and rs17592236 A-C haplotype was susceptible factors for diabetic kidney disease. |
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