Polymorphisms Of Candidate Genes Associated With Susceptibility To Type 1 Diabetes

Part1 The relationships between SUMO-4 gene A/G¹⁶³ polymorphism and type 1 diabetes mellitusObjective: To investigate the association of small ubiquitin-like modifer 4 (SUMO-4) gene polymorphism with type 1 diabetes in Chinese Han population.Design: Cross-sectional and case control study.Subjects and Methods: The A/G phenotype at position 163 of the SUMO-4 gene was determined by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP)method in 174 typical type 1 diabetes patients,176 latent autoimmune diabetes in adults (LADA) patients, 165 idiopathic type 1 diabetes patients and 264 healthy control subjects of Chinese Hart.The typical 1 diabetes patients were divided into juvenile-onset type diabetes (JO)and adult-onset type 1 diabetes (AO) according to the age at onset higher than 20 years or not, LADA patients were divided into LADA1 and LADA2 according to the titers higher than 0.3 or not, and idiopathic type 1 diabetes patients were divided into non-obesity and obesity idiopathic type 1 diabetes according to the BMI values higher than 25 or not. Results:1. The frequencies of the SUMO-4 A/G¹⁶³ allele and genotype were no significantly difference in total type 1 diabetes and healthy control subjects.2. The frequenies of the SUMO-4 A/G¹⁶³ allele and genotype were no significantly difference in typical type 1 diabetes patients, LADA patients and healthy control subjects. The frequencies of the SUMO-4 G¹⁶³ allele and GG genotype were significantly higher in idiopathic type 1 diabetes patients than in control subjects(P<0.0), AA genotype was significantly lower in idiopathic type 1 diabetes patients than in control subjects(P<0.05).3. The frequency of the SUMO-4 G¹⁶³ allele was significantly higher and AA genotype was significantly lower in JO patients than control subjects (P<0.05). The frequency of the SUMO-4 A/G¹⁶³ allele and genotype was no significantly difference in AO patients,LADA 1, LADA2, obesity-idiopathic type 1 diabetes patients and control subjects. The frequencies of the SUMO4 G¹⁶³ allele was significantly higher and AA genotype was significantly lower in non obesity-idiopathic type 1 diabetes patients than control subj ect(P<0.01 ).4. The age at onset and BMI were no significantly difference in GG genotype, AG genotype and AA genotype.5. The frequency of the SUMO4 G¹⁶³ allele was significantly higher in GAD-Ab posititve typical type 1 diabetes patients than GAD-Ab negative typical type 1 diabetes patients(p＜0.05)The frequency of the SUMO4 G¹⁶³ allele was no significantly difference in IA2-Ab posititve and IA2-Ab negative typical type 1 diabetes patients.Conclusion:1.The polymorphism of SUMO-4 gene A/G¹⁶³ confers susceptibility to juvenile-onset typical type 1 diabetes patients and non-obesity idiopathic type 1 diabetes patients.2.The CTLA-4 gene susceptibility to type 1 diabetes patients was not associated with sex, onset and BMI.3.The frequency of the GAD-Ab posititve was associated with SUMO-4 G¹⁶³ allele. To investigate the association of cytotoxic T lymphocyte-associated antigen-4(CTLA-4)gene polymorphism with type 1 diabetes in Chinese Han population.Design: Cross-sectional and case control study.Subject and Methods: The A/G phenotype at position 49 of the CTLA-4 gene was determined by polymerase chain reaction restriction fragment length polymorphism(PCR-RFLP)method in 176 typical type 1 diabetes patients, 181 latent autoimmune diabetes in adults (LADA) patients, 179 idiopathic type 1 diabetes patients and 290 healthy control subjects of Chinese Han. The typical 1 diabetes patients were divided into juvenile-onset type 1 diabetes (JO)and adult-onset type 1 diabetes(AO) according to the age at onset higher than 20 years or not, LADA patients were divided into LADA1 and LADA2 according to the titers higher than 0.3 or not, and idiopathic type 1 diabetes patients were divided into non-obesity and obesity idiopathic type 1 diabetes according to the BMI values higher than 25 or not.Results:1. The frequencies of the G⁴⁹ allele and GG genotype were significantly higher and AA genotype was significantly lower in total type 1 diabetes patients than control subjects(P＜0.01).2. The frequencies of the G⁴⁹ allele and GG genotype were significantly higher and AA genotype was significantly lower in typical type 1 diabetes patients, LADA patients and idiopathic type 1 diabetes patients than control subjects(P＜0.01).3. The frequencies of the G⁴⁹ allele and GG genotype were significantly higher in JO, AO, LADA1 and non obesity-idiopathic type 1 diabetes than control subjects(P＜0.01). The frequencies of the G⁴⁹ allele was significantly higher in LADA2 than control subjects(P＜0.01). The frequency of the AA genotype was significantly lower in JO and AO than control subjects(P＜0.01). The frequency of the CTLA-4 A/G⁴⁹ allele and genotype were no significantly difference in obesity-idiopathic type 1 diabetes and control subjects.4. The frequency of GG genotype was significantly higher in total female type 1 diabetes than male type 1 diabetes(P＜0.05). The frequencies of AA genotype was significantly higher in male typical typel diabetes than female typical type 1 diabetes(P＜0.01). The age at onset and BMI were no significantly difference in GG genotype, AG genotype and AA genotype.5. The frequency of the G⁴⁹ allele was no significantly difference in GAD-Ab posititve and GAD-Ab negative, IA2-Ab posititve and IA2-Ab negative typical type 1 diabetes patients. Conclusion:1. Excepet obesity-idiopathic type 1 diabetes patients, the polymorphism of CTLA-4 allele G⁴⁹ confers susceptibility to type 1 diabetes patients.2. The CTLA-4 gene susceptibility to type 1 diabetes patients was associated with sex, and was not associated with the onset, BMI.3. The frequencies of the GAD-Ab and IA-2-Ab posititve were not associated with CTLA-4 G¹⁶³ allele. To investigate the association of lymphoid tyrosine phosphatase(PTPN22)C/T¹⁸⁵⁸ gene and INS-VNTR polymorphism with type 1 diabetes in Chinese Han population.Design: Cross-sectional and case control study.Methods: The polymorphisms of PTPN22 gene C/T¹⁸⁵⁸, INS-VNTR were typed by PCR-RFLP method.Results:1. There was no mutant at a position 1858 of the PTPN22 gene in type 1 diabetes patients and control subjects.2. The frequencies of Classâ… and Classâ…¢were no significantly difference in typical type 1 diabetes, LADA, idiopathic type 1 diabetes patients and control subjects.Conclusion:1. There was no mutant at a position 1858 of the PTPN22 gene in China Han population2. The polymorphism of INS-VNTR was no association with type 1 diabetes in China Han population. To investigate the interactive effects of HLA-DQ, SUMO-4 and CTLA-4 gene in different subgroups of type 1 diabetes.Design: Cross-sectional and case control study.Methods: The polymorphisms of HLA-DQ were typed by PCR sequencing-base method, SUMO-4 and INS-VNTR were typed by PCR-RFLP method.Result:1. The frequencies of HLA-DQA1*03 and HLA-DQB1*0303 alleles were significantly higher in JO, AO and typical type 1 diabetes patients than control subjects(P＜0.01).2. The frequencies of coexistence HLA-DQA1*03+ and SUMO-4-GG, HLA-DQA1*03- and SUMO-4-GG; HLA-DQB1*0303+ and SUMO-4-GG, HLA-DQB1*0303-and SUMO-4-GG were no significantly difference in JO and control subjects. The frequencies of coexistence HLA-DQA1*03- and CTLA-4-GG, HLA-DQB1*0303- and CTLA-4-GG were significantly higher in typical type 1 diabetes than control subjects(P＜0.01). The frequencies of coexistence HLADQA1*03- and CTLA4-AA, HLA-DQB1*0303- and CTLA-4-AA were significantly lower in typical type 1 diabetes than control subjects (p＜0.05). 3. The frequencies of coexistence SUMO-4 -GG and CTLA-4 GG were significantly higher in JO(8.8%) and non-obesity idiopathic type 1 diabetes(6.1%)than control subjects (1.1%).Conclusion:1. HLA-DQA1*03 and HLA-DQB1*0303 are susceptible alleles to typical type 1 diabetes in China Han population.2. The susceptible effect of HLA-DQ and SUMO-4 is independent, and the two genes have no synergistic action in JO. The coexistence HLA-DQA1*03-and CTLA-4-GG, HLA-DQB1*0303- and CTLA-4-GG have synergistic action in typical type 1 diabetes.3. The interaction of SUMO-4 gene and CTLA-4 gene was synergistic In JO and non-obesity idiopathic type 1 diabetes.