1型糖尿病锌转运体8自身抗体与HLA-DR-DQ及lFlH1基因多态性的关联
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摘要
第一部分湖南汉族经典1型糖尿病HLA-DR-DQ基因多态性分析
目的：系统探讨湖南汉族经典1型糖尿病(T1DM)易感性与保护性HLA-DR-DQ基因型与单体型。
方法：采用聚合酶链反应直接测序法(PCR-SBT)对558例经典T1DM和930例正常对照的HLA-DRB1.DQA1与DQB1位点进行基因分型,通过PHASE软件进行单体型构建。病例组与对照组的基因频率比较采用卡方检验。
结果：
①9种DR与DQ等位基因在T1DM中的频率显著增高,相对风险最高的前3种为：DRB1*0301(21.37%vs.5.78%,OR=4.43,注：患者组vs.对照组,Pc<0.001,以下同)、DRB1*0401(2.25%vs.0.60%,OR=3.84).DQB1*0201(23.46%vs.7.4%,OR=3.84)；16种等位基因在T1DM中的频率显著减低,保护性最强的前3种分别为:DRB1*1301(0.41%vs.2.45%,OR=0.16).DRB1*0406(0.51%vs.2.92%,OR=0.17).DQB1*0602(1.03%vs.4.79%,OR=0.21).
②13种DR与DQ基因型在T1DM中的频率显著增加,相对风险最高的前3种基因型为：DQA1*03/03(39.76%vs.1.81%,OR=35.83).DQA1*03/05(21.67%vs.1.03％,OR=26.49).DRB1*0405/0701(1.84%va.0.12%,OR=15.71)；7种基因型在T1DM中的频率显著减低,保护性最强的前3种为:DRB1*0803/0803(0.61%vs.5.13%,OR=0.11).DQA1*0102/0102(0.60%vs.3.88%,OR=0.15)与DQA1*010X/0102(010X=0101或0104；0.80%vs.4.91%,OR=0.16)。
③19种DR-DQ单体型在T1DM中的频率显著增加,相对风险最高的前3种为：DRB1*0901-DQA1*03(30.73%vs.0.22%,OR=203.07).DRB1*0301-DQA1*03(6.19%vs.0.07%,OR=90.77). DQA1*03-DQB1*0201(3.52%vs.0.07%,OR=51.82)；22种DR-DQ单体型在T1DM中的频率显著减低,保护性最强的前3种为：DRB1*0803-DQA1*03-DQB1*0601(0.12%vs.3.95%,OR=0.03). DRB1*0901一DQA1*0102(0.11%vs.1.96%,OR=0.06).DQA1*03-DQB1*0601(0.325vs.4.57%,OR=0.07).
④本研究人群(中国人)与高加索人、日本人及韩国人比,四个种族共有的等位基因为易感性的DQB1*0303与DRB1*0405,保护性的DQB1*0301,DQB1*0601与DQB1*0602.1种保护性等位基因(DQB1*0502).4种易感单体型(DRB1*0301-DQB1*0303. DRB1*0301-DQA1*03-DQB1*020.DRB1*0301-DQA1*03一DQB1*0303与DRB1*0901-DQA1*05-DQB1*0201)与3种保护性单体型(DRB1*0406-DQB1*0302.DRB1*0803-DQA1*03-DQB1*0601. DRB1*1202-DQA1*060Y-DQB1*0301)为中国汉族人群特有性的风险等位基因或单体型。
结论：本研究发现中国汉族8种特有性的DR-DQ风险等位基因与单体型,HLA-DR-DQ易感基因型与单体型对TIDM的遗传效应有显著的异质性。
第二部分锌转运体8自身抗体与HLA-DR-DQ基因多态性关联
目的：探讨锌转运体8自身抗体(ZnT8A)与HLA-DR-DQ基因多态性的关联,以阐明ZnT8A产生的HLA遗传学基础。
方法：选取422例由放射配体法检测的ZnT8A.谷氨酸脱羧酶抗体(GADA)或蛋白酪氨酸磷酸酶抗体(IA-2A)阳性的1型糖尿病(T1DM)患者,同时采用PCR-直接测序法进行患者HLA-DR-DQ基因分型。采用二元关联检验与卡方检验分析ZnT8A与HLA-DR-DQ易感基因型及单体型的关系。
结果：
①湖南汉族经典T1DM患者ZnT8A阳性率为36.3%(153/422),其中单一ZnT8A阳性率为6.8%(28/412),ZnT8A与GADA双阳性率为25.1%(104/415)；ZnT8A与IA-2A双阳率者为18.2%(75/412)；ZnT8A.GADA与IA-2A三阳性率为15%(62/412)。
②ZnT8A滴度与易感基因DQA1*05(Υ2,2=0.126,P=0.012)及DQA1*03/05(Υ2=0.138,P=0.006)呈正相关,与易感基因型DQB1*0303/0303(Υ2=-0.142,P=0.006)及DRB1*0901/0901(Υ2=-0.114,P=0.029)呈负相关。
③携带基因型DQA1*03/05(45.8%vs.32.7%)的T1DM患者ZnT8A阳性率分别显著高于非携带者(P<0.05)；而携带基因型DQB1*0303/0303(25.0%vs.38.5%).DRB1*0901/0901(26.6%vs.39.2%)、单体型DQA1*0102-DQB1*0601(12.5%vs.37.2%)与DRB1*0901-DQA1*03(29.6%vs.41.6%)T1DM患者ZnT8A阳性率分别低于这些基因非携带者(P均<0.05)。
④携带易感基因DQA1*03/060Y(75.00%vs.16.67%).DQB1*0301/0301(44.44%vs.17.14%),DRB1*1401-DQA1*010X(80.00%vs.17.12%)者单一ZnT8A阳性率显著高于非携带者(P<0.05)；携带易感基因DQA1*03/05(6.98%vs.16.67%).DRB1*0901-DQA1*03-DQB1*0303(4.88%vs.25.35%)者单一ZnT8A阳性率显著低于非携带者。
结论：ZnT8的自身免疫反应与DRB1*1401-DQA1*0l0X与DRB1*0901-DQA1*03-DQB1*0303单体型有关,结果也进一步表明特异性胰岛自身抗体的产生与HLA-Ⅱ类基因相关。
第三部分湖南汉族1型糖尿病IFIH1基因rs1990760多态性分析
目的：分析患者IFIH1基因rs1990760多态性与湖南汉族急性起病1型糖尿病(T1DM)及成人隐匿性自身免疫性糖尿病(LADA)的关系。
方法：设计病例对照研究,应用TaqMan探针实时荧光PCR技术对930例湖南汉族T1DM患者、434例LADA患者与1010例正常对照的IFIH1基因rs1990760多态性进行基因分型。比较T1DM患者、LADA患者与正常对照等位基因与基因型的频率,并分析rs1990760多态性与临床表型、胰岛自身免疫及HLA-DR-DQ基因型的关系。
结果：①IFIH1基因rs1990760多态性等位基因C(79.8%vs.80.7%)与T(20.2%vs.19.3%)在T1DM组与对照中频率差异无显著性。CC(63.1%vs.65.0%),CT(33.5%vs.31.3%)与TT(3.5%vs.3.7%)基因型频率分布在两组间亦无统计学意义(P均>0.05)。②等位基因C与T在LADA组与对照组频率(80.6%vs.80.7%；19.4%vs.19.3%)差异无显著性(P>0.05),CC, CT, TT基因型频率分布在两组间亦无统计学意义(P均>0.05)。③T1DM与LADA患者IFIH1基因rs1990760多态性与起病年龄、体重指数、糖化血红蛋白、胰岛功能及代谢指标等临床特征均无相关性(P均>0.05)。④T1DM患者ZnT8A、GADA与IA-2A的阳性率与滴度在rs1990760多态性CC、CT、TT基因型之间均无显著性差异(P>0.05)。⑤携带易感DQB1*0303等位基因者C等位基因的频率低于非携带者,具有边界性统计学意义(76.76%vs.81.42%,P=0.048)。IFIH1基因rs1990760多态性与HLA-DRB1、DQA1、DQB1高危或低危风险基因型无交互作用(P均>0.05)。
结论：IFIH1基因SNP rs1990760多态性对湖南汉族T1DM与LADA患者无遗传易感作用,与临床特征、胰岛自身免疫及HLA-DR-DQ风险基因均无显著性关联。
第四部分IFIH1基因rs1990760多态性与1型糖尿病发病风险的Meta分析
目的：综合定量评价IFIH1基因rs1990760多态性与1型糖尿病(T1DM)发病风险的关系。
方法：计算机检索PubMed和Web of Knowledge等数据库,检索时间截至2013年1月1日,提取IFIH1基因rs1990760多态性与T1DM易感性关系的病例-对照研究。以T1DM组与对照组人群等位基因与基因型分布的OR值及其95%CI为效应指标。在加性模型、纯合子模型、显性模型和隐性模型中采用固定或随机效应模型进行Meta分析,并进行发表偏倚评估与敏感性分析。统计分析采用Stata11.0软件。
结果：
①共纳入13个病例对照研究,总计19932例T1DM患者和28606例对照,其中10项研究对象为欧洲血统人群,3项研究对象为亚洲人群。
②加性模型情况下, IFIH1基因rs1990760多态性等位基因A与T1DM有显著相关性[A vs.G：OR(95%CI)=1.14(1.08～1.22),P=0.000]；在显性遗传模型中,AA+AG基因型与T1DM风险有显著相关性[AA+AG vs. GG:OR(95%CI)=1.25(1.16-1.34), P=0.000]；在纯合子比较与隐性遗传模型中,AA基因型与T1DM风险有显著相关性[AA vs. GG:OR(95%CI)=1.36(1.26～1.47), P=0.000; AA vs. AG+GG:OR(95%CI)=1.159(1.06～1.27), P=0.001]；在杂合子比较中,AG基因型与T1DM风险有显著相关性[AG vs.GG:OR(95%CI)=1.15(1.07～1.24),P=0.000].
③基于人种的亚组分析显示欧洲血统人群中IFIH1基因rs1990760变异位点的等位基因与基因型在所有遗传模型中均与T1DM有显著相关性[A vs.G:OR(95%CI)=1.18(1.11～1.26),P-0.000]；而在亚洲人群中rs1990760变异位点在所有遗传模型中与T1DM发病均无相关性[A vs.G:OR(95%CI)=0.97(0.86～1.08),P=0.921].
④发表偏倚评估未见发表偏倚,敏感性分析提示结果比较稳定可靠。
结论：IFIH1基因rs1990760多态性是欧洲血统人群T1DM患者的遗传风险变异,A等位基因携带者增加T1DM易感性,但rs1990760多态性不是亚洲人群T1DM的遗传危险因素。
Part I Polymorphisms of HLA-DR-DQ genes in classical type1diabetes from Hunan Han population
Objective:To investigate the susceptible and protective HLA-DR-DQ genotypes and haplotypes in classical type1diabetes (T1DM) from Hunan Han population.
Methods:All subjects including558classical T1DM patients and930healthy controls were genotyped at HLA-DRB1, DQA1and DQB1locus by PCR-direct sequencing. The HLA-DR-DQ haplotypes were constructed by the PHASE programme. Frequencies of genotypes and haplotypes between patients and controls were compared by chi square test.
Results:
①The frequencies of nine DR and DQ alleles in T1DM patients were were significantly higher than those in control subjects.The top three alleles with the highest odds ratio (OR) were DRB1*0301(21.37%vs.5.78%, OR=4.43, Note:cases vs. controls, Pc<0.001, the same as below), DRB1*0401(2.25%vs.0.60%, OR=3.84), DQBl*0201(23.46%vs.7.4%, OR=3.84). The frequencies of sixteen alleles were significantly reduced in TlDM patients. The top three alleles with the strongest protection were DRB1*1301(0.41%vs.2.45%, OR=0.16), DRB1*0406(0.51%vs.2.92%, OR=0.17), DQBl*0602(1.03%vs.4.79%, OR=0.21).
②The frequencies of thirteen DR and DQ genotypes in TlDM patients were were significantly higher than those in control subjects. The top three genotypes with the highest OR were DQA1*03/03(39.76%vs.1.81%, OR=35.83), DQA1*03/05(21.67%vs.1.03%, OR=26.49), DRB1*0405/0701(1.84%vs.0.12%, OR=15.71). The frequencies of seven genotypes were significantly reduced in TlDM patients. The top three genotypes with the strongest protection were DRB1*0803/0803(0.61%vs.5.13%, OR=0.11), DQA1*0102/0102(0.60%vs.3.88%, OR=0.15) and DQA1*010X/0102(010X=0101or0104;0.80%vs.4.91%, OR=0.16).
③The frequencies of nineteen DR-DQ haplotypes in TlDM patients were were significantly higher than those in control subjects.The top three haplotypes with the highest OR were DRB1*0901-DQA1*03(30.73%vs.0.22%, OR=203.07), DRB1*0301-DQA1*03(6.19%vs.0.07%, OR=90.77), DQA1*03-DQB1*0201(3.52%vs.0.07%, OR=51.82). The frequencies of twenty-two haplotypes were significantly reduced in TlDM patients. The top three haplotypes with the strongest protection were DRB1*0803-DQA1*03-DQB1*0601(O.12%vs.3.95％,OR=0.03),DRB1*0901-DQA1*0102(0.11%vs.1.96%,OR=0.06),DQA1*03-DQB1*0601(O.32%vs.4.57%,OR=0.07).
④There are similarties and differences about HLA-DR-DQ risk markers among Chinese Han,Caucasian,Japanese and Korean.The common genes in these populations are susceptible DQB1*0303,DRB1*0405and protective DQB1*0301, DQB1*0601, DQB1*0602.One protective allele(DQB1*0502),four susceptible haplotypes(DRB1*0301-DQB1*0303, DRB1*0301-DQA1*03-DQB1*0201, DRB1*0301-DQA1*03-DQB1*0303,DRB1*0901-DQA1*05-DQB1*0201) and three protective haplotypes(DRB1*0406-DQB1*0302,DRB1*0803-DQA1*03-DQB1*0601,DRB1*1202-DQA1*060Y-DQB1*0301) have been identified for Chinese Han specific DR-DQ alleles or haplotypes that confer risk of TlDM.
Conclusions:Eight Chinese-specific DR-DQ risk markers are identified and these results reveal significant genetic heterogeneity of the contribution of HLA-DR-DQ genes to susceptibility to TlDM.
Part II Association of zinc transporter8autoantibodies with HLA-DR-DQ gene polymorphisms
Objective:To explore the relationship between zinc transporter8autoantibodies (ZnT8A) and susceptible HLA-DR-DQ genes in the patients with classical type1diabetes (TlDM).
Methods:Four hundred twenty two TlDM patients with ZnT8A, glutamic acid carboxylase antibody(GADA) or protein tyrosine phosphatase antibody (IA-2A) positive were selected. All autoantibodies were detected by radioligand assay. These patients were also genotyped at HLA-DRBl, DQAl and DQBl locus by PCR-direct sequencing. Association of ZnT8A with HLA-DR-DQ susceptible genes was analyzed by bivariate correlation test or chi square test.
Results:
①The prevalence of ZnT8A+was36.3%(153/422) in TIDM patients and the prevalence of the ZnT8A+alone was6.8%(28/412). The overlapping prevalence were25.1%(104/415),18.2%(75/412) for ZnT8A+and GADA+, ZnT8A+and IA-2A+, respectively.15%(62/412) of them were positive for three autoantibodies combined.
②The levels of ZnT8A were positively correlated with suscepitable allele DQA1*05(Υ2=0.126, P=0.012) and genotype DQA1*03/05(Υ2=0.138, P=0.006). And ZnT8A levels were negatively associated with suscepitable genotypes DQB1*0303/0303(Υ2=-0.142, P=0.006) and DRB1*0901/0901(Υ2=-0.114,p=0.029).
③The prevalence of ZnT8A+in the patients with DQA1*03/05(45.8%vs.32.7%)were significantly higher than those of non-carriers(P<0.05).The prevalence of ZnT8A+in the patients with DQB1*0303/0303(25.0%vs.38.5%),DRB1*0901/0901(26.6%vs.39.2%), DQA1*0102-DQB1*0601(12.5%vs.37.2%)and DRB1*0901-DQA1*03(29.6%vs.41.6%) were significantly lower than those of non-carrers,respectively(all P<0.05).
④The prevalence of ZnT8A+alone in patients with susceptible DQA1*03/060Y(75.00%vs.16.67%).DQB1*0301/0301(44.44%vs.17.14%),DRB1*1401-DQA1*010X(80.00%vs.17.12%) were significantly higher than those of non-carriers,respectively(all P<0.05).The prevalence of ZnT8A+alone in patients with protective DQA1*03/05(6.98%vs.16.67%). DRB1*0901-DQA1*03-DQB1*0303(4.88%vs.25.35％)were significantly lower than those of non-carriers(Both P<0.05).
Conclusions:ZnT8-specific humoral autoimmunity is linked to DRB1*1401-DQA1*010X and DRB1*0901-DQA1*03-DQB1*0303haplotypes.These data provide further evidence that production of major autoantibody specificities are associated with HLA class II genes.
Part III Analysis of IFIH1gene rs1990760polymorphism in type1diabetes from Hunan Han population
Objective:To investigate whether IFIH1gene rs1990760polymorphism has a role in genetic predisposition of type1diabetes (T1DM) and latent autoimmune diabetes in adults (LADA) in Hunan Han population.
Methods:All subjects including930T1DM patients,434LADA patients and1010healthy controls were genotyped for IFIH1rs1990760polymorphism using the Custom TaqMan SNP genotyping assay. The frequencies of alleles and genotypes of rs1990760were compared between cases and controls and genotype-phenotype correlation were carried out.
Results:
①Allele C (79.8%vs.80.7%) and T (20.2%vs.19.3%) of IFIH1gene rs1990760polymorphism were similar in T1DM and control subjects, respectively (P>0.05). At the genotypic level, the frequencies of the CC (63.1%vs.65.0%), CT(33.5%vs.31.3%) and TT (3.5%vs.3.7%) genotypes were similar in cases and control subjects, respectively (all P>0.05).
②There was no significant difference of allele C/T frequencies of the rs1990760polymorphism between LADA and control groups (80.6%vs.80.7%;19.4%vs.19.3%, respectively, both P>0.05). Similarly, no significant differences in the genotypic (CC, CT, TT) frequencies were found (all P>0.05).
③The results did not show significant difference among genotypes in each subset including age of onset, body mass index, waist to hip, HbAlc, islet beta cell function and metablism components from TlDM and LADA patients (all P>0.05).
④The prevalence and titer of ZnT8A, GADA and IA-2A among the CC, CT and TT genotypes of IFIHl gene rs1990760polymorphism in TlDM patients were not statistically significant (all P>0.05).
⑤The frequency of allele C of rs1990760polymorphism in patients with susceptible allele DQB1*0303were lower than those of non-carrier. However, it was boundary statistical differences (76.76%vs.81.42%, P=0.048). The alleles and genotypes of IFIH1gene rs1990760polymorphism had no interaction with high risk or low risk HLA-DRBl,DQAl,DQBl genotypes (all P>0.05).
Conclusions:These results suggest no contribution from IFIHl gene rs1990760polymorphism to the genetic predisposition of TIDM and LADA in Hunan Han population. There is no association of rs1990760polymorphism with clinical features, islet-associated autoimmunity as well as HLA-DR-DQ risk markers in TlDM.
Part IV Association between IFIH1gene rs1990760polymorphism and type1diabetes:a Meta-analysis
Objective:To explore comprehensively the relationship between IFIH1gene rs1990760polymorphism and susceptibility to type1diabetes (TlDM).
Methods:References were retrieved through the computerized PubMed and Web of Knowledge.The number of allele or genotype of rs1990760polymorphism were taken in case-control studies.The unpublished data of our study was also included. The pools ORs with95%CI were calculated to assess the association strength. Either the fixed or random effect model was applied to conducted Meta-analysis in additive model, homozygote comparison, heterozygote comparison, dominant and recessive genetic models. Publication bias and sensitivity were evaluated at the same time. All analyses were conducted with Stata11.0software.
Results:
①A total of thirteen case-control studies were enrolled, including19932cases of TlDM and28606controls.The subjects enrolled in ten studied were European descent, others were Asian population.
②The results of Meta-analyses showed the A allele was associated with the risk of TlDM in a additive model [A vs G:OR(95%CI)=1.14(1.08～1.22), P=0.000]; the AA+AG genotype was associated with the risk of TlDM in a dominant genetic model [AA+AG vs. GG: OR(95%CI)=1.25(1.16～1.34), P=0.000]; the AA genotype was associated with the risk of T1DM in homozygote comparison and recessive genetic models[AA vs. GG:OR(95%CI)=1.36(1.26～1.47), P=0.000; AA vs. AG+GG:OR(95%CI)=1.159(1.06～1.27), P=0.001]; the AG genotype was associated with the risk of T1DM in heterozygote comparison[AG vs. GG:OR(95%CI)=1.15(1.07～1.24), P=0.000].
③After stratification according to European descent and Asian ethnicity, the variant allele and genotype of rs1990760was associated with the risk of T1DM from European descent in all genetic models [A vs. G: OR(95%CI)=1.18(1.11-1.26), P=0.000]. Conversely, there was no difference of those in Asian population [A vs. G:OR(95%CI)=0.97(0.86-1.08),P=0.921].
④Sensitivity analysis showed that the aboved combined results could not be effected by individual study, no publication bias was found, the conclusions were reliable.
Conclusions:The meta-analysis suggests that the IFIH1gene rs1990760polymorphism is a genetic risk factor for T1DM of European descent, and the A allele elevates the risk of T1DM. But it is not a definite risk of T1DM in Asian population.
目的：系统探讨湖南汉族经典1型糖尿病(T1DM)易感性与保护性HLA-DR-DQ基因型与单体型。
方法：采用聚合酶链反应直接测序法(PCR-SBT)对558例经典T1DM和930例正常对照的HLA-DRB1.DQA1与DQB1位点进行基因分型,通过PHASE软件进行单体型构建。病例组与对照组的基因频率比较采用卡方检验。
结果：
①9种DR与DQ等位基因在T1DM中的频率显著增高,相对风险最高的前3种为：DRB1*0301(21.37%vs.5.78%,OR=4.43,注：患者组vs.对照组,Pc<0.001,以下同)、DRB1*0401(2.25%vs.0.60%,OR=3.84).DQB1*0201(23.46%vs.7.4%,OR=3.84)；16种等位基因在T1DM中的频率显著减低,保护性最强的前3种分别为:DRB1*1301(0.41%vs.2.45%,OR=0.16).DRB1*0406(0.51%vs.2.92%,OR=0.17).DQB1*0602(1.03%vs.4.79%,OR=0.21).
②13种DR与DQ基因型在T1DM中的频率显著增加,相对风险最高的前3种基因型为：DQA1*03/03(39.76%vs.1.81%,OR=35.83).DQA1*03/05(21.67%vs.1.03％,OR=26.49).DRB1*0405/0701(1.84%va.0.12%,OR=15.71)；7种基因型在T1DM中的频率显著减低,保护性最强的前3种为:DRB1*0803/0803(0.61%vs.5.13%,OR=0.11).DQA1*0102/0102(0.60%vs.3.88%,OR=0.15)与DQA1*010X/0102(010X=0101或0104；0.80%vs.4.91%,OR=0.16)。
③19种DR-DQ单体型在T1DM中的频率显著增加,相对风险最高的前3种为：DRB1*0901-DQA1*03(30.73%vs.0.22%,OR=203.07).DRB1*0301-DQA1*03(6.19%vs.0.07%,OR=90.77). DQA1*03-DQB1*0201(3.52%vs.0.07%,OR=51.82)；22种DR-DQ单体型在T1DM中的频率显著减低,保护性最强的前3种为：DRB1*0803-DQA1*03-DQB1*0601(0.12%vs.3.95%,OR=0.03). DRB1*0901一DQA1*0102(0.11%vs.1.96%,OR=0.06).DQA1*03-DQB1*0601(0.325vs.4.57%,OR=0.07).
④本研究人群(中国人)与高加索人、日本人及韩国人比,四个种族共有的等位基因为易感性的DQB1*0303与DRB1*0405,保护性的DQB1*0301,DQB1*0601与DQB1*0602.1种保护性等位基因(DQB1*0502).4种易感单体型(DRB1*0301-DQB1*0303. DRB1*0301-DQA1*03-DQB1*020.DRB1*0301-DQA1*03一DQB1*0303与DRB1*0901-DQA1*05-DQB1*0201)与3种保护性单体型(DRB1*0406-DQB1*0302.DRB1*0803-DQA1*03-DQB1*0601. DRB1*1202-DQA1*060Y-DQB1*0301)为中国汉族人群特有性的风险等位基因或单体型。
结论：本研究发现中国汉族8种特有性的DR-DQ风险等位基因与单体型,HLA-DR-DQ易感基因型与单体型对TIDM的遗传效应有显著的异质性。
第二部分锌转运体8自身抗体与HLA-DR-DQ基因多态性关联
目的：探讨锌转运体8自身抗体(ZnT8A)与HLA-DR-DQ基因多态性的关联,以阐明ZnT8A产生的HLA遗传学基础。
方法：选取422例由放射配体法检测的ZnT8A.谷氨酸脱羧酶抗体(GADA)或蛋白酪氨酸磷酸酶抗体(IA-2A)阳性的1型糖尿病(T1DM)患者,同时采用PCR-直接测序法进行患者HLA-DR-DQ基因分型。采用二元关联检验与卡方检验分析ZnT8A与HLA-DR-DQ易感基因型及单体型的关系。
结果：
①湖南汉族经典T1DM患者ZnT8A阳性率为36.3%(153/422),其中单一ZnT8A阳性率为6.8%(28/412),ZnT8A与GADA双阳性率为25.1%(104/415)；ZnT8A与IA-2A双阳率者为18.2%(75/412)；ZnT8A.GADA与IA-2A三阳性率为15%(62/412)。
②ZnT8A滴度与易感基因DQA1*05(Υ2,2=0.126,P=0.012)及DQA1*03/05(Υ2=0.138,P=0.006)呈正相关,与易感基因型DQB1*0303/0303(Υ2=-0.142,P=0.006)及DRB1*0901/0901(Υ2=-0.114,P=0.029)呈负相关。
③携带基因型DQA1*03/05(45.8%vs.32.7%)的T1DM患者ZnT8A阳性率分别显著高于非携带者(P<0.05)；而携带基因型DQB1*0303/0303(25.0%vs.38.5%).DRB1*0901/0901(26.6%vs.39.2%)、单体型DQA1*0102-DQB1*0601(12.5%vs.37.2%)与DRB1*0901-DQA1*03(29.6%vs.41.6%)T1DM患者ZnT8A阳性率分别低于这些基因非携带者(P均<0.05)。
④携带易感基因DQA1*03/060Y(75.00%vs.16.67%).DQB1*0301/0301(44.44%vs.17.14%),DRB1*1401-DQA1*010X(80.00%vs.17.12%)者单一ZnT8A阳性率显著高于非携带者(P<0.05)；携带易感基因DQA1*03/05(6.98%vs.16.67%).DRB1*0901-DQA1*03-DQB1*0303(4.88%vs.25.35%)者单一ZnT8A阳性率显著低于非携带者。
结论：ZnT8的自身免疫反应与DRB1*1401-DQA1*0l0X与DRB1*0901-DQA1*03-DQB1*0303单体型有关,结果也进一步表明特异性胰岛自身抗体的产生与HLA-Ⅱ类基因相关。
第三部分湖南汉族1型糖尿病IFIH1基因rs1990760多态性分析
目的：分析患者IFIH1基因rs1990760多态性与湖南汉族急性起病1型糖尿病(T1DM)及成人隐匿性自身免疫性糖尿病(LADA)的关系。
方法：设计病例对照研究,应用TaqMan探针实时荧光PCR技术对930例湖南汉族T1DM患者、434例LADA患者与1010例正常对照的IFIH1基因rs1990760多态性进行基因分型。比较T1DM患者、LADA患者与正常对照等位基因与基因型的频率,并分析rs1990760多态性与临床表型、胰岛自身免疫及HLA-DR-DQ基因型的关系。
结果：①IFIH1基因rs1990760多态性等位基因C(79.8%vs.80.7%)与T(20.2%vs.19.3%)在T1DM组与对照中频率差异无显著性。CC(63.1%vs.65.0%),CT(33.5%vs.31.3%)与TT(3.5%vs.3.7%)基因型频率分布在两组间亦无统计学意义(P均>0.05)。②等位基因C与T在LADA组与对照组频率(80.6%vs.80.7%；19.4%vs.19.3%)差异无显著性(P>0.05),CC, CT, TT基因型频率分布在两组间亦无统计学意义(P均>0.05)。③T1DM与LADA患者IFIH1基因rs1990760多态性与起病年龄、体重指数、糖化血红蛋白、胰岛功能及代谢指标等临床特征均无相关性(P均>0.05)。④T1DM患者ZnT8A、GADA与IA-2A的阳性率与滴度在rs1990760多态性CC、CT、TT基因型之间均无显著性差异(P>0.05)。⑤携带易感DQB1*0303等位基因者C等位基因的频率低于非携带者,具有边界性统计学意义(76.76%vs.81.42%,P=0.048)。IFIH1基因rs1990760多态性与HLA-DRB1、DQA1、DQB1高危或低危风险基因型无交互作用(P均>0.05)。
结论：IFIH1基因SNP rs1990760多态性对湖南汉族T1DM与LADA患者无遗传易感作用,与临床特征、胰岛自身免疫及HLA-DR-DQ风险基因均无显著性关联。
第四部分IFIH1基因rs1990760多态性与1型糖尿病发病风险的Meta分析
目的：综合定量评价IFIH1基因rs1990760多态性与1型糖尿病(T1DM)发病风险的关系。
方法：计算机检索PubMed和Web of Knowledge等数据库,检索时间截至2013年1月1日,提取IFIH1基因rs1990760多态性与T1DM易感性关系的病例-对照研究。以T1DM组与对照组人群等位基因与基因型分布的OR值及其95%CI为效应指标。在加性模型、纯合子模型、显性模型和隐性模型中采用固定或随机效应模型进行Meta分析,并进行发表偏倚评估与敏感性分析。统计分析采用Stata11.0软件。
结果：
①共纳入13个病例对照研究,总计19932例T1DM患者和28606例对照,其中10项研究对象为欧洲血统人群,3项研究对象为亚洲人群。
②加性模型情况下, IFIH1基因rs1990760多态性等位基因A与T1DM有显著相关性[A vs.G：OR(95%CI)=1.14(1.08～1.22),P=0.000]；在显性遗传模型中,AA+AG基因型与T1DM风险有显著相关性[AA+AG vs. GG:OR(95%CI)=1.25(1.16-1.34), P=0.000]；在纯合子比较与隐性遗传模型中,AA基因型与T1DM风险有显著相关性[AA vs. GG:OR(95%CI)=1.36(1.26～1.47), P=0.000; AA vs. AG+GG:OR(95%CI)=1.159(1.06～1.27), P=0.001]；在杂合子比较中,AG基因型与T1DM风险有显著相关性[AG vs.GG:OR(95%CI)=1.15(1.07～1.24),P=0.000].
③基于人种的亚组分析显示欧洲血统人群中IFIH1基因rs1990760变异位点的等位基因与基因型在所有遗传模型中均与T1DM有显著相关性[A vs.G:OR(95%CI)=1.18(1.11～1.26),P-0.000]；而在亚洲人群中rs1990760变异位点在所有遗传模型中与T1DM发病均无相关性[A vs.G:OR(95%CI)=0.97(0.86～1.08),P=0.921].
④发表偏倚评估未见发表偏倚,敏感性分析提示结果比较稳定可靠。
结论：IFIH1基因rs1990760多态性是欧洲血统人群T1DM患者的遗传风险变异,A等位基因携带者增加T1DM易感性,但rs1990760多态性不是亚洲人群T1DM的遗传危险因素。
Part I Polymorphisms of HLA-DR-DQ genes in classical type1diabetes from Hunan Han population
Objective:To investigate the susceptible and protective HLA-DR-DQ genotypes and haplotypes in classical type1diabetes (T1DM) from Hunan Han population.
Methods:All subjects including558classical T1DM patients and930healthy controls were genotyped at HLA-DRB1, DQA1and DQB1locus by PCR-direct sequencing. The HLA-DR-DQ haplotypes were constructed by the PHASE programme. Frequencies of genotypes and haplotypes between patients and controls were compared by chi square test.
Results:
①The frequencies of nine DR and DQ alleles in T1DM patients were were significantly higher than those in control subjects.The top three alleles with the highest odds ratio (OR) were DRB1*0301(21.37%vs.5.78%, OR=4.43, Note:cases vs. controls, Pc<0.001, the same as below), DRB1*0401(2.25%vs.0.60%, OR=3.84), DQBl*0201(23.46%vs.7.4%, OR=3.84). The frequencies of sixteen alleles were significantly reduced in TlDM patients. The top three alleles with the strongest protection were DRB1*1301(0.41%vs.2.45%, OR=0.16), DRB1*0406(0.51%vs.2.92%, OR=0.17), DQBl*0602(1.03%vs.4.79%, OR=0.21).
②The frequencies of thirteen DR and DQ genotypes in TlDM patients were were significantly higher than those in control subjects. The top three genotypes with the highest OR were DQA1*03/03(39.76%vs.1.81%, OR=35.83), DQA1*03/05(21.67%vs.1.03%, OR=26.49), DRB1*0405/0701(1.84%vs.0.12%, OR=15.71). The frequencies of seven genotypes were significantly reduced in TlDM patients. The top three genotypes with the strongest protection were DRB1*0803/0803(0.61%vs.5.13%, OR=0.11), DQA1*0102/0102(0.60%vs.3.88%, OR=0.15) and DQA1*010X/0102(010X=0101or0104;0.80%vs.4.91%, OR=0.16).
③The frequencies of nineteen DR-DQ haplotypes in TlDM patients were were significantly higher than those in control subjects.The top three haplotypes with the highest OR were DRB1*0901-DQA1*03(30.73%vs.0.22%, OR=203.07), DRB1*0301-DQA1*03(6.19%vs.0.07%, OR=90.77), DQA1*03-DQB1*0201(3.52%vs.0.07%, OR=51.82). The frequencies of twenty-two haplotypes were significantly reduced in TlDM patients. The top three haplotypes with the strongest protection were DRB1*0803-DQA1*03-DQB1*0601(O.12%vs.3.95％,OR=0.03),DRB1*0901-DQA1*0102(0.11%vs.1.96%,OR=0.06),DQA1*03-DQB1*0601(O.32%vs.4.57%,OR=0.07).
④There are similarties and differences about HLA-DR-DQ risk markers among Chinese Han,Caucasian,Japanese and Korean.The common genes in these populations are susceptible DQB1*0303,DRB1*0405and protective DQB1*0301, DQB1*0601, DQB1*0602.One protective allele(DQB1*0502),four susceptible haplotypes(DRB1*0301-DQB1*0303, DRB1*0301-DQA1*03-DQB1*0201, DRB1*0301-DQA1*03-DQB1*0303,DRB1*0901-DQA1*05-DQB1*0201) and three protective haplotypes(DRB1*0406-DQB1*0302,DRB1*0803-DQA1*03-DQB1*0601,DRB1*1202-DQA1*060Y-DQB1*0301) have been identified for Chinese Han specific DR-DQ alleles or haplotypes that confer risk of TlDM.
Conclusions:Eight Chinese-specific DR-DQ risk markers are identified and these results reveal significant genetic heterogeneity of the contribution of HLA-DR-DQ genes to susceptibility to TlDM.
Part II Association of zinc transporter8autoantibodies with HLA-DR-DQ gene polymorphisms
Objective:To explore the relationship between zinc transporter8autoantibodies (ZnT8A) and susceptible HLA-DR-DQ genes in the patients with classical type1diabetes (TlDM).
Methods:Four hundred twenty two TlDM patients with ZnT8A, glutamic acid carboxylase antibody(GADA) or protein tyrosine phosphatase antibody (IA-2A) positive were selected. All autoantibodies were detected by radioligand assay. These patients were also genotyped at HLA-DRBl, DQAl and DQBl locus by PCR-direct sequencing. Association of ZnT8A with HLA-DR-DQ susceptible genes was analyzed by bivariate correlation test or chi square test.
Results:
①The prevalence of ZnT8A+was36.3%(153/422) in TIDM patients and the prevalence of the ZnT8A+alone was6.8%(28/412). The overlapping prevalence were25.1%(104/415),18.2%(75/412) for ZnT8A+and GADA+, ZnT8A+and IA-2A+, respectively.15%(62/412) of them were positive for three autoantibodies combined.
②The levels of ZnT8A were positively correlated with suscepitable allele DQA1*05(Υ2=0.126, P=0.012) and genotype DQA1*03/05(Υ2=0.138, P=0.006). And ZnT8A levels were negatively associated with suscepitable genotypes DQB1*0303/0303(Υ2=-0.142, P=0.006) and DRB1*0901/0901(Υ2=-0.114,p=0.029).
③The prevalence of ZnT8A+in the patients with DQA1*03/05(45.8%vs.32.7%)were significantly higher than those of non-carriers(P<0.05).The prevalence of ZnT8A+in the patients with DQB1*0303/0303(25.0%vs.38.5%),DRB1*0901/0901(26.6%vs.39.2%), DQA1*0102-DQB1*0601(12.5%vs.37.2%)and DRB1*0901-DQA1*03(29.6%vs.41.6%) were significantly lower than those of non-carrers,respectively(all P<0.05).
④The prevalence of ZnT8A+alone in patients with susceptible DQA1*03/060Y(75.00%vs.16.67%).DQB1*0301/0301(44.44%vs.17.14%),DRB1*1401-DQA1*010X(80.00%vs.17.12%) were significantly higher than those of non-carriers,respectively(all P<0.05).The prevalence of ZnT8A+alone in patients with protective DQA1*03/05(6.98%vs.16.67%). DRB1*0901-DQA1*03-DQB1*0303(4.88%vs.25.35％)were significantly lower than those of non-carriers(Both P<0.05).
Conclusions:ZnT8-specific humoral autoimmunity is linked to DRB1*1401-DQA1*010X and DRB1*0901-DQA1*03-DQB1*0303haplotypes.These data provide further evidence that production of major autoantibody specificities are associated with HLA class II genes.
Part III Analysis of IFIH1gene rs1990760polymorphism in type1diabetes from Hunan Han population
Objective:To investigate whether IFIH1gene rs1990760polymorphism has a role in genetic predisposition of type1diabetes (T1DM) and latent autoimmune diabetes in adults (LADA) in Hunan Han population.
Methods:All subjects including930T1DM patients,434LADA patients and1010healthy controls were genotyped for IFIH1rs1990760polymorphism using the Custom TaqMan SNP genotyping assay. The frequencies of alleles and genotypes of rs1990760were compared between cases and controls and genotype-phenotype correlation were carried out.
Results:
①Allele C (79.8%vs.80.7%) and T (20.2%vs.19.3%) of IFIH1gene rs1990760polymorphism were similar in T1DM and control subjects, respectively (P>0.05). At the genotypic level, the frequencies of the CC (63.1%vs.65.0%), CT(33.5%vs.31.3%) and TT (3.5%vs.3.7%) genotypes were similar in cases and control subjects, respectively (all P>0.05).
②There was no significant difference of allele C/T frequencies of the rs1990760polymorphism between LADA and control groups (80.6%vs.80.7%;19.4%vs.19.3%, respectively, both P>0.05). Similarly, no significant differences in the genotypic (CC, CT, TT) frequencies were found (all P>0.05).
③The results did not show significant difference among genotypes in each subset including age of onset, body mass index, waist to hip, HbAlc, islet beta cell function and metablism components from TlDM and LADA patients (all P>0.05).
④The prevalence and titer of ZnT8A, GADA and IA-2A among the CC, CT and TT genotypes of IFIHl gene rs1990760polymorphism in TlDM patients were not statistically significant (all P>0.05).
⑤The frequency of allele C of rs1990760polymorphism in patients with susceptible allele DQB1*0303were lower than those of non-carrier. However, it was boundary statistical differences (76.76%vs.81.42%, P=0.048). The alleles and genotypes of IFIH1gene rs1990760polymorphism had no interaction with high risk or low risk HLA-DRBl,DQAl,DQBl genotypes (all P>0.05).
Conclusions:These results suggest no contribution from IFIHl gene rs1990760polymorphism to the genetic predisposition of TIDM and LADA in Hunan Han population. There is no association of rs1990760polymorphism with clinical features, islet-associated autoimmunity as well as HLA-DR-DQ risk markers in TlDM.
Part IV Association between IFIH1gene rs1990760polymorphism and type1diabetes:a Meta-analysis
Objective:To explore comprehensively the relationship between IFIH1gene rs1990760polymorphism and susceptibility to type1diabetes (TlDM).
Methods:References were retrieved through the computerized PubMed and Web of Knowledge.The number of allele or genotype of rs1990760polymorphism were taken in case-control studies.The unpublished data of our study was also included. The pools ORs with95%CI were calculated to assess the association strength. Either the fixed or random effect model was applied to conducted Meta-analysis in additive model, homozygote comparison, heterozygote comparison, dominant and recessive genetic models. Publication bias and sensitivity were evaluated at the same time. All analyses were conducted with Stata11.0software.
Results:
①A total of thirteen case-control studies were enrolled, including19932cases of TlDM and28606controls.The subjects enrolled in ten studied were European descent, others were Asian population.
②The results of Meta-analyses showed the A allele was associated with the risk of TlDM in a additive model [A vs G:OR(95%CI)=1.14(1.08～1.22), P=0.000]; the AA+AG genotype was associated with the risk of TlDM in a dominant genetic model [AA+AG vs. GG: OR(95%CI)=1.25(1.16～1.34), P=0.000]; the AA genotype was associated with the risk of T1DM in homozygote comparison and recessive genetic models[AA vs. GG:OR(95%CI)=1.36(1.26～1.47), P=0.000; AA vs. AG+GG:OR(95%CI)=1.159(1.06～1.27), P=0.001]; the AG genotype was associated with the risk of T1DM in heterozygote comparison[AG vs. GG:OR(95%CI)=1.15(1.07～1.24), P=0.000].
③After stratification according to European descent and Asian ethnicity, the variant allele and genotype of rs1990760was associated with the risk of T1DM from European descent in all genetic models [A vs. G: OR(95%CI)=1.18(1.11-1.26), P=0.000]. Conversely, there was no difference of those in Asian population [A vs. G:OR(95%CI)=0.97(0.86-1.08),P=0.921].
④Sensitivity analysis showed that the aboved combined results could not be effected by individual study, no publication bias was found, the conclusions were reliable.
Conclusions:The meta-analysis suggests that the IFIH1gene rs1990760polymorphism is a genetic risk factor for T1DM of European descent, and the A allele elevates the risk of T1DM. But it is not a definite risk of T1DM in Asian population.
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