LADA和T1D在爱沙尼亚人种中的两种不同的遗传风险概况
发布时间：2012-10-08 15:50:31浏览次数：3519次来源：中南大学湘雅二医院 摘自:Gene. 2012 Apr 15;497(2):285-91. Epub 2012 Feb 3.
目的/假说：本文的目的是分析先前被证明与糖尿病的自身免疫性相关的8个基因区域的17种多态性的联合作用。我们假定遗传易感性是不同的糖尿病表型形式和易感基因位点的不同组合风险的叠加和联合。
方法：本研究的样本均来自爱沙尼亚起源的同种人群，包括65名LADA患者，154名T1D患者，260名T2D患者和229名非糖尿病对照。检测这些人群的HLA-DQB1，胰岛素基因(rs689, rs3842729)，PHTF1–PTPN22片段(rs2476601, rs6679677)，CTLA4 片段(rs231806, rs16840252, rs5742909, rs231775, rs3087243, rs2033171)，ICOS片段(rs10932037, rs4675379)，CD25片段 (rs706778)，CD226片段(rs763361), NAA25片段 (rs17696736)的多态性/单体型。
结果： 与预期的一致，T1D的发病不但与HLA-DQB1单体型相关，还与INS和PHTF1–PTPN22区域的单体型及NAA25中的rs17696736相关，而与CTLA4无关。通常被认为是T1DM遗传位点的CD25 (IL2RA)区域的rs706778，在爱沙尼亚人种中与T1DM无关。但是LADA仅与T1D保护性HLA单体型和另外2种常见CTLA4单体型相关。CTLA4-ICOS区域的4种多态性与LADA显著相关，其中rs231775中的等位基因A（基因频率大），rs231806中的等位基因C（基因频率小），rs3087243中的等位基因A（基因频率小）为保护性基因。在PHTF1–PTPN22区域的2种单体型CC和CT与自身抗体阴性的T2DM相关，但由于基因频率过低（2.1%），其在人群中的影响微乎其微。与T1D遗传易感性相关的最佳拟合模型包含6个基因区域（HLA-DQB1, INS, PHTF1, CTLA4 +49, CD226 and NAA25），而与LADA遗传易感性相关的最佳拟合模型仅包含2个基因区域（HLA-DQB1 and CTLA4 +49），以上两种模型的AUCs分别为0.869 和 0.693。
结论：经典的HLA和某些非HLA位点相关的T1D-危险性单体型恰当地揭示了T1D，而不是LADA的遗传风险。尚需要更多的研究来探索进展更为缓慢的成人自身免疫性糖尿病的危险因素。
LADA and T1D in Estonian population — Two different genetic risk profiles
Aims/hypothesis: The aim of our study was to analyze combined impact of 17 polymorphisms at 8 gene regions previously shown to be associated with autoimmunity in diabetes. We hypothesized that the genetic predisposition is multiplicative and joint risk of different diabetic phenotypes forms by distinct combination of susceptibility loci.
Methods: An ethnically homogenous population of Estonian origin, including 65 LADA patients, 154 patients with T1D, 260 patients with T2D and 229 non-diabetic controls, was genotyped for polymorphisms/haplotypes in HLA-DQB1, insulin gene (rs689, rs3842729), PHTF1–PTPN22 region (rs2476601, rs6679677), CTLA4 region (rs231806, rs16840252, rs5742909, rs231775, rs3087243, rs2033171), ICOS region
(rs10932037, rs4675379), CD25 (rs706778), CD226(rs763361), NAA25 (rs17696736). Results: As expected, the risk of T1D was consistently attributed by HLA-DQB1 haplotypes, but also by haplotypes of INS and PHTF1–PTPN22 region, and rs17696736 in NAA25. By contrast, LADA was associated onlywith T1D-protective HLA haplotypes andwith twomore frequent haplotypes of the CTLA4. It is of interest, that seldom CT haplotype of PHTF1–PTPN22 region carried the risk for autoantibody-negative T2D. The final best-fitted model for T1D genetic risk contained six gene regions (HLA-DQB1, INS, PHTF1, CTLA4 +49, CD226 and NAA25) and for LADA only two (HLA-DQB1 and CTLA4 +49). The AUCs of these models are 0.869 and 0.693, respectively.
Conclusions: Classical T1D-risk haplotypes of HLA and some non-HLA loci describe quite well the genetic risk for T1D but not for LADA. The need of further studies should be stressed to discover the real risk factors for slower forms of autoimmune diabetes in adults.
