- 作者：Kalle Kisand ; kalle.kisand@ut.ee ; Raivo Uibo
- 关键词：AUC ; Area under the curve ; GADA ; GAD65 antibody ; LADA ; Latent autoimmune diabetes in adults ; IA2A ; IA-2 antibody ; ICA ; Islet cell antibody ; LD ; Linkage disequilibrium ; ROC ; Receiver operating characteristic ; SNP ; Single-nucleotide polymorphism ; T1D ; Type
- 刊名：Gene
- 出版年：2012
- 出版时间：15 April, 2012
- 年：2012
- 卷：497
- 期：2
- 页码：285-291
- 全文大小：310 K
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 only with T1D-protective HLA haplotypes and with two more 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.