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GENETIC SIMILARITIES BETWEEN LADA, TYPE 1 AND TYPE 2 DIABETES

¹Department of Clinical Sciences – Diabetes & Endocrinology, CRC, Malmö University Hospital, Lund University, Malmö, Sweden
²Department of Medicine, Malmö University Hospital, Lund University, Malmö, Sweden
³Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland
⁴Folkhalsan Research Centre, Helsinki, Finland
⁵Department of Clinical Sciences – Cellular Autoimmunity Unit, CRC, Malmö University Hospital, Lund University, Malmö, Sweden

Aim: LADA is often considered a slowly progressing subtype of type 1 diabetes, although the clinical picture resembles more type 2 diabetes. One way to improve classification is to study whether LADA shares genetic features with type 1 and/or type 2 diabetes.

Methods/Results: To accomplish this, we studied whether LADA shares variation in the HLA locus, INS VNTR, PTPN22 genes with type 1 or the TCF7L2 gene with type 2 diabetes, in 361 LADA, 718 type 1, 1676 type 2 diabetic patients and 1704 healthy control subjects from Sweden and Finland. LADA showed, compared to type 2 diabetic patients, increased frequency of risk HLA-DQB1 *0201/*0302 genotype (27% vs. 6.9%; p<1x10^–6), with similar frequency as to type 1 diabetes (36%). In addition, LADA showed higher frequencies of protective HLA-DQB1 *0602(3)/X than type 1 diabetic patients (8.1% vs. 3.2%, p=0.003). The AA-genotype of rs689, referring to the class I allele in the INS VNTR, as well as the CT/TT-genotypes of rs2476601 in the PTPN22 gene were increased both in T1D (p=3x10^–14 and p=1x10^–10, respectively) and LADA (p=0.001 and p=0.002), as compared to controls. Notably, the frequency of the type 2 diabetes-associated CT/TT-genotypes of rs7903146 in the TCF7L2 were increased in LADA (52.8%; p=0.03), to the same extent as in type 2 diabetes (54.1%, p=3x10^–7), as compared with controls (44.8%) and type 1 diabetes (43.3%).

Conclusions: LADA shares genetic features with both type 1 (HLA, INS VNTR and PTPN22) and type 2 (TCF7L2) diabetes, which justifies considering LADA as an admixture of the two major types of diabetes.

Key Words: LADA • genetics • diabetes • TCF7L2 • HLA • GAD • SNP • transcription factor

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