Genetic Similarities Between Latent Autoimmune Diabetes in Adults, Type 1 Diabetes, and Type 2 Diabetes

Abstract

OBJECTIVE—Latent autoimmune diabetes in adults (LADA) is often considered a slowly progressing subtype of type 1 diabetes, although the clinical picture more resembles type 2 diabetes. One way to improve classification is to study whether LADA shares genetic features with type 1 and/or type 2 diabetes. RESEARCH DESIGN AND METHODS—To accomplish this, we studied whether LADA shares variation in the HLA locus or INS VNTR and PTPN22 genes with type 1 diabetes or the TCF7L2 gene with type 2 diabetes in 361 LADA, 718 type 1 diabetic, and 1,676 type 2 diabetic patients, as well as 1,704 healthy control subjects from Sweden and Finland. RESULTS—LADA subjects showed, compared with type 2 diabetic patients, increased frequency of risk for the HLA-DQB1 *0201/*0302 genotype (27 vs. 6.9%; P < 1 × 10−6), with similar frequency as with type 1 diabetes (36%). In addition, LADA subjects 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 type 1 diabetic (P = 3 × 10−14 and P = 1 × 10−10, respectively) and LADA (P = 0.001 and P = 0.002) subjects compared with control subjects. Notably, the frequency of the type 2 diabetes–associated CT/TT genotypes of rs7903146 in the TCF7L2 were increased in LADA subjects (52.8%; P = 0.03), to the same extent as in type 2 diabetic subjects (54.1%, P = 3 × 10−7), compared with control subjects (44.8%) and type 1 diabetic subjects (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.

Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15–34 years) but not in middle-aged (40–59 years) diabetic patients

“…These findings complement and add to our previous paper [18] showing that frequency of the TCF7L2 variants markedly differs between young and middle-aged autoimmune diabetes, further supporting the view that LADA represents an admixture of type 1 and type 2 diabetes. It also shows that if the age at onset for definition of LADA is lowered below 35 years, the LADA group will include an increasing number of patients with classical type 1 diabetes.…”

“…Fasting plasma C-peptide was measured in 1,628 while HLA-DQB1 was genotyped in 1,365 and INS VNTR and PTPN22 in 1,312, and TCF7L2 in 1,614 patients. There was a 43% (701/1,632) overlap between the current data set of middle-aged type 2 diabetic patients from the Scania Diabetes Registry and a previous paper by Cervin et al [18]. Informed consent was obtained from all patients.…”

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

“…47 The inclusion only of patients with a relatively young age of onset is most likely to result in a clinically homogeneous patient population, presumably excluding atypical adult manifestations of T1D (including latent autoimmune diabetes in adults 48 ). Even though associations between MHC loci and age of onset have been suggested, 3,6,[25][26][27] such analyses were not justified in this study, as our analyses already included a large number of parameters in a relatively small population, with resulting loss of statistical power.…”

Prevalence and comorbidities of double diabetes

“…These persons often have a family history of type 2 diabetes (T2DM) [4] or hypertension [5]. Genetic similarities are seen between obese people with autoimmune diabetes and T2DM [6]. The prevalence of persons showing signs of both diabetes forms increases significantly because of lifestyle changes in the last decades with increasing obesity and decreasing physical activity, but epidemiologic data about this phenomenon are still scarce [2,7,8].…”