Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes

Abstract

Aims/hypothesis Latent autoimmune diabetes in adults (LADA) is phenotypically a hybrid of type 1 and type 2 diabetes. Genetically LADA is poorly characterised but does share genetic predisposition with type 1 diabetes. We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA). Methods We assessed 41 type 2 diabetes-associated gene variants in Finnish (phase I) and Swedish (phase II) patients with LADA (n =911) or type 1 diabetes (n = 406), all diagnosed after the age of 35 years, as well as in nondiabetic control individuals 40 years or older (n=4,002). Results Variants in the ZMIZ1 (rs12571751, p=4.1×10 ) loci were strongly associated with LADA. Variants in the KCNQ1 (rs2237895, p=0.0012), HHEX (rs1111875, p= 0.0024 in Finns) and MTNR1B (rs10830963, p=0.0039) loci showed the strongest association in patients with low GADA, supporting the hypothesis that the disease in these patients is more like type 2 diabetes. In contrast, variants in the KLHDC5 (rs10842994, p=9.5×10 −4 in Finns), TP53INP1 (rs896854, p=0.005), CDKAL1 (rs7756992, p=7.0×10; rs7754840, p=8.8×10 −4 ) and PROX1 (rs340874, p=0.003) loci showed the strongest Electronic supplementary material The online version of this article

Discovery of Coding Genetic Variants Influencing Diabetes-Related Serum Biomarkers and Their Impact on Risk of Type 2 Diabetes

“…Conditional analysis in the Danish part of the T2D association data showed an unchanged effect size of rs2650000 on T2D when conditioning on rs7957197 (unconditional OR 0.95, conditional OR 0.96), yet conditional analysis of DIAGRAM data is not available and future studies will be needed to conclude whether rs2650000 and rs7957197 are independent T2D association signals. Recently, rs2650000 was reported to be associated with type 1 diabetes in a small sample from Sweden and Finland (33). Of interest, direction of effect for rs265000 on serum CRP and T2D ( Figure 1) indicates that the effect of HNF1A variation on T2D is not mediated through serum CRP levels which is in line with previous studies of the pleiotropic effects of variants in HNF1A (34).…”

Overlap of Genetic Susceptibility to Type 1 Diabetes, Type 2 Diabetes, and Latent Autoimmune Diabetes in Adults

“…A very recent study expanded on the TCF7L2 observations by testing all established GWAS-implicated T2D loci in the context of LADA [69]. In addition to TCF7L2, the authors also found strong evidence for the zinc finger, MIZ-type containing 1 (ZMIZ1) locus being associated with the disease.…”

“…However, it is becoming increasingly clear that the magnitude of the association between LADA and TCF7L2 is correlated with antibody titer, where the lower it is, the stronger the association [69,81]. Furthermore, it has even been proposed that TCF7L2 genotype status can be used to discriminate between middle-aged antibody-positive patients from those that are young antibody-positive [82].…”

“…Most notably, there is no correlation between the TCF7L2 locus and T1D [66][67][68]. However, a recent study did implicate the T2D genes encoding melatonin receptor 1B (MTNR1B) and HNF1A in T1D [69]. In the latest trans-ethnic metaanalysis (also described above), given that POU5F1-TCF19 is within the major histocompatibility complex (MHC), the authors did also note that when they considered the T1D loci reported to date, they found a degree of evidence of association with two of them, namely GLIS3 and 6q22.32 [37].…”

Latent Autoimmune Diabetes in Adults (LADA): The Prevalent Form of Adult-Onset Autoimmune Diabetes in a Region of India

“…However, the association of DM-2 associated Transcription factor 7-like 2 (TCF7L2) and Zinc finger MIZ-type containing 1 (ZMIZ1) risk gene variants with LADA is important and against the arguments denying LADA as a distinct entity; also, the differences in human leukocyte antigen (HLA) haplotypes for both risk and protection complement the idea of LADA as a separate identity [9][10][11][12][13].…”