Genetic heterogeneity in latent autoimmune diabetes is linked to various degrees of autoimmune activity: results from the Nord-Trøndelag Health Study

Abstract

Objective: Previous studies have indicated that the latent autoimmune diabetes in adults (LADA) phenotype is heterogeneous and that LADA patients share features of type 1 and type 2 diabetes in various proportions. We tested for association of known type 1 and type 2 diabetes susceptibility genes in LADA subjects and analyzed relationships to a marker of autoimmune activity (titers of anti-GAD) and a phenotypic risk factor of type 2 diabetes (BMI).

Research design and methods: Data were assembled from the Nord-Trøndelag Health Study (HUNT) study, which comprises the adult population of an entire county in Norway. We genotyped 60 single nucleotide polymorphisms (SNPs) known to be associated with type 1 or type 2 diabetes, including 14 tag SNPs used for HLA haplotyping in 120 type 1 diabetic, 126 LADA, and 1,090 type 2 diabetic patients and 1,503 age- and sex-matched nondiabetic subjects.

Results: The majority of the strongly associated HLA haplotypes for type 1 diabetes were significantly associated with LADA in general, but mainly with high anti-GAD LADA patients. Two distinct HLA haplotypes were associated only with LADA and mainly in low anti-GAD LADA patients. There were no associations of non-HLA type 1 diabetes loci with LADA. Of type 2 diabetes-associated genes, the CC/CT genotypes of rs7961581 (TSPAN8) and the obesity-linked AA/AC genotypes of rs8050136 (FTO) were associated with LADA in general, but mainly in low anti-GAD LADA patients (P = 0.004 and P = 0.004, respectively).

Conclusions: Genetic heterogeneity in LADA is linked to various degrees of autoimmune activity and may be partly distinct from both type 1 and type 2 diabetes.

FIG. 1.

Schematic diagram of the tag SNPs used for HLA haplotyping in the MHC region on chromosome 6 including nearby located genes. The HLA genes that are predicted by the tag SNPs are shown as black boxes; other HLA genes are shown as hatched boxes. Additional genes are shown as white boxes.

FIG. 2.

Average HLA haplotype frequencies in different types of diabetes, calculated from the seven strongest associated risk HLA haplotypes and the seven strongest protective HLA haplotypes with type 1 diabetes. T1D, type 1 diabetes; T2D, type 2 diabetes.