HLA Class II Allele Analyses Implicate Common Genetic Components in Type 1 and Non–Insulin-Treated Type 2 Diabetes

• Published in: The journal of clinical endocrinology and metabolism Vol. 105; no. 3; pp. e245 - e254
• Main Authors: Jacobi, Thomas, Massier, Lucas, Klöting, Nora, Horn, Katrin, Schuch, Alexander, Ahnert, Peter, Engel, Christoph, Löffler, Markus, Burkhardt, Ralph, Thiery, Joachim, Tönjes, Anke, Stumvoll, Michael, Blüher, Matthias, Doxiadis, Ilias, Scholz, Markus, Kovacs, Peter
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.03.2020; Copyright Oxford University Press
• Subjects: Alleles; Diabetes; Diabetes mellitus (insulin dependent); Diabetes mellitus (non-insulin dependent); DQA1 protein; Drb1 protein; Gene polymorphism; Genetic analysis; Genetic diversity; Genomes; Haplotypes; Histocompatibility antigen HLA; Insulin; Metabolism; Phenotyping; Single-nucleotide polymorphism; type 1 diabetes; haplotype; type 2 diabetes; single nucleotide polymorphism; genotype imputation; HLA class II; association
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgaa027

Abstract Context Common genetic susceptibility may underlie the frequently observed co-occurrence of type 1 and type 2 diabetes in families. Given the role of HLA class II genes in the pathophysiology of type 1 diabetes, the aim of the present study was to test the association of high density imputed human leukocyte antigen (HLA) genotypes with type 2 diabetes. Objectives and Design Three cohorts (Ntotal = 10 413) from Leipzig, Germany were included in this study: LIFE-Adult (N = 4649), LIFE-Heart (N = 4815) and the Sorbs (N = 949) cohort. Detailed metabolic phenotyping and genome-wide single nucleotide polymorphism (SNP) data were available for all subjects. Using 1000 Genome imputation data, HLA genotypes were imputed on 4-digit level and association tests for type 2 diabetes, and related metabolic traits were conducted. Results In a meta-analysis including all 3 cohorts, the absence of HLA-DRB5 was associated with increased risk of type 2 diabetes (P = 0.001). In contrast, HLA-DQB*06:02 and HLA-DQA*01:02 had a protective effect on type 2 diabetes (P = 0.005 and 0.003, respectively). Both alleles are part of the well-established type 1 diabetes protective haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02, which was also associated with reduced risk of type 2 diabetes (OR 0.84; P = 0.005). On the contrary, the DRB1*07:01~DQA1*02:01~DQB1*03:03 was identified as a risk haplotype in non–insulin-treated diabetes (OR 1.37; P = 0.002). Conclusions Genetic variation in the HLA class II locus exerts risk and protective effects on non–insulin-treated type 2 diabetes. Our data suggest that the genetic architecture of type 1 diabetes and type 2 diabetes might share common components on the HLA class II locus.