PMID- 31974565 OWN - NLM STAT- MEDLINE DCOM- 20201124 LR - 20201124 IS - 1945-7197 (Electronic) IS - 0021-972X (Linking) VI - 105 IP - 3 DP - 2020 Mar 1 TI - HLA Class II Allele Analyses Implicate Common Genetic Components in Type 1 and Non-Insulin-Treated Type 2 Diabetes. LID - dgaa027 [pii] LID - 10.1210/clinem/dgaa027 [doi] AB - 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. CI - (c) Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Jacobi, Thomas AU - Jacobi T AD - University of Leipzig Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany. FAU - Massier, Lucas AU - Massier L AD - University of Leipzig Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany. FAU - Kloting, Nora AU - Kloting N AD - University of Leipzig Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany. FAU - Horn, Katrin AU - Horn K AD - Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. AD - LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany. FAU - Schuch, Alexander AU - Schuch A AD - Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. FAU - Ahnert, Peter AU - Ahnert P AD - Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. FAU - Engel, Christoph AU - Engel C AD - Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. AD - LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany. FAU - Loffler, Markus AU - Loffler M AD - Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. FAU - Burkhardt, Ralph AU - Burkhardt R AD - LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany. AD - Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany. FAU - Thiery, Joachim AU - Thiery J AD - LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany. AD - Institute of Laboratory Medicine and Clinical Chemistry, University of Leipzig, Leipzig, Germany. FAU - Tonjes, Anke AU - Tonjes A AD - Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany. FAU - Stumvoll, Michael AU - Stumvoll M AD - University of Leipzig Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany. AD - Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany. FAU - Bluher, Matthias AU - Bluher M AD - University of Leipzig Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany. AD - Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany. FAU - Doxiadis, Ilias AU - Doxiadis I AD - Institute for Transfusion Medicine, University Hospital of Leipzig, Leipzig, Germany. FAU - Scholz, Markus AU - Scholz M AD - University of Leipzig Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany. AD - Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. AD - LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany. FAU - Kovacs, Peter AU - Kovacs P AD - University of Leipzig Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany. AD - Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany. LA - eng SI - ClinicalTrials.gov/NCT00497887 PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 SB - IM MH - Adult MH - Aged MH - Cohort Studies MH - DNA Mutational Analysis MH - Diabetes Mellitus, Type 1/epidemiology/*genetics/immunology MH - Diabetes Mellitus, Type 2/epidemiology/*genetics/immunology MH - Female MH - Gene Frequency MH - *Genes, MHC Class II MH - Genetic Association Studies MH - Genetic Predisposition to Disease MH - Germany/epidemiology MH - Haplotypes MH - Humans MH - Male MH - Middle Aged MH - Polymorphism, Single Nucleotide OTO - NOTNLM OT - HLA class II OT - association OT - genotype imputation OT - haplotype OT - single nucleotide polymorphism OT - type 1 diabetes OT - type 2 diabetes EDAT- 2020/01/25 06:00 MHDA- 2020/11/25 06:00 CRDT- 2020/01/25 06:00 PHST- 2019/09/25 00:00 [received] PHST- 2020/01/15 00:00 [accepted] PHST- 2020/01/25 06:00 [pubmed] PHST- 2020/11/25 06:00 [medline] PHST- 2020/01/25 06:00 [entrez] AID - 5715056 [pii] AID - 10.1210/clinem/dgaa027 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2020 Mar 1;105(3):dgaa027. doi: 10.1210/clinem/dgaa027.