Genetics of Type 1 Diabetes

Stephen S. Rich; Henry Erlich; Patrick Concannon

Genetics of Type 1 Diabetes

Review

In: Diabetes in America. 3rd edition. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases (US); 2018 Aug. CHAPTER 12.

Authors

Stephen S. Rich¹, Henry Erlich², Patrick Concannon³

Book Editors

Catherine C. Cowie¹, Sarah Stark Casagrande², Andy Menke², Michelle A. Cissell³, Mark S. Eberhardt⁴, James B. Meigs⁵, Edward W. Gregg⁶, William C. Knowler⁷, Elizabeth Barrett-Connor⁸, Dorothy J. Becker⁹, Frederick L. Brancati¹⁰, Edward J. Boyko¹¹, William H. Herman¹², Barbara V. Howard¹³, K. M. Venkat Narayan¹⁴, Marian Rewers¹⁵, Judith E. Fradkin¹⁶

Affiliations

¹ Dr. Stephen S. Rich is Director of the Center for Public Health Genomics, University of Virginia, Charlottesville, VA
² Dr. Henry Erlich is Senior Scientist at the Children’s Hospital Oakland Research Institute, Oakland, CA, and past Director of Human Genetics and Vice-President of Discovery Research, Roche Molecular Systems, Pleasanton, CA
³ Dr. Patrick Concannon is Director of the Genetics Institute, University of Florida, Gainesville, FL

Book Affiliations

¹ Senior Advisor and Director for Diabetes Epidemiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
² Senior Research Analyst, Social & Scientific Systems, Inc., Silver Spring, MD
³ Science Writer/Editor, Chicago, IL
⁴ Epidemiologist, Division of Health and Nutrition Examination Surveys, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD
⁵ Professor of Medicine, Harvard Medical School, and Physician, Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA
⁶ Chief, Epidemiology and Statistics Branch, Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, GA
⁷ Chief, Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ
⁸ Distinguished Professor, Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA
⁹ Professor of Pediatrics, Division of Endocrinology and Diabetes, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA
¹⁰ Distinguished Service Professor of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD
¹¹ Professor, University of Washington, and Staff Physician, Veterans Affairs Puget Sound, Seattle, WA
¹² Professor, Departments of Internal Medicine and Epidemiology, University of Michigan, Ann Arbor, MI
¹³ Professor of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, Georgetown University Hospital, and Senior Scientist, MedStar Health Research Institute, Hyattsville, MD
¹⁴ Director, Emory Global Diabetes Research Center, Ruth and O.C. Hubert Professor of Global Health and Epidemiology, Rollins School of Public Health, and Professor of Medicine, School of Medicine, Emory University, Atlanta, GA
¹⁵ Professor of Pediatrics and Medicine, Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
¹⁶ Director, Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

PMID: 33651545
Bookshelf ID: NBK567984

Excerpt

Type 1 diabetes is a complex disease that has both genetic and environmental determinants. Based on twin and family studies, the estimated contribution of genetic factors to type 1 diabetes risk is ~50%. Genes and their variants within the human major histocompatibility complex (MHC), including the human leukocyte antigen (HLA) class I (HLA-A, -B, and -C) and class II (HLA-DR, -DQ, and -DP) loci, account for about one-half of the genetic risk of type 1 diabetes. Three amino acid positions in HLA-DQ and HLA-DR define ~90% of the variation in the MHC, with evidence of interactions between pairs of HLA haplotypes that affect antigen binding. Other major contributors to type 1 diabetes genetic risk have been identified through candidate gene and linkage studies and include variants in or near the INS, CTLA4, IL2RA, and PTPN22 genes. Genome-wide association approaches have revealed additional loci containing common variants with relatively small individual effects on type 1 diabetes risk. International efforts led by the Type 1 Diabetes Genetics Consortium and others have identified over 40 non-MHC loci and narrowed the likely candidate genes and variants substantially. The majority of non-MHC variants affect gene regulation rather than directly altering protein structure. Both analytic and molecular work are required to assess the functional significance of the variants in type 1 diabetes susceptibility genes in order to identify critical biologic pathways that could lead to novel interventions and therapeutics.

Sections

Publication types

Review