Diabetes

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

review article
Mechanisms of Disease

Genetics of Type 1A Diabetes
Patrick Concannon, Ph.D., Stephen S. Rich, Ph.D., and Gerald T. Nepom, M.D., Ph.D.
From the Center for Public Health Genomics (P.C., S.S.R.) and the Departments of Biochemistry and Molecular Genetics (P.C.) and Public Health Sciences (S.S.R.), University ofVirginia, Charlottesville; and the Diabetes Research Program, Benaroya Research Institute, Seattle (G.T.N.). Address reprint requests to Dr. Concannon at the Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, or at patcon@virginia.edu. N Engl J Med 2009;360:1646-54.
Copyright © 2009 Massachusetts Medical Society.

n 1976, the noted human geneticist James Neeltitled a book chapter “Diabetes Mellitus: A Geneticist’s Nightmare.”1 Over the past 30 years, however, the phenotypic and genetic heterogeneity of diabetes has been painstakingly teased apart to reveal a family of disorders that are all characterized by the disruption of glucose homeostasis but that have fundamentally different causes. Recently, the availability of detailed information on thestructure and variation of the human genome and of new high-throughput techniques for exploiting these data has geneticists dreaming of unraveling the genetic complexity that underlies these disorders. This review focuses on type 1 diabetes mellitus and includes an update on recent progress in understanding genetic factors that contribute to the disease and how this information may contribute to newapproaches for prediction and therapeutic intervention. Type 1 diabetes becomes clinically apparent after a preclinical period of varying length, during which autoimmune destruction reduces the mass of beta cells in the pancreatic islets to a level at which blood glucose levels can no longer be maintained in a physiologic range. The disease has two subtypes: 1A, which includes the common,immune-mediated forms of the disease; and 1B, which includes nonimmune forms. In this review, we focus on subtype 1A, which for simplicity will be referred to as type 1 diabetes. Although there are rare monogenic, immune-mediated forms of type 1 diabetes,2,3 the common form is thought to be determined by the actions, and possible interactions, of multiple genetic and environmental factors. The concordance fortype 1 diabetes in monozygotic twins is less than 100%, and although type 1 diabetes aggregates in some families, it does not segregate with any clear mode of inheritance.4-7 Despite these complexities, knowledge of genetic factors that modify the risk of type 1 diabetes offers the potential for improved prediction, stratification of patients according to risk, and selection of possibletherapeutic targets. As germ-line factors, genetic risk variants are present and amenable to study at all times ― before, during, and after the development of diabetes. Thus, genetic information can serve as a potential predictive tool and provide insights into pathogenetic factors occurring during the preclinical phase of the disease, when preventive measures might be applied.

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Gene t ic S t udie sBecause of the uncertainty regarding the number and action of genes involved in type 1 diabetes, genetic studies have tended to focus on approaches that require few assumptions about the underlying model of disease risk. The two primary approaches have been linkage studies (using pairs of affected relatives, typically siblings) and association studies (using either case–control or family-baseddesigns). Linkage studies using affected sibling pairs seek to identify regions of the genome that are shared
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n engl j med 360;16 nejm.org april 16, 2009

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mechanisms of disease

more frequently than by chance alone among siblings who share the phenotype of type 1...