A study of the epigenetics of type 1 diabetes using identical twins
Published: 11 October 2006

Principle Researcher
David Leslie, MD, FRCP

Research Grant
Duration: 01/03/06 - 30/06/09

Objectives

Type 1 diabetes mellitus (T1DM) remains a common cause of morbidity and mortality in the developed world, and there is still much to learn about the molecular complexities of T1DM before we can develop effective strategies to prevent or cure this autoimmune disease. We propose that in addition to genetic and environmental influences, epigenetic factors also impact on T1DM etiology and we would like to perform genome-wide and high-resolution screens to identify epigenetic variants associated with T1DM.

Background/Rationale

The conventional wisdom on genes goes something like this: DNA is transcribed onto RNA, which form proteins, which are responsible for just about every process in the body, from eye colour to ability to fight off illness. The science of epigenetics, attempts to explain the mysterious inner layers of the genetic onion that may account for why identical twins aren’t exactly identical and why one twins gets diabetes and the other does not. Only two percent of our DNA - via RNA - codes for proteins. Until very recently, the rest was considered "junk," the by product of millions of years of evolution. Now scientists are discovering that some of this junk DNA switches on RNA that may do the work of proteins and interact with other genetic material. "Malfunctions in these genes," can cause disease or conversely protect from it. Epigenetics delves deeper into the process, involving "information stored in the proteins and chemicals that surround and stick to DNA." Called,Methylation. Methylation is a chemical process that, among other things, aids in the transcription of DNA to RNA and is believed to defend the genome against parasitic genetic elements called transpons. A 2003 MIT study created mice with an inborn deficiency of a methylating enzyme. Eighty percent of these mice died of cancer within nine months. This study aims to look at identical twins discordant for TID to look at these important methylation differences or similarities between twins. T1DM affects at least 30 million people worldwide and, tragically, is still associated with increased morbidity and mortality. Therefore, there are ongoing efforts to develop better diagnostics and therapeutics for T1DM. We propose that epigenetic factors impact on T1DM aetiology, in combination with genetic and environmental influences.

Description of Project

Research Design and Methods: Selection of subjects.  We have in excess of 200 MZ twin pairs that are either discordant or concordant for T1DM. Ascertainment of these MZ twin pairs has been previously described (Diabetes 46: 1270-1275 1997 ,BMJ 318:698-702 1998). Twin pairs discordant for T1DM and at low risk of becoming concordant (<2% risk per pair) will be ascertained and blood samples taken either at home or clinic as previously described . Sixty MZ pairs discordant for T1DM will be selected from the total cohort according to the criteria of the American Diabetes Association (The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1998). Control MZ twin pairs will be obtained from the local community with a similar age range and sex ratio to the diabetic MZ twins and without any clinical disease, therapy, clinical signs of illness or family history of autoimmune disease.

Anticipated Outcome

The aetiology of T1DM is largely a mystery. In light of the facts that only a few genomic susceptibility regions have been found, and no environmental agents conclusively identified, we propose that the penetrance of T1DM may be influenced by epigenetic factors. The study described here will be the first ever investigation into the role of epigenetic variants in the pathogenesis of T1DM (or any other autoimmune disease). We will use genome-wide screens and high-throughput DNA methylation analysis technology to identify and analyze T1DM-associated epigenetic variants in a large cohort of MZ twins. Access to the twin cohort, high-throughput methylation analysis technology, and our expertise in the genetics and epigenetics of the MHC places us in a unique and competitive position to carry out the proposed project. Our study has two main deliverables: 1. Identification of T1DM-specific epigenetic variants. 2. Identification of epigenetic variants that distinguish childhood- from adult-onset T1DM.

Relevance to Type 1 Diabetes

These findings will provide mechanistic insights into disease pathogenesis since methylation is an important modulator of gene expression. Furthermore, they have the potential for improved diagnostics and therapeutics as comparison of an individual’s DNA methylation profile with healthy or T1DM-specific profiles could help predict disease, and aberrant T1DM-associated epigenetic profiles may identify potential targets for certain drugs to alter the disease course. Finally, this study will identify candidate T1DM-specific epimutations, which will lay the groundwork for integration into the large population-based study of T1DM being performed by the Sanger Institute as part of the Wellcome Trust Case-Control Consortium.