Biography
Dr. Altshuler’s laboratory aims to characterize and catalogue patterns of human genetic variation, and to apply this information to understand the inherited contribution to common diseases.
Dr. Altshuler was a leader in the SNP Consortium and International HapMap Consortium, public-private partnerships that created genome-wide maps of human genetic diversity that now guide the design and interpretation of genetic association studies. Dr. Altshuler’s group has also contributed to identifying the role of common genetic variants in type 2 diabetes, prostate cancer, and lupus.
Dr. Altshuler is a Clinical Scholar in Translational Research of the Burroughs Wellcome Fund, a Charles E. Culpeper Medical Scholar, and winner of the Stephen Krane Award of the Massachusetts General Hospital. He received the Richard and Susan Smith Pinnacle Award of the American Diabetes Association, and the “Freedom to Discover” Award from the Foundation of Bristol-Myers Squibb. He is a member of Advisory Boards at The National Institutes of Health, The Juvenile Diabetes Research Foundation, The Wellcome Trust and Merck Research Laboratories, on the Editorial Board of Annual Reviews of Human Genetics and Genomics, and the Board of Reviewing Editors at Science. Professor Altshuler is one of four Founding Members and Director of the Program in Medical and Population Genetics of The Broad Institute of Harvard and MIT, a unique research collaboration of Harvard, MIT, The Whitehead Institute, and the Harvard Hospitals.
Abstract
Discovery and Clinical Application Type 2 Diabetes Genes
Despite great progress in biomedical research, the root causes of common diseases remain largely unknown; we have limited ability to prevent disease before it occurs, and few cures to offer once present. The long-term objective of our research is to identify inherited DNA variations that predispose to type 2 diabetes (T2D), and using this information, deploy existing treatments more effectively and design more effective interventions.
Our work is based on the observation that family history is one of the strongest influences on any disease: that is, rates of disease are more correlated in first degree relatives than in unrelated individuals, and strikingly more so in identical twins. Our past efforts have helped create a foundation of knowledge and methods that make possible systematic study of human genome sequence variation for its contribution to T2D and other diseases. We are currently testing 500,000 common genetic variations for association to T2D in 1,500 cases and 1,500 matched controls, and other such studies are ongoing. It is reasonable to expect that these (and even more powerful methods to come) will soon yield novel insights into the biological basis and population risk of T2D. Translating this information to clinical medicine is the goal of this proposal.
First, we will study whether and how DNA variants associated with risk of T2D might offer clinical information about progression from impaired glucose tolerance to T2D, and response to interventions. Specifically, single nucleotide polymorphisms found to be reproducibly associated with T2D in the whole genome scans will be genotyped in DNA samples from the Diabetes Prevention Program (DPP), a randomized intervention trial of patients with impaired glucose tolerance (IGT), with progression to T2D as an endpoint. Together with colleagues in the DPP we will ask whether these genetic variants predict progression from IGT to T2D, and of altered response to lifestyle and pharmacological interventions that delay onset of T2D. Based on these findings we will design a clinical trial asking whether genetically tailored diagnosis and therapy improves outcomes compared to standard care.
Second, we will develop new therapeutic leads based on novel information about inherited variants that predispose to risk of T2D. Specifically, we will study cells from carriers of specific risk genotypes, and in which the level of confirmed risk genes have been modified using RNAi and over-expression. Using genome-wide expression profiling we will search for signatures of altered gene sequence and activity. We will then use gene-expression high throughput screening (GE-HTS) to search for small molecules that reverse the signature of the at-risk genotypes or altered level of gene function, aiming to identify lead compounds for future study.
Third, we will create a suite of educational programs to enhance the mentoring and training of clinical investigators interested in applying genetics and genomics to clinical practice. Specifically, we will develop educational materials tailored for use on the wards, and organize an annual symposium for investigators who are embarking on careers in clinical genomic research, with the goal of having them get to know one another, to share ideas, and to brainstorm together about important goals and how to overcome obstacles to progress.
The proposed research aims to translate genetic information into more effective use of existing therapies, to catalyze discovery of new therapies, and to train the next generation of clinical genetic investigators.