News & Research

Massachusetts General Hospital Boston, Massachusetts

Functional analysis of genome-wide association studies of cholesterol and triglyceride blood levels

General Research Subject: Type 2 Diabetes

Focus: Genetics\Type 2 Diabetes, Integrated Physiology\Fatty Acid Metabolism

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2008

Project End Date: June 30, 2012

Research Description

Heart attack is a primary cause of death in diabetic patients. High blood levels of LDL ('bad') cholesterol and triglycerides, a form of fat, and low blood levels of HDL ('good') cholesterol increase the risk of coronary artery disease, which causes amongst others, heart attack and stroke. The blood levels of cholesterol and triglycerides are influenced not only by environmental factors, such as diet and exercise, but also by genetic factors, i.e. differences between individuals' DNA sequences that affect gene function. Understanding these differences may have important implications for assessing peoples' disease risk, prevention plans, and personally tailored drug design. By comparing DNA sequences of many diabetic and healthy people, in what is called a genome-wide association study, the group of David Altshuler identified multiple regions in the human genome correlated with cholesterol and triglyceride blood levels. Still, finding the specific genes in these regions that are responsible for differences in lipid levels, and understanding through what biological processes they exert their effect is a difficult and important problem. To address this, Ayellet Segrè proposes to computationally search, among all possible combinations of genes in these regions, for particular combinations of genes that interact with each other and have related functions in the cell. She will test the predictions by sequencing the candidate genes across many individuals, and searching for genetic differences associated with cholesterol and triglyceride levels. This strategy, once developed and tested, can be extended to study the genetic factors causing type 2 diabetes.

Reseacher Profile

Mentor: David Altshuler, MD, PhD    Postdoctoral Fellow: Ayellet Segre, PhD

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes? 

Our research project aims to use emerging methods from genetics and genomics to discover new genes and biological processes that affect blood cholesterol levels (HDL, LDL and triglycerides), which are associated with risk of cardiovascular disease in diabetic patients. As the leading cause of death amongst diabetic patients is heart attack, understanding the mechanisms that link diabetes, cholesterol and heart attack offers the hope of improved risk prediction, understanding, and ultimately, improved prevention and treatment.

In the past year, we and others have performed genome-wide association studies, testing hundreds of thousands of genetic variants in thousands of individuals to identify genetic differences influencing diabetes, cholesterol and heart attack.  These studies have led to the discovery of 19 regions in the human genome that contain DNA variants affecting LDL, HDL and/or triglyceride levels, 16 regions that contain DNA variants affecting type 2 diabetes, and five regions influencing heart attack. While this progress is very promising, only a small fraction of the heritability of each trait has been explained, indicating that many more genetic determinants remain to be discovered. Moreover, the actual genes within the associated regions that affect cholesterol and triglycerides levels or type 2 diabetes are in many cases unknown.

In this project, we aim to identify the specific genes responsible for novel associations to lipid levels, to understand the biological processes in which they act, and using these insights, to identify additional genes contributing to risk. In addition to illuminating lipid biology, we will generate a list of potential new drug targets for alterting cholesterol levels in diabetic patients to decrease risk of heart attack.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? 

Type 2 diabetes is associated with a variety of serious complications, most prominently heart attack, kidney failure, nerve damage, and blindness.  At present our ability to predict, prevent and treat these complications is limited.  Our researrch aims to use new methods from human genetics and genomics to uncover the genes and biological pathways responsible for diabetic complications, and thus to provide new hypotheses to guide development of more specific diagnoses, risk stratification for prevention strategies, and therapy.

Our approach leverages the unique ability of human genetics (enabled by the human genome project) to undertake an unbiased search for genes that affect a given trait or disease. The unbiased nature of the search is critically important, as it makes possible to discover causal genes not yet identified by other methods.

While the methods we are developing in this research project will initially be applied to cholesterol and triglyceride serum levels (important risk factors of cardiovascular disease), they are applicable to genetic studies of type 1 and type 2 diabetes, and other related conditions, such as thyroid disease, body mass index, insulin resistance.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts? 

As a physician who has cared for many diabetic patients, and as the child of a diabetic, I am acutely aware of the suffering caused by diabetes and its complications.  As a researcher and teacher who studies diabetes and its causes, I am also acutely aware of the limitations in our current knowledge of the underlying biological causes of diabetes and how hyperglycemia leads to complications.  These two perspectives lead me to conclude that in order to develop improved methods to prevent and treat our patients and our families, we need to go back to the basics and better understand the root causes of this disabling disease. The major enabling advance in our research is the human genome project, and the tools it offers to unravel the genetic basis of disease.  Our generation is the first to benefit from these tools, and it is our obligation to rapidly and effectively turn this opportunity into useful knowledge for medicine. 

The current award will support the training and research of a spectacular young scientitst whose aim is to understand the biological links between genes, type 2 diabetes, elevated cholesterol and vascular complications. We will develop novel analytical methods, use them to discover genes that affect cholesterol and triglyceride blood levels, and from this information derive new hypotheses about approaches to predict and lower risk of complications.

In what direction do you see the future of diabetes research going?

I see two main directions for diabetes research.

First, we need to better deploy the methods for managing diabetes in the clinic and at home.  This includes point-of-care and home monitoring, evidenced-based strategies for treatment, and patient education. Much clinical research is required to understand how to best use existing appraoches to care for diabetic patients.  While I don't personally do such research, I believe it is extremely important. 

The other main thrust of research, in my view, should be to discover the root casuses of diabetes in human patients, and to direct our energy to understanding these factors.  The human genome offers a powerful and unbiased appraoch to seek the genetic risk factors for diabetes and its complications; when we deploy these tools, we find that most of the genes thereby found are not previously known.  We must let the patient (and his / her DNA) teach us what causes disease in human patients, and then develop cell, animal and molecular models of these causal processes.  By putting the patient first, I believe we can focus attention on those biological processes that may not previously have been identified, but have the best chance of mattering to patients and their families in the years to come.