News & Research

    University of Maryland School of Medicine, Baltimore, Maryland

Genetic determinants of Lipoprotein (a) levels related to risk of atherosclerosis

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Clinical Therapeutics/New Technology\Glucose Monitoring and Sensing, Complications, Complications\ Macrovascular-Atherosclerotic CVD and Human Diabetes, Diabetic Dyslipidemia, Genetics, Genetics\Type 2 Diabetes

Type of Grant: Clinical Translational Research

Project Start Date: July 1, 2012

Project End Date: June 30, 2015

Research Description

The incidence of cardiovascular disease (CVD) in patients with diabetes is markedly increased. A high cholesterol level in the blood is an important independent risk factor for atherosclerosis, the underlying cause of CVD. Recent evidence from large cohorts suggest that a particular protein that is associated with cholesterol, called Lp(a) may be an important determinant of coronary heart disease and stroke. Lp(a) levels are genetically determined; however, the specific genes involved are not completely known. Moreover, no practical method for pharmacologic lowering of Lp(a) levels is currently available.

The objective of this proposal is to define the genetic architecture of Lp(a) to glean insights into mechanisms of Lp(a) regulation in patients with diabetes. They propose to use a multi-pronged high-throughput genomics approach to identify specific gene variations that influence Lp(a) levels. They will sequence genes on two chromosomal regions that they have previously found to be associated with Lp(a) levels in the Old Order Amish. The gene variations they identify will be prioritized and the most likely functional variations further tested to see if they are associated with changes in the expression of genes, Lp(a) levels, and atherosclerosis in patients. Identification of the genes that influence Lp(a) levels may lead to the design of novel therapeutic strategies to lower Lp(a) levels to  prevent or treat CVD in patients with diabetes.

Research Profile

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

The incidence of cardiovascular disease in patients with diabetes is markedly increased. Moreover, myocardial ischemia due to coronary atherosclerosis commonly occurs without symptoms in patients with diabetes. Dyslipidemia is an important independent risk factor for this increase. Lp(a) consists of a cholesterol-laden LDL particle and a plasminogen-like glycoprotein, suggests that Lp(a) may contribute both to the process of atherosclerosis and thrombosis. Recent evidence from large cohorts suggest a causal relationship between Lp(a) and thrombo-atherogenic disease. High Lp(a) in blood is a risk factor for coronary heart disease, cerebrovascular disease, atherosclerosis, thrombosis, and stroke. Our project will study diabetic dyslipidemia to reduce recurrent CHD events in patients with diabetes.
 
Lp(a) levels are highly heritable that are minimally influenced by age, gender, weight, and diet. Most commonly prescribed lipid-reducing drugs have little or no effect on Lp(a) concentration. The objective of this proposal is to define the genetic architecture of Lp(a) to glean insights into mechanisms of Lp(a) regulation and the design of novel therapeutic strategies for prevention or treatment of cardiovascular disease in patients with diabetes.

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

In our project, we will study genetic susceptibility of Lp(a) levels and correlations between atherosclerosis and causative  variants of Lp(a). These results will provide following benefits to diabetic patients:
1) A predictive genetic testing would be offered to diabetic patients. Through genetic testing, individuals at high risk for Lp(a) levels and cardiovascular disease could be identified prior to the onset of the disease – at a time when primary prevention strategies could be safely administered.
2) The susceptibility genes of Lp(a) may be drug targets that will develop novel drugs for cardiovascular disease in patient with diabetes.
3) To determine genetic variations that influence positive and negative responses to Lp(a) therapies may help to choose specific pharmacologic agent for diabetic individuals.

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

I had been a physician and took care of diabetic patients. The disease affects almost every organs and causes a host of complications including "macrovascular" diseases (ischemic heart disease, stroke and peripheral vascular disease) and "microvascular" complications (kidney failure, blindness and amputation). Up to now, diabetes still cannot be cured. Diabetic patients will suffer this disease for their whole life. Moreover, diabetic incidence is rapidly increasing, and by 2030, an estimated over 500 million people had diabetes in the world. In order to effectively combat this disease, we must gain a greater understanding of the complex genetic, molecular, and behavioral factors that lead to type 2 diabetes.

Lp(a) is a highly heritable trait. The main aim of our research is to discover genetic causes of variation in Lp(a) and to evaluate relationship between genetic variation and atherosclerosis. This award will support us to screen two loci (6q25-46 and 11q23) that are significantly associated with Lp(a) levels to identify causal variations in Lp(a). This award also will support us to evaluate if theses causal variations will increase the risk of atherosclerosis.

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

Diabetes and their complications have strong genetic bases. Identifying genetic susceptibility of diabetes and their complications is a key to development of strategies for prevention and treatment of diabetes. To identify the genetic and other causes of diabetes and their complications is an important future direction of diabetes research.

I also think another future direction is to study the causes of beta cells dysfunction that will inform efforts to replicate, regenerate, or replace beta cells and restore normal insulin production.