Upon joining the UT Southwestern faculty in the Center for Human Nutrition, the first project Dr. Cohen undertook was to identify genetic polymorphism that is the basis for much of the variation in plasma lipoprotein levels in humans. At that time, the heritability of plasma lipoprotein levels had been clearly established, but little was known about which specific genes were responsible for variation in lipoprotein levels in the general population. Dr. Cohen instituted a program to better understand the genetic basis of abnormal lipoprotein levels.
His initial studies confirmed that about 50% of the variability in HDL levels in the general population derive from genetic polymorphism. Moreover, through sibling-pair linkage analysis, he found that two genes--those encoding for hepatic lipase and apolipoprotein A1--account for 50% of the genetic variability. Dr. Cohen then focused his genetic studies on hepatic lipase, which seemed to be the most robust determinant of HDL levels. In follow-up studies on hepatic lipase he found that a polymorphism in the promoter region of the hepatic lipase gene that regulates the expression of this protein. He found through association studies that individuals who possess a common polymorphism of in this region have elevated HDL levels. Subsequent studies with Center investigators proved that these individuals have a reduced expression of hepatic lipase.
Thereafter, he demonstrated a prime reason why African Americans generally have higher HDL levels than Caucasians. African Americans have a high incidence of the promoter polymorphism that Dr. Cohen had discovered. In addition, he found that African Americans have other polymorphisms in the coding region of the hepatic- lipase gene. This combination of polymorphisms is linked to the higher HDL levels of African Americans. It was further observed in collaboration with investigators both in our Center and with outside investigators that African Americans have very low activities of hepatic lipase. In further studies, Dr. Cohen extended the same general approach to the genetic determinants of plasma LDL-cholesterol levels. Although it had long been anticipated that genetic variation in the genes for the LDL receptor and apolipoprotein B would be the major reason for genetic variation in LDL-cholesterol levels, he found through linkage analysis that this is not true. Although they are major determinants of LDL-cholesterol levels, variation in the LDL-receptor and apolipoproteins B loci account for little of the variation in LDL-cholesterol levels in the general population. One previous genetic determinant of lipoprotein levels is known to be polymorphism in the gene encoding apolipoprotein E (apo E). Dr. Cohen showed by completely independent methods, i.e., sibling-pair linkage analysis, that variation in the apo E gene does in indeed explain about 15% of the variability of LDL levels in the general population. Moreover, in the same analysis he demonstrated that genetic polymorphism in cholesterol 7-alpha hydroxylase contributes another 15% to the inter-individual variation in plasma LDL cholesterol levels in the American population. Further, he identified a polymorphism in the gene encoding this enzyme that is associated with elevated LDL levels.
Recently, Dr. Cohen has extended his research on genetic regulation of lipids and lipoproteins into the area of fatty acid oxidation. The liver's metabolism of fatty acids appears to be a key determinant of both plasma lipoprotein concentrations and liver fat content. The regulation of fatty acid metabolism in the liver thus could have an impact on both atherosclerotic disease and fatty liver. Dr. Cohen cloned and sequenced the human gene encoding malonyl CoA decarboxylase, which appears to be one of the gatekeepers for the initiation of fatty acid oxidation in the liver, and identified mutations causing its deficiency in several patients. He is currently investigating the metabolic role of the enzyme.
Role in the Center for Human Nutrition:
The Center for Human Nutrition is seeking to integrate nutrition and genetic studies to explain human metabolism and susceptibility to chronic disease. Dr. Cohen's laboratory links the strong basic research program at UT Southwestern and clinical investigators in the Center for Human Nutrition. He provides a vital link that will help to keep the Center's research on the cutting edge of molecular medicine.
Laboratory Interests:
The major interest of Dr. Cohen's laboratory is the genetic determinants of plasma lipoprotein levels. Dr. Cohen has used family studies to identify DNA sequence polymorphisms in genes that influence plasma levels of high density and low density lipoproteins in the general population. Currently, families of individuals with high plasma triglyceride concentrations are being collected to identify genes that underlie the plasma lipoprotein disorders and the metabolic syndrome.
Laboratory Personnel:
- Liangcai Nie, MD
Research Scientist
- Fang Xu, MD
Postdoctoral Research Fellow
