JCL roundtable: Lessons from genetic variants altering lipoprotein metabolism

•Discovery of major and minor gene variants is providing important information about relationships with lipoprotein abnormalities.•The phenotypic expression of lipoprotein abnormalities is often explained by multiple minor gene variants discovered in large genome-wide association studies.•Mendelian randomization is a method of comparing groups of individuals with a particular gene variant (or group of variants) to the entire population regarding associated phenotypic abnormalities in both prevalence and incidence studies.•Such studies have confirmed theory regarding drug benefits and have identified new protein functionality in lipoprotein physiology.

Because the Human Genome Project reached its first major milestone in completing the full sequence of human DNA, many new discoveries have been made relating genetic variants to disease. The new methodology that allows much more rapid and focused analyses of selected genes and the ability to screen the entire exome of any individual has provided tools to examine literally thousands of individuals for a given study. Genetic analysis has become a large-scale epidemiologic tool for examining variants in gene structure and correlating them with phenotypic markers of human disorders. These genome-wide association studies have been quite revealing about the mechanism of disorders of many types. These tools have been applied to the appearance of clinical atherosclerosis and to the chronic metabolic risk factors for this disease process. We are joined by 2 individuals who have made very significant contributions to this area of research: Dr Brian Ference of Wayne State University School of Medicine and Dr Sekar Kathiresan from Massachusetts General Hospital and Harvard Medical School. In our discussion, we are going to focus on genetic variants, which lead to changes in lipoprotein concentrations and those that have an association with earlier onset of clinical vascular disease. This roundtable was recorded during the November 2016 American Heart Association Scientific Sessions in Orlando, Florida.