Keck School of Medicine
- Genetics of complex diseases
Our main research interests are to identify the genes and pathways that contribute to phenotypes with a complex etiology, with a particular emphasis on cardiovascular and metabolic disorders. Such endeavors have historically been difficult due to a variety of factors, including the genetic complexity of these diseases and/or the influence of environmental factors. However, over the last few years, complex trait genetics has been revolutionized by the ability to carry out association studies on a genome-wide basis (GWAS) with hundreds of thousands of single nucleotide polymorphisms (SNPs) in very large populations. For example, such GWAS studies have resulted in the identification of hundreds of novel genetic variants for traits such as cardiovascular disease (CVD), diabetes, cancer, various inflammatory conditions, and quantitative phenotypes associated with such disease states. Despite this success, these susceptibility alleles still only explain a small fraction of the overall genetic heritability for any particular disease, which implies either 1) the existence of additional genes with smaller effect sizes that are not detected in a typical GWAS study, 2) higher order interactions between genes and environmental factors, 3) and/or rare susceptibility alleles that are not included on current genotyping platforms. Moreover, even for those validated genes, an understanding of the underlying pathophysiological mechanism through which they contribute to disease processes is still lacking and awaits more detailed functional experiments. As part of our contribution towards advancing the field and addressing these issues, we employ a variety of complementary approaches to elucidate complex diseases at the epidemiological, genetic, and molecular level.
Large-scale Human Genetic Studies
One of our main focuses are large-scale human studies using DNA samples from thousands of patients and control subjects. Each cohort is specific for a particular phenotype (i.e. CVD or diabetes) and, typically, SNPs within candidate genes or on a genome-wide basis are tested for association using molecular and statistical genetics experiments. Our selection of candidates is derived from what is known about the disease process in humans, the generation of animal models, and/or other genomics approaches. In addition to candidate gene studies, we are carrying out GWAS studies to identify additional CVD genes, particularly those that are associated with non-traditional risk factors, such as inflammation. These studies have also led us into the emerging field of nutrigenomics where we are seeking to understand how genes interact with dietary factors to affect disease risk. Ultimately, we carry out functional experiments to identify underlying the molecular mechanisms for those variants that are confirmed to be associated with disease phenotypes.
Mouse models provide an excellent example of another viable strategy to gene discovery for complex human diseases. Since the conservation of evolutionary relationships at both the genetic and biochemical level between humans and mice is well established, the mouse has emerged as an extraordinarily useful tool for genetic studies that can be translated to humans. Furthermore, the mouse provides certain experimental advantages that simply cannot be realized in human studies, including the ability to manipulate its genome with either the overexpression or targeted ablation of candidate genes under study. Thus, we also use mouse models of CVD and diabetes for gene discovery and to understand disease mechanisms in vivo. Based on these experiments, we can then test potentially new candidate genes in our human studies or develop therapeutic strategies that can be translated back to humans.
As a third and complementary method, our lab also integrates genomics technologies into genetic studies, such as microarray expression profiling of tissues from patients and control subjects or animal models. The goals of such experiments are to identify gene expression networks and pathways that are perturbed in disease states, thus providing, for example, additional candidate genes for study. In addition, such “expression signatures” can also be used as intermediate phenotypes in genetic studies with either mice or humans. Lastly, as part of our nutrigenomics studies, we are attempting to understand how dietary factors influence expression signatures in cells/tissues from subjects participating in various clinical trials.