My research currently focuses on identifying susceptibility loci of common, complex diseases and modifier genes of monogenic diseases. The phenotypes are all related to the circulatory system: blood cells, angiogenesis, and blood pressure. Blood pressure (BP) is the product of two entities: cardiac output and peripheral vascular resistance. Essential hypertension (EH) results from the deregulation of one of the two and the inadequate compensatory action of the other. So far the genes underlying monogenic forms of hyper- and hypotension all encode for proteins that are directly or indirectly involved in renal salt-water balance, hence affecting the cardiac output portion of the BP. My work with the Family Blood Pressure Program established chromosome 1q as a region containing an EH susceptibility locus that has been confirmed by multiple genome-wide linkage scans in human and both mouse and rat hypertension models. At least three 1q genes have shown significant association to EH.  As with many other common disease genes, there are no coding variants in these three genes. Presently my laboratory is working on characterizing the functional relationships between non-coding variants of these three genes and BP regulation.

The challenge of finding modifier genes for monogenic disorders is perfectly illustrated by sickle cell disease and thalassemia. The primary molecular lesion and physiological consequences are well characterized, but we have inadequate understanding of their clinical manifestations and few satisfactory therapeutic options. For both disorders, high adult levels of fetal hemoglobin (HbF) production ameliorate the disease severity and genes regulating adult HbF levels are known important modifier of these 2 diseases.  In order to identify genes that regulate adult HbF production, my laboratory is studying families of b-thalassemia intermedia who have no detectable b-globin synthesis yet require transfusion only in the second decades of their life (compared to typical patients who are transfusion-dependent shortly after birth).