Genetic, Biochemical and Functional Analyses of Genes in the Highly Atherogenic Disorder Familial Combined Hyperlipidemia (FCHL). (360G-Wellcome-099107_Z_12_Z)

Background: Genetic hyperlipidemias are a common cause of premature coronary heart disease. Familial Combined Hyperlipidemia(FCHL) is a prevalent form of inherited hyperlipidemia. Elucidating the aetiologies of FCHL have been difficult because the condition is genetically heterogeneous, and common variants that raise blood lipid levels in the general population have almost no effect in this disorder(s). FCHL is likely to run in families because causative lesions have a moderate-to-large impact o n lipid levels. Aims: The aim of my Fellowship is to acquire data that will ultimately lead to genetic (and definitive) diagnosis of FCHL (and reduce its clinical consequences), similar to that implemented for monogenic Familial Hypercholesterolemia. Methods: By considering very recent genetic and biological data, I have started screening the largest assembled cohort of FCHL families worldwide for deleterious lesions in three 'new' genes. I am continuing my in-depth sequence analyses in f urther patients, and will undertake cell-based studies to determine the relationships between gene variants/mutations, impaired protein function(s) and FCHL-lipid abnormalities. Scientific and Medical Opportunities: These include understanding the mechanistic and biochemical processes regulating blood lipid levels. Identifying the aetiologies of FCHL will lead to development of targeted and effective therapeutic options, thereby reducing associated cardiovascular manifestations.