Finding novel causes and new cases of hereditary dyslipidemia in Sweden - clinical, genetic and experimental studies

Bakgrund:

Monogenic dyslipidemias are common (~2% of the population) and have a high risk for premature cardiovascular disease. Familial hypercholesterolemia (FH) is present in ~50,000 Swedes, the majority of which is unaware of their diagnosis and thereby excluded from life-saving therapy. There is a clear demand to develop and implement better tools for diagnosis and treatment in such individuals.

While the majority of patients with FH have mutations in the LDL receptor (LDLR), apolipoprotein B (APOB) or proprotein convertase subtilisin/kexin type 9 (PCKS9), at least 20% develop disease due to yet unknown molecular mechanisms. Målsättning:

To identify and characterize novel molecular mechanisms of disease in monogenic dyslipidemias, particularly FH, and thereby propose potential targets for diagnosis and treatment. To promote the implementation of this knowledge to improve health. Arbetsplan:

Patients with probable FH are screened following a validated algorithm: (a) Characterization of extended pedigree; lipids; serum; DNA. (b) screen for common mutations in LDLR, APOB, PCSK9; (c) if not diagnosed in screen, deep exome sequencing of these genes; (d) if still negative, screening for serum markers of bile acid and cholesterol metabolites to identify those with very low bile acid synthesis or sitosterolemia; before (e) whole exome screening of family and identification of rare damaging mutations; (f) possible cell or animal expression of identified gene mutations; (g) analysis of candidate gene mutations in other FH cohorts; (h) extensive clinical phenotyping in patients with candidate mutations.

Families with other monogenic dyslipidemias undergo detailed metabolic phenotyping and whole exome sequencing to identify gene variants (damaging mutations) coupled to the metabolic defects to pinpoint novel target genes. Causality explored in animal and cell models and in unrelated families with similar metabolic phenotype. Frequency of new disease established in population cohorts. Selective therapies interacting with novel pathways tested with industry.

Betydelse:

Monogenic dyslipidemias are common and potently increase the risk of premature cardiovascular disease. Knowledge of genetic alterations causing such conditions will improve diagnosis and follow-up, and eventually lead to new therapies. Scientific and clinical collaborations will have extensive secondary health effects including better care for this important patient group.