This review presents recent basic and clinical developments in familial combined hyperlipidemia (FCHL).
A variety of experiments have contributed to the elucidation of this complex disease. They consist of dynamic and gene expression studies in adipocytes, confirming the role of dysfunctional adipose tissue in the pathogenesis of FCHL and identifying potential new pathways, such as complement activation. Whole exome sequencing and classical linkage studies in FCHL pedigrees, some conducted with new traits (e.g. plasma proprotein convertase subtilisin/kexin type 9 [PCSK9] and phospholipid transfer protein activity), have revealed new genes of interest, among which SLC25A40 and LASS4. Finally, gene expression studies in liver biopsies and liver cell culture experiments have gained further insight in the role of upstream stimulatory factor 1, one of the most replicated genes in FCHL, in its pathogenesis.
On the basis of these observations and recent phase II clinical trials, PCSK9 antagonizing is the most promising lipid-lowering therapy to be added to our current arsenal of statins and fibrates in FCHL treatment.
Ongoing basic research provides a steady growth in our knowledge on the genes that are involved in FCHL as well as their metabolic function(s). This field of research may be enhanced when data are expanded and integrated for systems biology approaches. Our growing insights in the cause of FCHL allow for better, targeted treatment of dyslipidemia and prevention of cardiovascular complications.
aDepartments of Internal Medicine and Endocrinology, Maastricht University Medical Centre
bCARIM School for Cardiovascular Diseases/Laboratory for Metabolism and Vascular Medicine, Maastricht University, Maastricht
cDivision of Vascular Medicine, Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
Correspondence to Marleen M.J. van Greevenbroek, PhD, Department of Internal Medicine, Cardiovascular Research School CARIM, Maastricht University, Universiteitssingel 50, PO Box 616 (UNS50, box 14), 6200 MD, Maastricht, The Netherlands. Tel: +31 43 3882135; e-mail: email@example.com