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Personalized Medicine in Familial Hypercholesterolemia : diagnosis, stratification of cardiovascular disease risk and lipid therapy management
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| 7.95 MB | Adobe PDF |
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Familial hypercholesterolemia (FH) is a common lipid metabolism disorder, caused by pathogenic variants in LDLR, APOB and PCSK9. It is characterized by life-long elevated cholesterol concentrations, making it a high cardiovascular disease (CVD) risk condition. Treatment of FH is made primarily with statins, but recently other cholesterol lowering therapies were approved. FH patients present a wide variability in response to statins, which could be caused by type of FH variant and/or genetic variants associated with statin pharmacogenetics. Thus, FH is a perfect model for Personalized Medicine, as patient’s genetic background and additional risk factors can ensure correct diagnosis and guide prevention and treatment options. However, FH is severely underdiagnosed worldwide. Consequently, this work aims at producing evidence to improve FH genetic diagnosis and treatment. A database of all published FH-associated variants was constructed to ensure quick access to data for genetic diagnosis. This was the basis to develop an internationally approved guideline for LDLR variant pathogenicity classification, by joining efforts with an international consortium. With the network of FH experts created, FH variant data publicly available at a reference repository of clinical genetic data increased 10-fold. Specific adaptations for APOB and PCSK9 variant classification were also proposed. To improve CVD prevention, treatment patterns were studied, individual risk factors and overall risk were analyzed in FH patients and in the Portuguese general population. Results showed that four times more FH patients had had CVD events, and although more likely to be medicated, they are less likely to meet recommended target lipid values. Finally, a preliminary study on statin pharmacogenetics yielded some promising results that, if validated in larger studies, could explain variability of response to statins. An accurate diagnosis of FH, precise individual CVD risk stratification and individually adjusted therapy to maximize CVD prevention are the basis of Personalized Medicine in FH.
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Hipercolesterolemia familiar risco de doença cardiovascular classificação de patogenicidade de variantes e diagnóstico terapia hipolipemiante farmacogenómica de estatinas Familial Hypercholesterolemia cardiovascular disease risk variant pathogenicity classification and diagnosis lipid-lowering therapy statin pharmacogenomics