Joost Besseling1, Roeland Huijgen2, Seth S Martin3, Barbara A Hutten4, John J P Kastelein2, G Kees Hovingh2. 1. Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands. Electronic address: j.besseling@amc.nl. 2. Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands. 3. Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, USA. 4. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, The Netherlands.
Abstract
BACKGROUND AND AIM: We evaluated whether the severity of the familial hypercholesterolemia (FH) phenotype, i.e. increased levels of low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) risk, decreases in more distantly related patients within one family. METHODS: We included heterozygous FH patients identified by genetic cascade screening in the Netherlands from 1994 to 2014. A cascade starts with identification of a genetically proven FH patient ("index patient") followed by testing in first degree relatives. If a mutation carrier is identified, their first degree relatives are tested as well, and so on. The associations between distance-to-index (expressed as family relationship) and both LDL-C levels and CVD risk, were evaluated using multivariable linear and Cox regression models. RESULTS: Distance-to-index could be determined in 13,374 patients. Mean (± standard error) levels of LDL-C did not differ significantly in 1st, 2nd, 3rd, and 4th or more family members: 5.46 (1.42), 5.17 (1.42), 4.89 (1.37), and 4.58 (1.27) mmol/L, respectively (adjusted p-for-trend: 0.104). The adjusted hazard ratio of increasing distance-to-index for CVD was 0.92 (95% CI: 0.82-1.03). CONCLUSION: This study was the first to investigate the association between distance-to-index and the phenotype of a monogenetic disorder. The absence of a decrease of phenotype severity lends support for genetic cascade testing in FH.
BACKGROUND AND AIM: We evaluated whether the severity of the familial hypercholesterolemia (FH) phenotype, i.e. increased levels of low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) risk, decreases in more distantly related patients within one family. METHODS: We included heterozygous FHpatients identified by genetic cascade screening in the Netherlands from 1994 to 2014. A cascade starts with identification of a genetically proven FHpatient ("index patient") followed by testing in first degree relatives. If a mutation carrier is identified, their first degree relatives are tested as well, and so on. The associations between distance-to-index (expressed as family relationship) and both LDL-C levels and CVD risk, were evaluated using multivariable linear and Cox regression models. RESULTS: Distance-to-index could be determined in 13,374 patients. Mean (± standard error) levels of LDL-C did not differ significantly in 1st, 2nd, 3rd, and 4th or more family members: 5.46 (1.42), 5.17 (1.42), 4.89 (1.37), and 4.58 (1.27) mmol/L, respectively (adjusted p-for-trend: 0.104). The adjusted hazard ratio of increasing distance-to-index for CVD was 0.92 (95% CI: 0.82-1.03). CONCLUSION: This study was the first to investigate the association between distance-to-index and the phenotype of a monogenetic disorder. The absence of a decrease of phenotype severity lends support for genetic cascade testing in FH.
Authors: Anna E Semenova; Igor V Sergienko; Diego García-Giustiniani; Lorenzo Monserrat; Anna B Popova; Diana N Nozadze; Marat V Ezhov Journal: J Cardiovasc Dev Dis Date: 2020-05-14