TY - JOUR
T1 - Clinical phenotype in relation to the distance-to-index-patient in familial hypercholesterolemia
AU - Besseling, Joost
AU - Huijgen, Roeland
AU - Martin, Seth S.
AU - Hutten, Barbara A.
AU - Kastelein, John J.P.
AU - Hovingh, G. Kees
N1 - Funding Information:
JB, RH and BAH have no conflicts of interest. SSM is supported by the Pollin Cardiovascular Prevention Fellowship, Marie-Josee and Henry R. Kravis endowed fellowship, and a National Institutes of Health training grant ( T32HL07024 ). JJPK is a recipient of the Lifetime Achievement Award of the Netherland Heart Foundation (NHS, project number 2010T082 ). JJPK received consulting fees or honoraria from Aegerion, Amgen, AstraZeneca, Boehringer Ingelheim, Catabasis, Cerenis, Cymabay, CSL Behring, Dezima Pharmaceuticals, Eli Lilly, Esperion, Gemphire, ISIS, The Medicines Company, MSD, Novartis, Pfizer, Pronova, Regeneron, Sanofi and UniQur; none of these did have an impact on this study. GHK is a recipient of a VENI grant from the Netherlands Organisation for Scientific Research (NWO, project number 91612122 ) and his department did receive lecture fees for GKH from Aegerion, Amgen, Eli Lilly, Pfizer, and Sanofi; none of these did have an impact on this study.
Publisher Copyright:
© 2015 Elsevier Ireland Ltd.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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.
AB - 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.
KW - Distance-to-index
KW - Familial hypercholesterolemia
KW - Genotype-phenotype relation
KW - Low-density lipoprotein cholesterol
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U2 - 10.1016/j.atherosclerosis.2015.12.033
DO - 10.1016/j.atherosclerosis.2015.12.033
M3 - Article
C2 - 26745182
AN - SCOPUS:84952322507
VL - 246
SP - 1
EP - 6
JO - Atherosclerosis
JF - Atherosclerosis
SN - 0021-9150
ER -