title: Clinical phenotype in relation to the distance-to-index-patient in familial hypercholesterolemia.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands. Electronic address: j.besseling@amc.nl.
authors.forename: Joost
authors.initials: J
authors.lastname: Besseling
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Roeland
authors.initials: R
authors.lastname: Huijgen
authors.affiliation: Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Seth S
authors.initials: SS
authors.lastname: Martin
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, The Netherlands.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Hutten
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000401:mortality; D002648:Child; D008078:Cholesterol, LDL / Q000097:blood*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016016:Proportional Hazards Models; D011973:Receptors, LDL / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D008078:Cholesterol, LDL; C573412:LDLR protein, human; D011973:Receptors, LDL
keywords: Distance-to-index; Familial hypercholesterolemia; Genotype–phenotype relation; Low-density lipoprotein cholesterol