title: Maternal inheritance of familial hypercholesterolemia caused by the V408M low-density lipoprotein receptor mutation increases mortality.
abstract: OBJECTIVE
  Fetal exposure to maternal hypercholesterolemia increases the extent of fatty-streak formation in fetal aortas as well as the rate of progression, and may therefore increase coronary heart disease (CHD) risk later in life. We hypothesized that the risk of CHD in untreated individuals with familial hypercholesterolemia (FH) is more extreme when the disease is transmitted maternally.
  
  
  METHODS
  In a large Dutch pedigree carrying the V408M mutation in the low-density lipoprotein (LDL) receptor gene, 161 individuals over seven generations were identified for which FH status and parent of origin of FH were known. We calculated standardized mortality ratios (SMR) and compared the consequences of maternal and paternal inheritance of FH by Poisson regression analysis.
  
  
  RESULTS
  Maternally inherited FH was associated with significantly higher excess mortality than FH transmitted by fathers (relative risk 2.2; p = 0.048): the SMR of maternal inheritance was 2.49 (95% confidence interval (CI) 1.45-3.99; p = 0.001), whereas it was not significantly increased in paternally inherited FH (SMR 1.30, 95% CI 0.65-2.32; p = 0.234).
  
  
  CONCLUSIONS
  Mortality rates are more increased when FH is inherited through the mother, supporting the fetal origin of adulthood disease hypothesis with all cause death, the most indisputable outcome measure. Future research should explore safe options for cholesterol-lowering therapy of pregnant women with FH in order to prevent unfavourable (epigenetic) consequences leading to atherosclerosis in their children.
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jorie
authors.initials: J
authors.lastname: Versmissen
authors.forename: Ilse P G
authors.initials: IP
authors.lastname: Botden
authors.forename: Roeland
authors.initials: R
authors.lastname: Huijgen
authors.forename: Daniëlla M
authors.initials: DM
authors.lastname: Oosterveer
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.forename: Thea C
authors.initials: TC
authors.lastname: Heil
authors.forename: Anouk
authors.initials: A
authors.lastname: Muntz
authors.forename: Janneke G
authors.initials: JG
authors.lastname: Langendonk
authors.forename: Arend F L
authors.initials: AF
authors.lastname: Schinkel
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Eric J G
authors.initials: EJ
authors.lastname: Sijbrands
mesh_terms: D005220:Fathers; D005260:Female; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics* / Q000401:mortality*; D008297:Male; D009035:Mothers; D009154:Mutation; D009426:Netherlands; D010375:Pedigree; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D011973:Receptors, LDL; C036053:VLDL receptor