title: High intestinal cholesterol absorption is associated with cardiovascular disease and risk alleles in ABCG8 and ABO: evidence from the LURIC and YFS cohorts and from a meta-analysis.
abstract: OBJECTIVE
  This study sought to determine whether high intestinal cholesterol absorption represents a cardiovascular risk factor and to link ABCG8 and ABO variants to cardiovascular disease (CVD).
  
  
  BACKGROUND
  Plant sterol-enriched functional foods are widely used for cholesterol lowering. Their regular intake yields a 2-fold increase in circulating plant sterol levels that equally represent markers of cholesterol absorption. Variants in ABCG8 and ABO have been associated with circulating plant sterol levels and CVD, thereby suggesting atherogenic effects of plant sterols or of cholesterol uptake.
  
  
  METHODS
  The cholestanol-to-cholesterol ratio (CR) was used as an estimate of cholesterol absorption because it is independent of plant sterols. First, we investigated the associations of 6 single nucleotide polymorphisms in ABCG8 and ABO with CR in the LURIC (LUdwisghafen RIsk and Cardiovascular health study) and the YFS (Young Finns Study) cohorts. Second, we conducted a systematic review and meta-analysis to investigate whether CR might be related to CVD.
  
  
  RESULTS
  In LURIC, the minor alleles of rs4245791 and rs4299376 and the major alleles of rs41360247, rs6576629, and rs4953023 of the ABCG8 gene and the minor allele of rs657152 of the ABO gene were significantly associated with higher CR. Consistent results were obtained for rs4245791, rs4299376, rs6576629, and rs4953023 in YFS. The meta-analysis, including 6 studies and 4,362 individuals, found that CR was significantly increased in individuals with CVD.
  
  
  CONCLUSIONS
  High cholesterol absorption is associated with risk alleles in ABCG8 and ABO and with CVD. Harm caused by elevated cholesterol absorption rather than by plant sterols may therefore mediate the relationships of ABCG8 and ABO variants with CVD.
authors.affiliation: Department of Angiology, Swiss Cardiovascular Center, University of Bern, Bern, Switzerland. guenther.silbernagel@insel.ch
authors.forename: Günther
authors.initials: G
authors.lastname: Silbernagel
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.forename: Bernd
authors.initials: B
authors.lastname: Genser
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Kleber
authors.forename: Günter
authors.initials: G
authors.lastname: Fauler
authors.forename: Hubert
authors.initials: H
authors.lastname: Scharnagl
authors.forename: Tanja B
authors.initials: TB
authors.lastname: Grammer
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Kari-Matti
authors.initials: KM
authors.lastname: Mäkelä
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.forename: Rafael
authors.initials: R
authors.lastname: Carmena
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Rietzschel
authors.forename: Eric
authors.initials: E
authors.lastname: Bruckert
authors.forename: John E
authors.initials: JE
authors.lastname: Deanfield
authors.forename: Tatu A
authors.initials: TA
authors.lastname: Miettinen
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Winfried
authors.initials: W
authors.lastname: März
mesh_terms: D000017:ABO Blood-Group System / Q000235:genetics*; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011159:Population Surveillance / Q000379:methods; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: C416946:ABCG8 protein, human; D000017:ABO Blood-Group System; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol
keywords: ABCG8; ABO; CI; CVD; GWA; LDL; RR; SMD; SNP; cardiovascular disease; cholestanol; confidence interval; genome-wide association; intestinal cholesterol absorption; low-density lipoprotein; plant sterols; risk ratio; single nucleotide polymorphism; standardized mean difference