title: Genome-wide association study pinpoints a new functional apolipoprotein B variant influencing oxidized low-density lipoprotein levels but not cardiovascular events: AtheroRemo Consortium.
abstract: BACKGROUND
  Oxidized low-density lipoprotein may be a key factor in the development of atherosclerosis. We performed a genome-wide association study on oxidized low-density lipoprotein and tested the impact of associated single-nucleotide polymorphisms (SNPs) on the risk factors of atherosclerosis and cardiovascular events.
  
  
  RESULTS
  A discovery genome-wide association study was performed on a population of young healthy white individuals (N=2080), and the SNPs associated with a P<5×10(-8) were replicated in 2 independent samples (A: N=2912; B: N=1326). Associations with cardiovascular endpoints were also assessed with 2 additional clinical cohorts (C: N=1118; and D: N=808). We found 328 SNPs associated with oxidized low-density lipoprotein. The genetic variant rs676210 (Pro2739Leu) in apolipoprotein B was the proxy SNP behind all associations (P=4.3×10(-136), effect size=13.2 U/L per allele). This association was replicated in the 2 independent samples (A and B, P=2.5×10(-47) and 1.1×10(-11), effect sizes=10.3 U/L and 7.8 U/L, respectively). In the meta-analyses of cohorts A, C, and D (excluding cohort B without angiographic data), the top SNP did not associate significantly with the age of onset of angiographically verified coronary artery disease (hazard ratio=1.00 [0.94-1.06] per allele), 3-vessel coronary artery disease (hazard ratio=1.03 [0.94-1.13]), or myocardial infarction (hazard ratio=1.04 [0.96-1.12]).
  
  
  CONCLUSIONS
  This novel genetic marker is an important factor regulating oxidized low-density lipoprotein levels but not a major genetic factor for the studied cardiovascular endpoints.
authors.affiliation: Department of Clinical Chemistry, Finn-Medi 2, PO Box 2000, FI-33521 Tampere, Finland. kari-matti.makela@uta.fi
authors.forename: Kari-Matti
authors.initials: KM
authors.lastname: Mäkelä
authors.forename: Ilkka
authors.initials: I
authors.lastname: Seppälä
authors.forename: Jussi A
authors.initials: JA
authors.lastname: Hernesniemi
authors.forename: Leo-Pekka
authors.initials: LP
authors.lastname: Lyytikäinen
authors.forename: Niku
authors.initials: N
authors.lastname: Oksala
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Kleber
authors.forename: Hubert
authors.initials: H
authors.lastname: Scharnagl
authors.forename: Tanja B
authors.initials: TB
authors.lastname: Grammer
authors.forename: Jens
authors.initials: J
authors.lastname: Baumert
authors.forename: Barbara
authors.initials: B
authors.lastname: Thorand
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.forename: Nina
authors.initials: N
authors.lastname: Hutri-Kähönen
authors.forename: Markus
authors.initials: M
authors.lastname: Juonala
authors.forename: Tomi
authors.initials: T
authors.lastname: Laitinen
authors.forename: Reijo
authors.initials: R
authors.lastname: Laaksonen
authors.forename: Pekka J
authors.initials: PJ
authors.lastname: Karhunen
authors.forename: Kjell C
authors.initials: KC
authors.lastname: Nikus
authors.forename: Tuomo
authors.initials: T
authors.lastname: Nieminen
authors.forename: Jari
authors.initials: J
authors.lastname: Laurikka
authors.forename: Pekka
authors.initials: P
authors.lastname: Kuukasjärvi
authors.forename: Matti
authors.initials: M
authors.lastname: Tarkka
authors.forename: Jari
authors.initials: J
authors.lastname: Viik
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Johannes
authors.initials: J
authors.lastname: Kettunen
authors.forename: Markku
authors.initials: M
authors.lastname: Ahotupa
authors.forename: Jorma S A
authors.initials: JS
authors.lastname: Viikari
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.forename: Mahir
authors.initials: M
authors.lastname: Karakas
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Bernhard R
authors.initials: BR
authors.lastname: Winkelmann
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001055:Apolipoproteins B / Q000235:genetics* / Q000378:metabolism*; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide
chemical_list: D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein