title: Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study.
abstract: BACKGROUND
  Plasma total cholesterol (TC) levels are highly genetically determined. Although ample evidence of genetic determination of separate lipoprotein cholesterol levels has been reported, using TC level directly as a phenotype in a relatively large broad-gene based association study has not been reported to date.
  
  
  RESULTS
  We genotyped 361 single nucleotide polymorphisms (SNPs) across 243 genes based on pathways potentially relevant to cholesterol metabolism in 3575 subjects that were examined thrice over 11 years. Twenty-three SNPs were associated with TC levels after adjustment for multiple testing. We used 12 of them (rs7412 and rs429358 in APOE, rs646776 in CELSR2, rs1367117 in APOB, rs6756629 in ABCG5, rs662799 in APOA5, rs688 in LDLR, rs10889353 in DOCK7, rs2304130 in NCAN, rs3846662 in HMGCR, rs2275543 in ABCA1, rs7275 in SMARCA4) that were confirmed in previous candidate association or genome-wide-association studies to define a gene risk score (GRS). Average TC levels increased from 5.23 ± 0.82 mmol/L for those with 11 or less cholesterol raising alleles to 6.03 ± 1.11 mmol/L for those with 18 or more (P for trend<0.0001). The association with TC levels was slightly stronger when the weighted GRS that weighted the magnitude of allelic effects was used.
  
  
  CONCLUSIONS
  A panel of common genetic variants in the genes pivotal in cholesterol metabolism could possibly help identify those people who are at risk of high cholesterol levels.
authors.affiliation: Division of Human Nutrition, Wageningen University and Research Center, PO Box 8129, 6700 EV Wageningen, The Netherlands. kevin.lu@wur.nl
authors.forename: Yingchang
authors.initials: Y
authors.lastname: Lu
authors.forename: Edith J M
authors.initials: EJ
authors.lastname: Feskens
authors.forename: Jolanda M A
authors.initials: JM
authors.lastname: Boer
authors.forename: Sandra
authors.initials: S
authors.lastname: Imholz
authors.forename: W M Monique
authors.initials: WM
authors.lastname: Verschuren
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Anika
authors.initials: A
authors.lastname: Vaarhorst
authors.forename: Eline
authors.initials: E
authors.lastname: Slagboom
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.forename: Martijn E T
authors.initials: ME
authors.lastname: Dollé
mesh_terms: D000328:Adult; D015992:Body Mass Index; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012306:Risk
chemical_list: D008074:Lipoproteins; C030104:lipoprotein cholesterol; D002784:Cholesterol