title: Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits.
abstract: BACKGROUND
  Genome-wide association studies (GWAS) have become a major strategy for genetic dissection of human complex diseases. Analysing multiple phenotypes jointly may improve both our ability to detect genetic variants with multiple effects and our understanding of their common features. Allelic associations for multiple biochemical traits (serum alanine aminotransferase, aspartate aminotransferase, butrylycholinesterase (BCHE), C-reactive protein (CRP), ferritin, gamma glutamyltransferase (GGT), glucose, high-density lipoprotein cholesterol (HDL), insulin, low-density lipoprotein cholesterol (LDL), triglycerides and uric acid), and body-mass index, were examined.
  
  
  METHODS
  We aimed to identify common genetic variants affecting more than one of these traits using genome-wide association analysis in 2548 adolescents and 9145 adults from 4986 Australian twin families. Multivariate and univariate associations were performed.
  
  
  RESULTS
  Multivariate analyses identified eight loci, and univariate association analyses confirmed two loci influencing more than one trait at p < 5 × 10-8. These are located on chromosome 8 (LPL gene affecting HDL and triglycerides) and chromosome 19 (TOMM40/APOE-C1-C2-C4 gene cluster affecting LDL and CRP). A locus on chromosome 12 (OASL gene) showed effects on GGT, LDL and CRP. The loci on chromosomes 12 and 19 unexpectedly affected LDL cholesterol and CRP in opposite directions.
  
  
  CONCLUSIONS
  We identified three possible loci that may affect multiple traits and validated 17 previously-reported loci. Our study demonstrated the usefulness of examining multiple phenotypes jointly and highlights an anomalous effect on CRP, which is increasingly recognised as a marker of cardiovascular risk as well as of inflammation.
authors.affiliation: Genetic Epidemiology Unit, Queensland Institute of Medical Research, Brisbane, Australia. Rita.Middelberg@qimr.edu.au
authors.forename: Rita P S
authors.initials: RP
authors.lastname: Middelberg
authors.forename: Manuel A R
authors.initials: MA
authors.lastname: Ferreira
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: John B
authors.initials: JB
authors.lastname: Whitfield
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D053302:Apolipoprotein C-I / Q000235:genetics*; D053304:Apolipoprotein C-II / Q000235:genetics*; D001056:Apolipoproteins C / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000235:genetics*; D004200:Diseases in Twins; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D015999:Multivariate Analysis; D010641:Phenotype; D012306:Risk
chemical_list: C505803:APOC1 protein, human; C097349:APOC4 protein, human; D053302:Apolipoprotein C-I; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human; C115020:OASL protein, human; D015088:2',5'-Oligoadenylate Synthetase; D008071:Lipoprotein Lipase