title: Linkage and association between distinct variants of the APOA1/C3/A4/A5 gene cluster and familial combined hyperlipidemia.
abstract: OBJECTIVE
  Combined hyperlipidemia is a common disorder, characterized by a highly atherogenic lipoprotein profile and a substantially increased risk of coronary heart disease. The purpose of this study was to establish whether variations of apolipoprotein A5 (APOA5), a newly discovered gene of lipid metabolism located 30 kbp downstream of the APOA1/C3/A4 gene cluster, contributes to the transmission of familial combined hyperlipidemia (FCHL).
  
  
  RESULTS
  We performed linkage and association tests on 128 families. Two independent alleles, APOA5c.56G and APOC3c.386G, of the APOA1/C3/A4/A5 gene cluster were overtransmitted in FCHL (P=0.004 and 0.007, respectively). This was paired with reduced transmission of the common APOA1/C3/A4/A5 haplotype (frequency 0.4461) to affected subjects (P=0.012). The APOA5c.56G genotype accounted for 7.3% to 13.8% of the variance in plasma triglyceride levels in probands (P<0.004). The APOC3c.386G genotypes accounted for 4.4% to 5.1% of the variance in triglyceride levels in FCHL spouses (P<0.007), suggesting that this allele marks a FCHL quantitative trait as well as representing a susceptibility locus for the condition.
  
  
  CONCLUSIONS
  A combined linkage and association analysis establishes that variation at the APOA1/C3/A4/A5 gene cluster contributes to FCHL transmission in a substantial proportion of northern European families.
authors.affiliation: Genomic & Molecular Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Eichenbaum-Voline
authors.forename: Michael
authors.initials: M
authors.lastname: Olivier
authors.forename: Emma L
authors.initials: EL
authors.lastname: Jones
authors.forename: Rossitza P
authors.initials: RP
authors.lastname: Naoumova
authors.forename: Bethan
authors.initials: B
authors.lastname: Jones
authors.forename: Brian
authors.initials: B
authors.lastname: Gau
authors.forename: Hetal N
authors.initials: HN
authors.lastname: Patel
authors.forename: Mary
authors.initials: M
authors.lastname: Seed
authors.forename: D John
authors.initials: DJ
authors.lastname: Betteridge
authors.forename: David J
authors.initials: DJ
authors.lastname: Galton
authors.forename: Edward M
authors.initials: EM
authors.lastname: Rubin
authors.forename: James
authors.initials: J
authors.lastname: Scott
authors.forename: Carol C
authors.initials: CC
authors.lastname: Shoulders
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
mesh_terms: D000483:Alleles; D016632:Apolipoprotein A-I / Q000235:genetics*; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D001053:Apolipoproteins / Q000235:genetics*; D001054:Apolipoproteins A / Q000235:genetics*; D001056:Apolipoproteins C / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D005810:Multigene Family
chemical_list: C437704:APOA5 protein, human; D016632:Apolipoprotein A-I; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D001053:Apolipoproteins; D001054:Apolipoproteins A; D001056:Apolipoproteins C; C022205:apolipoprotein A-IV