Association of the APOLIPOPROTEIN A1/C3/A4/A5 gene cluster with triglyceride levels and LDL particle size in familial combined hyperlipidemia.
The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P=0.001) and APOA5 (P=0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P=0.001) and a second haplotype was significantly enriched in the spouses (P=0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH.
Mar
Rebecca
R
Department of Human Genetics, University of California, Los Angeles, USA. beccamar@ucla.edu
Pajukanta
Päivi
P
Allayee
Hooman
H
Groenendijk
Martine
M
Dallinga-Thie
Geesje
G
Krauss
Ronald M
RM
Sinsheimer
Janet S
JS
Cantor
Rita M
RM
de Bruin
Tjerk W A
TW
Lusis
Aldons J
AJ
D000328:Adult; 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*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008077:Lipoproteins, LDL / Q000737:chemistry*; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D020125:Mutation, Missense; D009426:Netherlands / Q000453:epidemiology; D010316:Particle Size; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D018454:Spouses; D014280:Triglycerides / Q000097:blood*
C437704:APOA5 protein, human; D016632:Apolipoprotein A-I; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D001053:Apolipoproteins; D001054:Apolipoproteins A; D001056:Apolipoproteins C; D008077:Lipoproteins, LDL; D014280:Triglycerides; C022205:apolipoprotein A-IV