ArticleThe Journal of clinical investigation1997
Complex genetic contribution of the Apo AI-CIII-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes.
Article in The Journal of clinical investigation, 1997. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 112 citations in OpenAlex.
- Next-generation gene discovery for variants of large impact on lipid traits.Current opinion in lipidology · 2015Review
- A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans.Nature communications · 2014Article
- The genetics of familial combined hyperlipidaemia.Nature reviews. Endocrinology · 2012Review
- SstI Polymorphism of the Apolipoprotein CIII Gene in Iranian Hyperlipidemic Patients: A Study in Semnan Province.Iranian journal of basic medical sciences · 2011Article
- Triglyceride level-influencing functional variants of the ANGPTL3, CILP2, and TRIB1 loci in ischemic stroke.Neuromolecular medicine · 2011Article
- Genomic susceptibility Loci for brain atrophy, ventricular volume, and leukoaraiosis in hypertensive sibships.Archives of neurology · 2009Article
- The implications of pharmacogenomics in the treatment of HIV-1-infected patients of African descent.Pharmacogenomics and personalized medicine · 2009Article
- Genetic studies on the APOA1-C3-A5 gene cluster in Asian Indians with premature coronary artery disease.Lipids in health and disease · 2008Article
- An apolipoprotein A-V gene SNP is associated with marked hypertriglyceridemia among Asian-American patients.Journal of lipid research · 2008Article
- Associations among race/ethnicity, ApoC-III genotypes, and lipids in HIV-1-infected individuals on antiretroviral therapy.PLoS medicine · 2006Article
- Contribution of polymorphisms in the apolipoprotein AI-CIII-AIV cluster to hyperlipidaemia in patients with gout.Annals of the rheumatic diseases · 2005Article
- The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster.Human genetics · 2004Article
- Population prevalence of APOE, APOC3 and PPAR-alpha mutations associated to hypertriglyceridemia in French Canadians.Journal of human genetics · 2004Article
- Linkage and association between distinct variants of the APOA1/C3/A4/A5 gene cluster and familial combined hyperlipidemia.Arteriosclerosis, thrombosis, and vascular biology · 2004Article
- Study of apolipoproteinc3 Sstl polymorphism in healthy volunteers from Northern India.Indian journal of clinical biochemistry : IJCB · 2003Article
- Combined analysis of genome scans of dutch and finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.American journal of human genetics · 2003Article
- Article
- Monogenic dyslipidemias: window on determinants of plasma lipoprotein metabolism.American journal of human genetics · 2001Review
- A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11.American journal of human genetics · 1999Article
- Genetics of familial combined hyperlipidemia.Current atherosclerosis reports · 1999Review
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
Familial combined hyperlipidemia (FCH) is a common genetic lipid disorder in Western societies. In a recent report (Dallinga-Thie, G.M., X.D. Bu, M. van Linde-Sibenius Trip, J.I. Rotter, A.J. Lusis, and T.W.A. de Bruin. J. Lipid Res., 1996, 36:136-147) we have studied three restriction enzyme polymorphisms: XmnI, and MspI sites 5' of the apo AI gene and SstI site in the 3' untranslated region of exon 4 of the apo CIII gene in 18 FCH pedigrees, including 18 probands, 178 hyperlipidemic relatives, 210 normolipidemic relatives, and 176 spouses. DNA variations in the apo AI-CIII-AIV gene cluster had a modifying effect on plasma triglycerides, LDL cholesterol, and apolipoprotein CIII levels. In this study, combinations of haplotypes were analyzed to further characterize their interactions and effect on the expression of severe hyperlipidemia in FCH subjects. A specific combination of haplotypes with one chromosome carrying the X1M1S2 (1-1-2) haplotype and the other the X2M2S1 haplotype (2-2-1) was significantly more frequent in hyperlipidemic relatives (6%) than in normolipidemic relatives (3%) and spouses (0.5%). Associated with this combination of haplotypes were significantly elevated plasma cholesterol (P < 0.0001), triglycerides (P < 0.0001), and apo CIII (P < 0.001) levels when compared to the wild type combination of haplotypes 1-1-1/1-1-1. The only spouse with this specific combination of haplotypes showed a severe hyperlipidemic phenotype, similar to FCH. Furthermore, nonparametric sibpair linkage analysis revealed significant linkage between these markers in the gene cluster and the FCH phenotype (MspI P = 0.0088, SstI P = 0.044, and XMS haplotype P = 0.037). The present findings confirm that the apo AI-CIII-IV gene cluster contributes to the FCH phenotype, but this contribution is genetically complex. An epistatic interaction between different haplotypes of the gene cluster was demonstrated. The S2 allele on one haplotype was synergistic to the X2M2 allele on the other haplotype in its hyperlipidemic effect. Therefore, two different susceptibility loci exist in the gene cluster, demonstrating the paradigm of complex genetic contribution to FCH.
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