Summary
Familial combined hyperlipidemia (FCHL) is characterized by elevated levels of serum total cholesterol (TC), triglycerides (TG), or both in affected family members. FCHL is estimated to be common with a prevalence of 1% to 2% in Western populations. Despite intensive research the genetic and metabolic basis of FCHL has remained unknown, and consequently, FCHL lacks commonly accepted unequivocal diagnostic criteria. To explore the genetics of FCHL, we analyzed relevant candidate genes in the pathways of TC and TG metabolism in well-defined FCHL families from the genetically homogeneous Finnish population with well-known advantages in genetic mapping. We selected a strict phenotype for FCHL and used the 90th age-sex specific Finnish population percentiles for lipid traits as cut-points. Both parametric linkage analysis and affected sib-pair (ASP) analysis were performed to at least partially avoid problems associated with each of the analysis methods alone. No evidence for linkage existed between FCHL and intragenic markers of the candidate genes studied. However, one flanking marker for the apolipoprotein A-II (apoA2) gene resulted in a statistically significant lod score of 3.50 on chromosome Iq21-q23 [1]. In multipoint analysis the support for linkage was extended significantly; the lod score increased to 5.93. The most obvious candidate genes, apoA2 and the selectin gene cluster were positionally excluded, and thus the linkage seems to be caused by a novel gene for FCHL on chromosome Iq21-q23 [1].
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References
Pajukanta P, Nuotio I, Terwilliger JD, Porkka KVK, Ylitalo K, et al. (1998) Linkage of familial combined hyperlipidemia to chromosome Iq21-q23. Nat Genet 18: 369–373.
Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG (1973) Hyperlipidemia in coronary heart disease II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest 52: 1544–1568
Grundy SM, Chait A, Brunzell JD (1987) Familial combined hyperlipidemia workshop. Arteriosclerosis 7: 203–207
Nikkilä EA and Aro A (1973) Family study of serum lipids and lipoproteins in coronary heart disease. Lancet 1: 954–959
Rose HG, Kranz P, Weinstock M, Juliano J, Haft JL (1973) Inheritance of combined hyperlipoproteinemia: evidence for a new lipoprotein phenotype. Am J Med 54: 148–60
Brunzell JD, Albers JJ, Chait A, Grundy SM, Groszek E et al. (1983) Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. J Lipid Res 24: 147–155
Lander ES and Schork NJ (1994) Genetic dissection of complex traits. Science 265: 2037–2048
Gagne E, Genest J, Zhang H, Clark CA, Hayden MR (1994) Analysis of DNA changes in the LPL gene in patients with familial combined hyperlipidemia. Arterioscler Thromb 14: 1250–1257
Reymer PWA, Groenemeyer BE, Gagne E, Miao L, Appelman EEG et al. (1995) A frequently occurring mutation in the lipoprotein lipase gene (Asn291Ser) contributes to the expression of familial combined hyperlipidemia. Hum Mol Genet 4: 1543–1549
Marcil M, Boucher B, Gagne E, Davignon J, Hayden M et al. (1996) Lack of association of the apolipoprotein AI-CIII-AIV gene XmnI and SstI polymorphisms and of the lipoprotein lipase gene mutations in familial combined hyperlipoproteinemia in French Canadian subjects. J Lipid Res 37: 309–319
Wojciechowski AP, Farrall M, Cullen P, Wilson TM, Bayliss JD et al. (1991) Familial combined hyperlipidaemia linked to the apolipoprotein AI-CIII-AIV gene cluster on chromosome 1 Iq23-q24. Nature 349: 161–164
Dallinga-Thie GM, van Linde-Sibenius Trip M, Rotter JI, Cantor RM, Bu X et al. (1997) Complex genetic contribution of the apoAI-CIII-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes. J Clin Invest 99: 953–961
Wijsman EM, Brunzell JD, Jarvik GP, Austin MA, Motulsky AG et al. (1998) Evidence against linkage of familial combined hyperlipidemia to the apolipoprotein AI-CIII-AIV gene complex. Arterioscler Thromb Vasc Biol 18: 215–226
Pajukanta P, Porkka KVK, Antikainen M, Taskinen M-R, Perola M et al. (1997) No evidence of linkage between familial combined hyperlipidemia and genes encoding lipolytic enzymes in Finnish families. Arterioscler Thromb Vasc Biol 17: 841–850.
Pihlajamäki J, Rissanen J, Heikkinen S, Karjalainen L, Laakso M (1997) Codon 54 polymorphism of the human intestinal fatty acid binding protein 2 gene is associated with dyslipidemias but not with insulin resistance in patients with familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol 17: 1039–1044
Risch N and Giuffra L (1992) Model misspecification and multipoint linkage analysis. Hum Hered 42: 77–92
Terwilliger JD and Ott J (1993) A novel polylocus method for linkage analysis using the lod-score or affected sib-pair method. Genet Epidemiol 10: 477–482
Castellani LW, Weinreb A, Bodnar J, Goto AM, Doolittle M et al. (1998) Mapping a gene for combined hyperlipidaemia in a mutant mouse strain. Nat Genet 18: 374–377
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Pajukanta, P., Ehnholm, C., Taskinen, MR., Peltonen, L. (2000). Evidence of linkage in familial combined hyperlipidemia to chromosome 1q21-q23. In: Kita, T., Yokode, M. (eds) Lipoprotein Metabolism and Atherogenesis. Springer, Tokyo. https://doi.org/10.1007/978-4-431-68424-4_11
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DOI: https://doi.org/10.1007/978-4-431-68424-4_11
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