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Phenotype expression in familial combined hyperlipidemia

      Abstract

      Familial combined hyperlipidaemia (FCHL) is one of the most common hereditary disorders predisposing to early coronary death. The affected family members have elevations of serum total cholesterol, triglycerides or both. Despite intensive research efforts the genetic and metabolic defects underlying this complex disorder are still unknown. To dissect the metabolism and genetics of FCHL the phenotype of an individual must be precisely defined. We assessed the influence of different diagnostic criteria on the phenotype definition and studied factors affecting the phenotype expression in 16 large Finnish families (n=255) with FCHL. The fractile cut-points used to define abnormal lipid values had a profound influence on the diagnosis of FCHL. If the 90th percentile cut-point was used, approximately 45% of the family members were affected, in concord with the presumed dominant mode of transmission for FCHL. If the 95th percentile was used only 22% of study subjects were affected. To characterize the metabolic differences or similarities between the different lipid phenotypes, we determined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) particles separated by ultracentrifugation. In linkage analysis no single ultracentrifugation variable could discriminate reliably affected family members from non-affected family members. Our data emphasizes the need for re-evaluation of FCHL diagnostic criteria. Preferably, the diagnosis should be based on a single, reliable metabolic marker.

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      References

        • Goldstein J.L
        • Schrott H.G
        • Hazzard W.R
        • Bierman E.L
        • Motulsky A.G
        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. 1973; 52: 1544
        • Nikkilä E.A
        • Aro A
        Family study of serum lipids and lipoproteins in coronary heart disease.
        Lancet. 1973; 1: 954
        • Rose H.G
        • Kranz P
        • Weinstock M
        • Juliano J
        • Haft J.I
        Inheritance of combined hyperlipoproteinemia: evidence for a new lipoprotein phenotype.
        Am J Med. 1973; 54: 148
        • Genest Jr., J.J
        • Martin-Munley S.S
        • McNamara J.R
        • Ordovas J.M
        • Jenner J
        • Myers R.H
        • Silberman S.R
        • Wilson P.W
        • Salem D.N
        • Schaefer E.J
        Familial lipoprotein disorders in patients with premature coronary artery disease.
        Circulation. 1992; 85: 2025
        • Kwiterovich P.O
        Genetics and molecular biology of familial combined hyperlipidemia.
        Curr Opin Lipidology. 1993; 4: 133
        • Sniderman A
        • Brown B.G
        • Stewart B.F
        • Cianflone K
        From familial combined hyperlipidemia to hyperapoB: unravelling the overproduction of hepatic apolipoprotein B.
        Curr Opin Lipidology. 1992; 3: 137
        • Brunzell J.D
        • Albers J.J
        • Chait A
        • Grundy S.M
        • Groszek E
        • McDonald G.B
        Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia.
        J Lipid Res. 1983; 24: 147
        • Venkatesan S
        • Cullen P
        • Pacy P
        • Halliday D
        • Scott J
        Stable isotopes show a direct relation between VLDL apoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia.
        Arterioscler Thromb. 1993; 13: 1110
        • Austin M.A
        • Horowitz H
        • Wijsman E
        • Krauss R.M
        • Brunzell J
        Bimodality of plasma apolipoprotein B levels in familial combined hyperlipidemia.
        Atherosclerosis. 1992; 92: 67
        • Syvänne M
        • Vuorinen-Markkola H
        • Hilden H
        • Taskinen M.-R
        Gemfibrozil reduces postprandial lipemia in non-insulin-dependent diabetes mellitus.
        Arterioscler Thromb. 1993; 13: 286
        • Taskinen M.-R
        • Kuusi T
        • Helve E
        • Nikkilä E
        • Yki-Järvinen H
        Insulin therapy induces antiatherogenic changes of serum lipoproteins in noninsulindependent diabetes.
        Arteriosclerosis. 1988; 18: 168
        • Lehtimäki T
        • Moilanen T
        • Viikari J
        • Åkerblom H.K
        • Ehnholm C
        • Rönnemaa T
        • Marniemi J
        • Dahlen G
        • Nikkari T
        Apolipoprotein E phenotypes in Finnish youths: a cross-sectional and 6-year follow-up study.
        J Lipid Res. 1990; 31: 487
        • Cuthbert J.A
        • East C.A
        • Bilheimer D.W
        Detection of familial hypercholesterolemia by assaying functional low-density-lipoprotein receptors on lymphocytes.
        N Engl J Med. 1986; 314: 879
        • Vartiainen E
        • Puska P
        • Jousilahti P
        • Korhonen H.J
        • Tuomilehto J
        • Nissinen A
        Twenty-year trends in coronary risk factors in North Karelia and in other areas of Finland.
        Int J Epidemiol. 1994; 23: 495
        • Porkka K.V.K
        • Viikari J
        • Rönnemaa T
        • Marniemi J
        • Åkerblom H.K
        Age and gender specific serum lipid percentiles of Finnish children and young adults. The Cardiovascular Risk in Young Finns study.
        Acta Paediatr. 1994; 83: 838
      1. Ott J. In: Analysis of the human genetic linkage, 2nd ed. Baltimore: Johns Hopkins Press, 1991.

        • Lathrop G.M
        • Lalouel J.-M
        • Julier C.A
        • Ott J
        Strategies for multilocus linkage analysis in humans.
        Proc Natl Acad Sci USA. 1984; 81: 3443
        • Lathrop G.M
        • Lalouel J.-M
        • White R.L
        Construction of human genetic linkage maps: likelihood calculations for multilocus analysis.
        Genet Epidemiol. 1986; 3: 39
        • Cottingham R.W.J
        • Idury R.M
        • Shaffer A.A
        Faster sequential genetic linkage computations.
        Am J Hum Genet. 1993; 53: 252
        • Schaffer A.A
        • Gupta S.K
        • Shriram K
        • Cottingham R.W.J
        Avoiding recomputation in linkage analysis.
        Hum Hered. 1994; 44: 225
        • Cullen P
        • Farren B
        • Scott J
        • Farrall M
        Complex segregation analysis provides evidence for a major gene acting on serum triglyceride levels in 55 British families with familial combined hyperlipidemia.
        Arterioscler Thromb. 1994; 14: 1233
        • Babirak S.P
        • Brown B.G
        • Brunzell J.D
        Familial combined hyperlipidemia and abnormal lipoprotein lipase.
        Arterioscler Thromb. 1992; 12: 1176
        • Lander E.S
        • Schork N.J
        Genetic dissection of complex traits.
        Science. 1994; 265: 2037
        • Koivisto P.V.I
        • Koivisto U.-M
        • Miettinen T.A
        • Kontula K
        Diagnosis of heterozygous familial hypercholesterolemia. DNA analysis complements clinical examination and analysis of serum lipid levels.
        Arterioscler Thromb. 1992; 12: 584
        • Cortner J.A
        • Coates P.M
        • Gallagher P.R
        Prevalence and expression of familial combined hyperlipidemia in childhood.
        J Pediatr. 1990; 116: 514
        • Cortner J.A
        • Coates P.M
        • Liacouras C.A
        • Jarvik G.P
        Familial combined hyperlipidemia in children: clinical expression, metabolic defects, and management.
        J Pediatr. 1993; 123: 177
        • Cianflone K
        • Roncari D.A.K
        • Maslowska M
        • Baldo A
        • Forden J
        • Sniderman A.D
        The adipsin-acylation stimulating protein system in human adipocytes: regulation of triacylglycerol synthesis.
        Biochemistry. 1994; 33: 9489
        • Kwiterovich Jr., P
        • Motevalli M
        • Miller M
        Acylation-stimulatory activity in hyperapobetalipoproteinemic fibroblasts: enhanced cholesterol esterification with another serum basic protein, BP II.
        Proc Natl Acad Sci USA. 1990; 87: 8980
        • Reynisdottir S
        • Eriksson M
        • Angelin B
        • Arner P
        Impaired activation of adipocyte lipolysis in familial combined hyperlipidemia.
        J Clin Invest. 1995; 95: 2161
        • Sniderman A.D
        • Cianflone K
        Substrate delivery as a determinant of hepatic apoB secretion.
        Arterioscler Thromb. 1993; 13: 629
        • Kwiterovich Jr., P.O
        • Coresh J
        • Bachorik P.S
        Prevalence of hyperapobetalipoproteinemia and other lipoprotein phenotypes in men (aged < or =50 years) and women (< or =60 years) with coronary artery disease.
        Am J Cardiol. 1993; 71: 631
        • Castro Cabezas M
        • de Bruin T.W.A
        • de Valk H.W
        • Shoulders C.C
        • Jansen H
        • Erkelens D.W
        Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating hepatic apolipoprotein B overproduction and insulin resistance.
        J Clin Invest. 1993; 92: 160
      2. Castro Cabezas M, de Bruin TWA, Jansen H, Kock LAW, Kortlandt W, Erkelens DW. Impaired chylomicron remnant clearance in familial combined hyperlipidemia. Arteriosclerosis and Thrombosis 1994.