Download PDF
Semin Vasc Med 2004; 4(3): 229-240
DOI: 10.1055/s-2004-861490
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Diagnostic Criteria in Relation to the Pathogenesis of Familial Combined Hyperlipidemia

Jacqueline de Graaf1 , Gerly van der Vleuten1 , Anton F. H. Stalenhoef1
  • 1Department of Medicine, Division of General Internal Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands
Further Information

Publication History

Publication Date:
03 January 2005 (online)

    Permissions and Reprints

ABSTRACT

Familial combined hyperlipidemia (FCH) is the most common inherited hyperlipidemia in humans, affecting 1 to 3% of the adult population and up to 20% of patients with premature myocardial infarction. FCH is traditionally diagnosed by total plasma cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender; however, the diagnosis of FCH based on these diagnostic criteria is inconsistent in 26% of the subjects over a five-year period, emphasizing the need for re-evaluation of the diagnostic criteria for FCH. Recently, a nomogram was developed based on absolute apolipoprotein B levels in combination with triglyceride and total cholesterol levels adjusted for both age and gender to simply and accurately diagnose FCH. When percentiles of triglyceride and total cholesterol adjusted for age and gender are not available in a population, the definition of FCH can be established based on hypertriglyceridemia (> 1.5 mmol/l) and hyperapoB (> 1200 mg/l).

Standardized and simple diagnostic criteria are necessary to further delineate the pathogenesis of FCH. Several metabolic pathways have been suggested to be important in causing the FCH phenotype including hepatic VLDL overproduction either with or without impaired clearance of triglyceride-rich lipoproteins from plasma. The presence of insulin resistance and obesity in FCH patients further contribute to the expression of the lipidphenotype. A disturbed adipose tissue metabolism that results in an increased plasma free fatty acid pool may be the culprit in the pathogenesis of FCH.

KEYWORDS

Apolipoproteins - diagnosis - follow-up studies - hyperlipoproteinemia

REFERENCES

  • 1 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 1544-1568
    CrossrefPubMedSearch in Google Scholar
  • 2 Rose H G, Kranz P, Weinstock M, Juliano J, Haft J L. Inheritance of combined hyperlipoproteinemia: evidence for a new lipoprotein phenotype.  Am J Med. 1973;  54 148-160
    CrossrefPubMedSearch in Google Scholar
  • 3 Nikkila E A, Aro A. Family study of serum lipids and lipoproteins in coronary heart-disease.  Lancet. 1973;  1 954-959
    PubMedSearch in Google Scholar
  • 4 Shoulders C C, Jones E L, Naoumova R P. Genetics of familial combined hyperlipidemia and risk of coronary heart disease.  Hum Mol Genet. 2004;  13(suppl 1) R149-R160
    CrossrefPubMedSearch in Google Scholar
  • 5 Eurlings P M, van der Kallen C J, Geurts J M, van Greevenbroek M M, de Bruin T W. Genetic dissection of familial combined hyperlipidemia.  Mol Genet Metab. 2001;  74 98-104
    CrossrefPubMedSearch in Google Scholar
  • 6 De Graaf J, Stalenhoef A FH. Defects of lipoprotein metabolism in familial combined hyperlipidemia.  Curr Opin Lipidol. 1998;  9 189-196
    PubMedSearch in Google Scholar
  • 7 Bredie S JH, Demacker P NM, Stalenhoef A FH. Metabolic and genetic aspects of familial combined hyperlipidemia with emphasis on low-density lipoprotein heterogeneity.  Eur J Clin Invest. 1997;  27 802-811
    CrossrefPubMedSearch in Google Scholar
  • 8 de Graaf J, Veerkamp M J, Stalenhoef A FH. Metabolic pathogenesis of familial combined hyperlipidaemia with emphasis on insulin resistance, adipose tissue metabolism and free fatty acids.  J R Soc Med. 2002;  95(suppl 42) 46-53
    CrossrefPubMedSearch in Google Scholar
  • 9 Aouizerat B E, Allayee H, Bodnar J et al.. Novel genes for familial combined hyperlipidemia.  Curr Opin Lipidol. 1999;  10 113-122
    CrossrefPubMedSearch in Google Scholar
  • 10 Bredie S J, van Drongelen J, Kiemeney L A, Demacker P N, Beaty T H, Stalenhoef A F. Segregation analysis of plasma apolipoprotein B levels in familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 1997;  17 834-840
    PubMedSearch in Google Scholar
  • 11 Juo S H, Bredie S J, Kiemeney L A, Demacker P N, Stalenhoef A FH. A common genetic mechanism determines plasma apolipoprotein B levels and dense LDL subfraction distribution in familial combined hyperlipidemia.  Am J Hum Genet. 1998;  63 586-594
    CrossrefPubMedSearch in Google Scholar
  • 12 Jarvik G P, Brunzell J D, Austin M A, Krauss R M, Motulsky A G, Wijsman E. Genetic predictors of FCHL in four large pedigrees. Influence of ApoB level major locus predicted genotype and LDL subclass phenotype.  Arterioscler Thromb. 1994;  14 1687-1694
    PubMedSearch in Google Scholar
  • 13 Ayyobi A F, McGladdery S H, McNeely M J, Austin M A, Motulsky A G, Brunzell J D. Small, dense LDL and elevated apolipoprotein B are the common characteristics for the three major lipid phenotypes of familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 2003;  23 1289-1294
    CrossrefPubMedSearch in Google Scholar
  • 14 Veerkamp M J, de Graaf J, Bredie S J, Hendriks J C, Demacker P N, Stalenhoef A FH. Diagnosis of familial combined hyperlipidemia based on lipid phenotype expression in 32 families: results of a 5-year follow-up study.  Arterioscler Thromb Vasc Biol. 2002;  22 274-282
    PubMedSearch in Google Scholar
  • 15 Bredie S J, Kiemeney L A, de Haan A F, Demacker P N, Stalenhoef A FH. Inherited susceptibility determines the distribution of dense low-density lipoprotein subfraction profiles in familial combined hyperlipidemia.  Am J Hum Genet. 1996;  58 812-822
    PubMedSearch in Google Scholar
  • 16 Vakkilainen J, Jauhiainen M, Ylitalo K et al.. LDL particle size in familial combined hyperlipidemia: effects of serum lipids, lipoprotein-modifying enzymes, and lipid transfer proteins.  J Lipid Res. 2002;  43 598-603
    PubMedSearch in Google Scholar
  • 17 Hokanson J E, Krauss R M, Albers J J, Austin M A, Brunzell J D. LDL physical and chemical properties in familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 1995;  15 452-459
    PubMedSearch in Google Scholar
  • 18 Soro A, Jauhiainen M, Ehnholm C, Taskinen M R. Determinants of low HDL levels in familial combined hyperlipidemia.  J Lipid Res. 2003;  44 1536-1544
    PubMedSearch in Google Scholar
  • 19 Purnell J Q, Kahn S E, Schwartz R S, Brunzell J D. Relationship of insulin sensitivity and ApoB levels to intra-abdominal fat in subjects with familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 2001;  21 567-572
    PubMedSearch in Google Scholar
  • 20 Voors-Pette C, de Bruin T W. Excess coronary heart disease in familial combined hyperlipidemia, in relation to genetic factors and central obesity.  Atherosclerosis. 2001;  157 481-489
    CrossrefPubMedSearch in Google Scholar
  • 21 Aitman T J, Godsland I F, Farren B, Crook D, Wong H J, Scott J. Defects of insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 1997;  17 748-754
    PubMedSearch in Google Scholar
  • 22 van der Kallen C J, Voors-Pette C, Bouwman F G et al.. Evidence of insulin resistant lipid metabolism in adipose tissue in familial combined hyperlipidemia, but not type 2 diabetes mellitus.  Atherosclerosis. 2002;  164 337-346
    CrossrefPubMedSearch in Google Scholar
  • 23 Hopkins P N, Heiss G, Ellison R C et al.. Coronary artery disease risk in familial combined hyperlipidemia and familial hypertriglyceridemia: a case-control comparison from the National Heart, Lung, and Blood Institute Family Heart Study.  Circulation. 2003;  108 519-523
    CrossrefPubMedSearch in Google Scholar
  • 24 Austin M A, McKnight B, Edwards K L et al.. Cardiovascular disease mortality in familial forms of hypertriglyceridemia: a 20-year prospective study.  Circulation. 2000;  101 2777-2782
    CrossrefPubMedSearch in Google Scholar
  • 25 Sniderman A D, Ribalta J, Castro Cabezas M. How should FCHL be defined and how should we think about its metabolic bases?.  Nutr Metab Cardiovasc Dis. 2001;  11 412
    PubMedSearch in Google Scholar
  • 26 Porkka K V, Nuotio I, Pajukanta P et al.. Phenotype expression in familial combined hyperlipidemia.  Atherosclerosis. 1997;  133 245-253
    CrossrefPubMedSearch in Google Scholar
  • 27 Sniderman A D, Castro Cabezas M, Ribalta J et al.. A proposal to redefine familial combined hyperlipidaemia-third workshop on FCHL held in Barcelona from 3 to 5 May 2001, during the scientific sessions of the European Society for Clinical Investigation.  Eur J Clin Invest. 2002;  32 71-73
    CrossrefPubMedSearch in Google Scholar
  • 28 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;  24 147-156
    PubMedSearch in Google Scholar
  • 29 McNeely M J, Edwards K L, Marcovina S M, Brunzell J D, Motulsky A G, Austin M A. Lipoprotein and apolipoprotein abnormalities in familial combined hyperlipidemia: a 20-year prospective study.  Atherosclerosis. 2001;  159 471-481
    CrossrefPubMedSearch in Google Scholar
  • 30 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 1110-1118
    PubMedSearch in Google Scholar
  • 31 Kissebah A H, Alfarsi S, Evans D J. Low density lipoprotein metabolism in familial combined hyperlipidemia. Mechanism of the multiple lipoprotein phenotypic expression.  Arteriosclerosis. 1984;  4 614-624
    PubMedSearch in Google Scholar
  • 32 Rauh G, Schuster H, Muller B et al.. Genetic evidence from 7 families that the apolipoprotein B gene is not involved in familial combined hyperlipidemia.  Atherosclerosis. 1990;  83 81-87
    PubMedSearch in Google Scholar
  • 33 Austin M A, Wijsman E, Guo S W, Krauss R M, Brunzell J D, Deeb S. Lack of evidence for linkage between low-density lipoprotein subclass phenotypes and the apolipoprotein B locus in familial combined hyperlipidemia.  Genet Epidemiol. 1991;  8 287-297
    CrossrefPubMedSearch in Google Scholar
  • 34 Allayee A, Krass K L, Pajukanta P et al.. Locus for elevated apolipoprotein B levels on chromosome 1p31 in families with familial combined hyperlipidemia.  Circ Res. 2002;  90 926-931
    CrossrefPubMedSearch in Google Scholar
  • 35 Iwata F, Okada T, Kuromori Y, Hara M, Harada K. Screening for familial combined hyperlipidemia in children using lipid phenotypes.  J Atheroscler Thromb. 2003;  10 299-303
    PubMedSearch in Google Scholar
  • 36 Kuromori Y, Okada T, Iwata F, Hara M, Noto N, Harada K. Familial combined hyperlipidemia (FCHL) in children: the significance of early development of hyperapoB lipoproteinemia, obesity and aging.  J Atheroscler Thromb. 2002;  9 314-320
    PubMedSearch in Google Scholar
  • 37 Lapinleimu J, Nuotio I O, Lapinleimu H, Simell O G, Rask-Nissila L, Viikari S. Recognition of familial dyslipidemias in 5-year-old children using the lipid phenotypes of parents. The STRIP project.  Atherosclerosis. 2002;  160 417-423
    CrossrefPubMedSearch in Google Scholar
  • 38 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;  123 177-184
    PubMedSearch in Google Scholar
  • 39 Marcovina S M, Albers J J, Kennedy H et al.. International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. IV. Comparability of apolipoprotein B values by use of International Reference Material.  Clin Chem. 1994;  40 586-592
    PubMedSearch in Google Scholar
  • 40 Veerkamp M J, de Graaf J, Hendriks J CM, Demacker P NM, Stalenhoef A FH. Nomogram to diagnose familial combined hyperlipidemia on the basis of results of a 5 year follow-up study.  Circulation. 2004;  109 2980-2985
    CrossrefPubMedSearch in Google Scholar
  • 41 Contois J H, McNamara J R, Lammi-Keefe C J et al.. Reference intervals for plasma apolipoprotein B determined with a standardized commercial immunoturbidimetric assay: results from the Framingham Offspring Study.  Clin Chem. 1996;  42 515-523
    PubMedSearch in Google Scholar
  • 42 Lamarche B, Despres J P, Moorjani S et al.. Prevalence of dyslipidemic phenotypes in ischemic heart disease (prospective results from the Quebec Cardiovascular Study).  Am J Cardiol. 1995;  75 1189-1195
    CrossrefPubMedSearch in Google Scholar
  • 43 Talmud P J, Hawe E, Miller G J, Humphries S E. Nonfasting apolipoprotein B and triglyceride levels as a useful predictor of coronary heart disease risk in middle-aged UK men.  Arterioscler Thromb Vasc Biol. 2002;  22 1918-1923
    PubMedSearch in Google Scholar
  • 44 Vakkilainen J, Pajukanta P, Cantor R M et al.. Genetic influences contributing to LDL particle size in familial combined hyperlipidaemia.  Eur J Hum Genet. 2002;  10 547-552
    PubMedSearch in Google Scholar
  • 45 Marzetta C A, Foster D M, Brunzell J D. Conversion of plasma VLDL and IDL precursors into various LDL subpopulations using density gradient ultracentrifugation.  J Lipid Res. 1990;  31 975-984
    PubMedSearch in Google Scholar
  • 46 Tall A R. Plasma cholesteryl ester protein.  J Lipid Res. 1993;  34 1255-1271
    PubMedSearch in Google Scholar
  • 47 Griffin B A, Packard C J. Metabolism of VLDL and LDL subclasses.  Curr Opin Lipidol. 1994;  5 200-206
    PubMedSearch in Google Scholar
  • 48 Hokanson J E, Austin M A, Zambon A, Brunzell J D. Plasma triglyceride and LDL heterogeneity in familial combined hyperlipidemia.  Arterioscler Thromb. 1993;  13 427-434
    PubMedSearch in Google Scholar
  • 49 Bredie S JH, de Bruin T WA, Demacker P NM, Kastelein J JP, Stalenhoef A FH. Comparison of gemfibrozil versus simvastatin in familial combined hyperlipidemia and effects on apolipoprotein-B-containing lipoproteins, low-density lipoprotein subfraction profile and low density lipoprotein oxidizability.  Am J Cardiol. 1995;  75 348-353
    CrossrefPubMedSearch in Google Scholar
  • 50 Demacker P N, Veerkamp M J, Bredie S J, Marcovina S M, de Graaf J, Stalenhoef A FH. Comparison of the measurement of lipids and lipoproteins versus assay of apolipoprotein B for estimation of coronary heart disease risk: a study in familial combined hyperlipidemia.  Atherosclerosis. 2000;  153 483-490
    CrossrefPubMedSearch in Google Scholar
  • 51 Griffin B A, Freeman D J, Tait G W et al.. Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk.  Atherosclerosis. 1994;  106 241-253
    CrossrefPubMedSearch in Google Scholar
  • 52 Bredie S JH, Tack C JJ, Smits P, Stalenhoef A FH. Non-obese patients with familial combined hyperlipidemia are insulin resistant as compared with their non-affected relatives.  Arterioscler Thromb Vasc Biol. 1997;  17 1465-1471
    PubMedSearch in Google Scholar
  • 53 Karjalainen L, Pihlajamaki J, Karhapaa P, Laakso M. Impaired insulin-stimulated glucose oxidation and free fatty acid suppression in patients with familial combined hyperlipidemia: a precursor defect for dyslipidemia?.  Arterioscler Thromb Vasc Biol. 1998;  18 1548-1553
    PubMedSearch in Google Scholar
  • 54 Randle P, Hales C, Garland P, Newsholme E. The glucose fatty acid cycle and its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.  Lancet. 1963;  1 785-789
    PubMedSearch in Google Scholar
  • 55 Lewis G F, Uffelman K D, Szeto L W, Weller B, Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans.  J Clin Invest. 1995;  95 158-166
    CrossrefPubMedSearch in Google Scholar
  • 56 Pihlajamaki J, Karjalainen L, Karhapaa P, Vauhkonen I, Laakso M. Impaired free fatty acid suppression during hyperinsulinemia is a characteristic finding in familial combined hyperlipidemia, but insulin resistance is observed only in hypertriglyceridemic patients.  Arterioscler Thromb Vasc Biol. 2000;  20 164-170
    PubMedSearch in Google Scholar
  • 57 Vakkilainen J, Porkka K V, Nuotio I et al.. Glucose intolerance in familial combined hyperlipidaemia. EUFAM study group.  Eur J Clin Invest. 1998;  28 24-32
    CrossrefPubMedSearch in Google Scholar
  • 58 Lamarche B. Abdominal obesity and its metabolic complications: implications for the risk of ischaemic heart disease.  Coron Artery Dis. 1998;  9 473-481
    PubMedSearch in Google Scholar
  • 59 Castro C M, de Bruin T W, de Valk H W, Shoulders C C, Jansen H, Willem E D. Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating hepatic apolipoprotein B overproduction and insulin resistance.  J Clin Invest. 1993;  92 160-168
    PubMedSearch in Google Scholar
  • 60 Meijssen S, van Dijk H, Verseyden C, Erkelens D W, Cabezas M C. Delayed and exaggerated postprandial complement component 3 response in familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 2002;  22 811-816
    PubMedSearch in Google Scholar
  • 61 Halkes C J, van Dijk H, Verseyden C, de Jaegere P P, Plokker H W, Meijssen S, Erkelens D W, Cabezas M C. Gender differences in postprandial ketone bodies in normolipidemic subjects and in untreated patients with familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 2003;  23 1875-1880
    PubMedSearch in Google Scholar
  • 62 Meijssen S, Cabezas M C, Twickler T B, Jansen H, Erkelens D W. In vivo evidence of defective postprandial and postabsorptive free fatty acid metabolism in familial combined hyperlipidemia.  J Lipid Res. 2000;  41 1096-1102
    PubMedSearch in Google Scholar
  • 63 Sniderman A D, Cianflone K, Summers L, Fielding B, Frayn K. The acylation-stimulating protein pathway and regulation of postprandial metabolism.  Proc Nutr Soc. 1997;  56 703-712
    CrossrefPubMedSearch in Google Scholar
  • 64 Sniderman A D, Cianflone K, Arner P, Summers L KM, Frayn K N. The adipocyte, fatty acid trapping, and atherogenesis.  Arterioscler Thromb Vasc Biol. 1998;  18 147-151
    PubMedSearch in Google Scholar
  • 65 Cianflone K, Maslowska M, Sniderman A D. Impaired response to fibroblasts in patients with hyperapobetalipoproteinemia to acylation stimulating protein.  J Clin Invest. 1990;  85 722-730
    PubMedSearch in Google Scholar
  • 66 Zhang X J, Cianflone K, Genest J, Sniderman A D. Plasma acylation stimulating protein (ASP) in patients with hyperapoB.  Eur J Clin Invest. 1998;  28 730-739
    CrossrefPubMedSearch in Google Scholar
  • 67 Ylitalo K, Pajukanta P, Meri S et al.. Serum C3 but not plasma acylation-stimulating protein is elevated in Finnish patients with familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 2001;  21 838-843
    PubMedSearch in Google Scholar
  • 68 Reynisdottir S, Eriksson M, Angelin B, Arner P. Impaired activation of adipocyte lipolysis in familial combined hyperlipidemia.  J Clin Invest. 1995;  95 2161-2169
    PubMedSearch in Google Scholar
  • 69 Ylitalo K, Large V, Pajukanta P et al.. Reduced hormone-sensitive lipase activity is not a major metabolic defect in Finnish FCHL families.  Atherosclerosis. 2000;  153 373-381
    CrossrefPubMedSearch in Google Scholar
  • 70 Pajukanta P, Porkka K V, Antikainen M et al.. No evidence of linkage between familial combined hyperlipidemia and genes encoding lipolytic enzymes in Finnish families.  Arterioscler Thromb Vasc Biol. 1997;  17 841-850
    PubMedSearch in Google Scholar
  • 71 Pihlajamaki J, Valve R, Karjalainen L, Karhapaa P, Vauhkonen I, Laakso M. The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance.  Eur J Clin Invest. 2001;  31 302-308
    CrossrefPubMedSearch in Google Scholar
  • 72 Jacobson M S, Yoon D J, Frank G R. Serum leptin is elevated out of proportion to the body mass index in adolescent females with familial combined hyperlipidemia.  Clin Pediatr (Phila). 1999;  38 49-53
    PubMedSearch in Google Scholar
  • 73 Haluzik M, Fiedler J, Nedvidkova J, Ceska R. Serum leptin concentrations in patients with combined hyperlipidemia: relationship to serum lipids and lipoproteins.  Physiol Res. 1999;  48 363-368
    PubMedSearch in Google Scholar
  • 74 Hotamisligil G S, Arner P, Atkinson R L, Spiegelman B M. Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance.  Diabetes. 1997;  46 451-455
    PubMedSearch in Google Scholar
  • 75 Havel P J. Update on adipocyte hormones; regulation of energy balance and carbohydrate/lipid metabolism.  Diabetes. 2004;  53 S143-S151
    CrossrefPubMedSearch in Google Scholar
  • 76 Arner P. Is familial combined hyperlipidaemia a genetic disorder of adipose tissue?.  Curr Opin Lipidol. 1997;  8 89-94
    PubMedSearch in Google Scholar
  • 77 Eurlings P M, Van Der Kallen C J, Geurts J M, Kouwenberg P, Boeckx W D, De Bruin T W. Identification of differentially expressed genes in subcutaneous adipose tissue from subjects with familial combined hyperlipidemia.  J Lipid Res. 2002;  43 930-935
    PubMedSearch in Google Scholar
  • 78 Ylitalo K, Nuotio I, Viikari J, Auwerx J, Vidal H, Taskinen M R. C3, hormone-sensitive lipase, and peroxisome proliferator-activated receptor gamma expression in adipose tissue of familial combined hyperlipidemia patients.  Metabolism. 2002;  51 664-670
    CrossrefPubMedSearch in Google Scholar
  • 79 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 1233-1249
    PubMedSearch in Google Scholar
  • 80 Pihlajamaki J, Austin M, Edwards K, Laakso M. A major gene effect on fasting insulin and insulin sensitivity in familial combined hyperlipidemia.  Diabetes. 2001;  50 2396-2401
    PubMedSearch in Google Scholar
  • 81 Pajukanta P, Nuotio I, Terwilliger J D et al.. Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23.  Nat Genet. 1998;  18 369-373
    PubMedSearch in Google Scholar
  • 82 Pajukanta P, Terwilliger J D, Perola M et al.. Genomewide scan for familial combined hyperlipidemia genes in Finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels.  Am J Hum Genet. 1999;  64 1453-1463
    CrossrefPubMedSearch in Google Scholar
  • 83 Aouizerat B E, Allayee H, Cantor R M et al.. A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11.  Am J Hum Genet. 1999;  65 397-412
    CrossrefPubMedSearch in Google Scholar
  • 84 Aouizerat B E, Allayee H, Cantor R M et al.. Linkage of a candidate gene locus to familial combined hyperlipidemia: lecithin:cholesterol acyltransferase on 16q.  Arterioscler Thromb Vasc Biol. 1999;  19 2730-2736
    PubMedSearch in Google Scholar
  • 85 Naoumova R P, Bonney S A, Eichenbaum-Voline S et al.. Confirmed locus on chromosome 11p and candidate loci on 6q and 8p for the triglyceride and cholesterol traits of combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 2003;  23 2070-2077
    PubMedSearch in Google Scholar
  • 86 Pei W, Baron H, Muller-Myhsok B et al.. Support for linkage of familial combined hyperlipidemia to chromosome 1q21-q23in Chinese and German families.  Clin Genet. 2000;  57 29-34
    CrossrefPubMedSearch in Google Scholar
  • 87 Coon H, Myers R H, Borecki I B et al.. Replication of linkage of familial combined hyperlipidemia to chromosome 1q with additional heterogeneous effect of apolipoprotein A-I/C-III/A-IV locus. The NHLBI Family Heart Study.  Arterioscler Thromb Vasc Biol. 2000;  20 2275-2280
    PubMedSearch in Google Scholar
  • 88 Pajukanta P, Allayee H, Krass K L et al.. Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.  Am J Hum Genet. 2003;  72 903-917
    CrossrefPubMedSearch in Google Scholar
  • 89 Hoffer M J, Bredie S J, Snieder H et al.. Gender-related association between the -93T→G/D9N haplotype of the lipoprotein lipase gene and elevated lipid levels in familial combined hyperlipidemia.  Atherosclerosis. 1998;  138 91-99
    CrossrefPubMedSearch in Google Scholar
  • 90 Hoffer M J, Bredie S J, Boomsma D I et al.. The lipoprotein lipase (Asn291→Ser) mutation is associated with elevated lipid levels in families with familial combined hyperlipidaemia.  Atherosclerosis. 1996;  119 159-167
    CrossrefPubMedSearch in Google Scholar
  • 91 Yang W S, Nevin D N, Peng R, Brunzell J D, Deeb S S. A mutation in the promoter of the lipoprotein lipase (LPL) gene in a patient with familial combined hyperlipidemia and low LPL activity.  Proc Natl Acad Sci U S A. 1995;  92 4462-4466
    PubMedSearch in Google Scholar
  • 92 Hoffer M J, Snieder H, Bredie S J et al.. The V73M mutation in the hepatic lipase gene is associated with elevated cholesterol levels in four Dutch pedigrees with familial combined hyperlipidemia.  Atherosclerosis. 2000;  151 443-450
    CrossrefPubMedSearch in Google Scholar
  • 93 Pihlajamaki J, Karjalainen L, Karhapaa P et al.. G-250A substitution in promoter of hepatic lipase gene is associated with dyslipidemia and insulin resistance in healthy control subjects and in members of families with familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 2000;  20 1789-1795
    PubMedSearch in Google Scholar
  • 94 Xu C F, Talmud P, Schuster H, Houlston R, Miller G, Humphries S. Association between genetic variation at the APO AI-CIII-AIV gene cluster and familial combined hyperlipidaemia.  Clin Genet. 1994;  46 385-397
    PubMedSearch in Google Scholar
  • 95 Wojciechowski A P, Farrall M, Cullen P et al.. Familial combined hyperlipidaemia linked to the apolipoprotein AI-CII-AIV gene cluster on chromosome 11q23-q24.  Nature. 1991;  349 161-164
    CrossrefPubMedSearch in Google Scholar
  • 96 Ribalta J, La Ville A E, Vallve J C, Humphries S, Turner P R, Masana L. A variation in the apolipoprotein C-III gene is associated with an increased number of circulating VLDL and IDL particles in familial combined hyperlipidemia.  J Lipid Res. 1997;  38 1061-1069
    PubMedSearch in Google Scholar
  • 97 Tahvanainen E, Pajukanta P, Porkka K et al.. Haplotypes of the ApoA-I/C-III/A-IV gene cluster and familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 1998;  18 1810-1817
    PubMedSearch in Google Scholar
  • 98 Groenendijk M, De Bruin T W, Dallinga-Thie G M. Two polymorphisms in the apo A-IV gene and familial combined hyperlipidemia.  Atherosclerosis. 2001;  158 369-376
    CrossrefPubMedSearch in Google Scholar
  • 99 Groenendijk M, Cantor R M, De Bruin T W, Dallinga-Thie G M. New genetic variants in the apoA-I and apoC-III genes and familial combined hyperlipidemia.  J Lipid Res. 2001;  42 188-194
    PubMedSearch in Google Scholar
  • 100 Eichenbaum-Voline S, Olivier M, Jones E L et al.. Linkage and association between distinct variants of the APOA1/C3/A4/A5 gene cluster and familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 2004;  24 167-174
    PubMedSearch in Google Scholar
  • 101 Geurts J M, Janssen R G, van Greevenbroek M M et al.. Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia.  Hum Mol Genet. 2000;  9 2067-2074
    CrossrefPubMedSearch in Google Scholar
  • 102 Pihlajamaki J, Rissanen J, Heikkinen S, Karjalainen L, Laakso M. 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. 1997;  17 1039-1044
    PubMedSearch in Google Scholar
  • 103 Pihlajamaki J, Rissanen J, Valve R, Heikkinen S, Karjalainen L, Laakso M. Different regulation of free fatty acid levels and glucose oxidation by the Trp64Arg polymorphism of the beta3-adrenergic receptor gene and the promoter variant (A-3826G) of the uncoupling protein 1 gene in familial combined hyperlipidemia.  Metabolism. 1998;  47 1397-1402
    CrossrefPubMedSearch in Google Scholar
  • 104 Pihlajamaki J, Miettinen R, Valve R et al.. The Pro12A1a substitution in the peroxisome proliferator activated receptor gamma 2 is associated with an insulin-sensitive phenotype in families with familial combined hyperlipidemia and in nondiabetic elderly subjects with dyslipidemia.  Atherosclerosis. 2000;  151 567-574
    CrossrefPubMedSearch in Google Scholar
  • 105 Eurlings P M, van der Kallen C J, Vermeulen V M, de Bruin T W. Variants in the PPARgamma gene affect fatty acid and glycerol metabolism in familial combined hyperlipidemia.  Mol Genet Metab. 2003;  80 296-301
    CrossrefPubMedSearch in Google Scholar
  • 106 Castellani L W, Weinreb A, Bodnar J et al.. Mapping a gene for combined hyperlipidaemia in a mutant mouse strain.  Nat Genet. 1998;  18 374-377
    PubMedSearch in Google Scholar
  • 107 Pajukanta P, Bodnar J S, Sallinen R et al.. Fine mapping of Hyplip1 and the human homolog, a potential locus for FCHL.  Mamm Genome. 2001;  12 238-245
    CrossrefPubMedSearch in Google Scholar
  • 108 Van der Vleuten G M, Hijmans A, Kluijtmans L AJ, Blom H J, Stalenhoef A FH, de Graaf J. The thioredoxin interacting protein in Dutch families with familial combined hyperlipidemia.  Am J Med Genet. 2004;  130A 73-75
    CrossrefPubMedSearch in Google Scholar
  • 109 Pajukanta P, Lilja H E, Sinsheimer J S, Cantor R M, Lusis A J, Gentile M et al.. Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1).  Nat Genet. 2004;  36 371-376
    PubMedSearch in Google Scholar

 Dr.
J. de Graaf

Department of Medicine, Division of General Internal Medicine 541, University Medical Center Nijmegen

P.O. Box 9101, 6500 HB Nijmegen, The Netherlands