Diagnostic Criteria in Relation to the Pathogenesis of Familial Combined Hyperlipidemia

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.

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
• 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
• 3 Nikkila E A, Aro A. Family study of serum lipids and lipoproteins in coronary heart-disease.  Lancet. 1973;  1 954-959
• 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
• 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
• 6 De Graaf J, Stalenhoef A FH. Defects of lipoprotein metabolism in familial combined hyperlipidemia.  Curr Opin Lipidol. 1998;  9 189-196
• 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
• 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
• 9 Aouizerat B E, Allayee H, Bodnar J et al.. Novel genes for familial combined hyperlipidemia.  Curr Opin Lipidol. 1999;  10 113-122
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 26 Porkka K V, Nuotio I, Pajukanta P et al.. Phenotype expression in familial combined hyperlipidemia.  Atherosclerosis. 1997;  133 245-253
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 46 Tall A R. Plasma cholesteryl ester protein.  J Lipid Res. 1993;  34 1255-1271
• 47 Griffin B A, Packard C J. Metabolism of VLDL and LDL subclasses.  Curr Opin Lipidol. 1994;  5 200-206
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 58 Lamarche B. Abdominal obesity and its metabolic complications: implications for the risk of ischaemic heart disease.  Coron Artery Dis. 1998;  9 473-481
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 75 Havel P J. Update on adipocyte hormones; regulation of energy balance and carbohydrate/lipid metabolism.  Diabetes. 2004;  53 S143-S151
• 76 Arner P. Is familial combined hyperlipidaemia a genetic disorder of adipose tissue?.  Curr Opin Lipidol. 1997;  8 89-94
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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