Novel genes for familial combined hyperlipidemia

Current Opinion in Lipidology

Volumn 10, Issue 2, 1999, Pages 113-122

  Aouizerat, Bradley E ^a   Allayee, Hooman ^a   Bodnar, Jackie ^a   Krass, Kelly L ^a   Peltonen, Leena ^b,c   De Bruin, Tjerk W A ^d   Rotter, Jerome I ^e   Lusis, Aldons J ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c NATIONAL PUBLIC HEALTH INSTITUTE   (Finland)

^d MAASTRICHT UNIVERSITY   (Netherlands)

^e Steven Spielberg Pediatric Research Center   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHROMOSOME 3; FAMILIAL DISEASE; GENE; GENE LOCUS; GENE MAPPING; HUMAN; HYPERLIPIDEMIA; MOUSE; NONHUMAN; PRIORITY JOURNAL; REVIEW;

AGE FACTORS; ANIMALS; DISEASE MODELS, ANIMAL; FINLAND; HUMANS; HYPERLIPIDEMIA, FAMILIAL COMBINED; INSULIN RESISTANCE; LINKAGE (GENETICS); MICE; MODELS, BIOLOGICAL; PHENOTYPE;

MURINAE;

EID: 0032918283     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/00041433-199904000-00005     Document Type: Review

References (77)

1. Venjatesan 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; 13:110-118.
2. Castro Cabezas M, de Bruin TWA, Erkelens DW Familial combined hyperlipidemia 1973-91. Neth J Med 1992; 40:83-95
3. Kwiterovich PO. Genetics and molecular biology of familial combined hyperlipidemia. Curr Opin Lipidol 1993, 4.133-143.
4. Cullen P, Farren B, Scott J, Farrall W. 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.
5. de Bruin TWA, Castro Cabezas M, Dallinga-Thie GM, Erkelens DW. Familial combined hyperlipidemia-do we understand the pathophysiology and genetics? In: Lipids: current perspectives. Betteridge DJ (editior). London: Martin Dunitz; 1996. pp 109-114.
6. Bredie SJH, Demacker PNM, Stalenhoef AFH Metabolic and genetic aspects of familial combined hyperlipidemia with emphasis on low-density lipoprotein heterogeneity Eur J Clin Invest 1997; 27:802-811.
7. de Graaf J, Stalenhoef AFH. Defects of lipoprotein metabolism in familial combined hyperlipidemia. Curr Opin Lipidol 1998; 9:189-196.
8. de Bruin TWA. Lipid metabolism. Curr Opin Lipidol 1998; 9:275-278.
9. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. 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.
10. Williams WR, Lalouel JM Complex segregation analysis of hyperlipidemia in a Seattle sample. Hum Hered 1982; 32:24-36
11. Babirak SP, Brown BG, Brunzell JD. Familial combined hyperlipidemia and abnormal LPL. Arterioscler Thromb 1992, 12:1178-1183.
12. Jarvik GP, Brunzell JD, Austin MA, Krauss RM, Motulsky AG, 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. Bredie SJH, Kiemeney LA, de Haan AFJ, Demacker PNM, Stalenhoef AFH. Low-density lipoprotein subfraction profiles in familial combined hyperlipidemia. Am J Hum Genet 1996; 58:812-822.
14. Dallinga-Thie GM, van Linde-Sibenius Trip M, Rotter JI, Cantor RM, Bu X, Lusis AJ, de Bruin TW. Complex genetic contribution of the apoAI-CIII-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes. J Clin Invest 1997; 99:953-961 Combinations of haplotypes at the AI-CIII-AIV locus were characterized with respect to possible interactions in FCHL subjects. Certain combinations were found to occur more frequently in hyperlipidemic individuals and were strongly associated (P<0 0001) with levels of triglycerides and cholesterol. The results provide evidence of epistatic interations between haplotypes in the gene cluster.
15. Juo SHH, Beaty TH, Kwiterovich PO. Etiologic heterogenetity of hyperapobe talipoproteinemia (hyperapoB). Results from segregation analysis in families with premature coronary artery disease. Arterioscler Thromb Vasc Biol 1997, 187: 2729-2730. This paper provides evidence for etiologic heterogeneity of hyperapoB, a trait which has overlapping etiology with FCHL. Among 55 families with hypertriglyceridemic individuals, the data were consistent with a Mendelian mode of inheritance, whereas among 72 families in which hyperapoB individuals were normolipidemic, no clear inheritance pattern was observed. Moreover, among the former families, a Mendelian recessive pattern of inheritance best explained the results.
16. Bredie SJH, van Drongelen J, Kiemeney LA, Demacker PN, Beaty TH, Stalenhoef AF. Segregation analysis of plasma apolipoprotein B levels in familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol 1997; 17:834-840.
17. Allayee H, Aouizerat BE, Cantor RM, Dallinga-Thie GM, Krauss RM, Lanning CD, et al. Familial combined hyperlipidemic families and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype. Am J Hum Genet 1998; 63:577-585. This study examined the genetic factors controlling the atherogenic lipoprotein phenotype (ALP) in a series of Dutch FCHL families. The results demonstrated that the ALP was enriched 10-fold in FCHL probands compared with spouses and that three of the loci demonstrating linkage to ALP were shared between FCHL and CAD families. Thus, the observed association between FCHL and ALP was consistent with previous studies, and the multigenic hypothesis for ALP was further supported.
18. Juo SHH, Bredie SJH, Kiemeney LA, Demacker PNM, Stalenhoef AFH. A common mechanism determines plasma apolipoprotein B levels and dense LDL subfraction distribution in familial combined hyperlipidemia. Am J Hum Genet 1998; 63 586-594. Segregation analysis was employed to determine whether a common genetic mechanism controls LDL particle size and apolipoprotein B levels in FCHL families. The results supported the involvement of one common major gene with pleiotropic effects on both traits which may be the gene underlying FCHL in these particular families.
19. Pajukanta P, Nuotio I, Terwilliger JD, Porkka KV, Ylitalo K, Pihlajamaki J, et al. Linkage of familial combined hyperlipidemia to chromosome 1q21-q23. Nature Genet 1998; 18:369-373. Linkage studies of 31 extended families with FCHL from Finland revealed strong evidence of linkage (LOD score 5 93) to a locus on chromosome 1q21-q23. The locus is near certain candidate genes, including apolipoprotein All, but the candidates appear to reside outside the interval of maximal linkage, suggesting that a novel gene is responsible for the linkage. The linkage was observed with a dominant model of inheritance in which unaffected individuals were not considered
20. Coresh J, Kwiterovich PO, Smith HH, Bachorik PS. Association of plasma triglyceride concentration and LDL particle diameter, density, and chemical composition with premature coronary artery disease in men and women. J Lipid Res 1993; 34:1687-1697.
21. Nevanlinna HR. Further evidence of the inhabitation in a marginal population. Hereditas 1973; 74:127-131.
22. de la Chapelle A. Disease gene mapping in isolated human populations: the example of Finland. J Med Genet 1993; 30:857-865.
23. Paigen B, Mitchell D, Reue K, Morrow A, Lusis AJ, LeBoeuf RC. Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc Natl Acad Sci USA 1987; 84:3763-3767.
24. •]).
25. Masucci-Magoulas L, Goldberg IJ, Bisgaier CL, Serajuddin H, Francone OL, Breslow JL, Tall AR. A mouse model with features of familial combined hyperlipidemia Science 1997; 275:391-394. The authors describe the development of a mouse model displaying some of the phenotypic characteristics of FCHL. The synergistic interaction of the human apolipoprotein CIII transgene with a null LDLR gene results in increased total cholesterol and atherosclerosic lesions. In addition, the human CETP transgene was introduced into this background to produce lower HDL levels. Although apolipoprotein CIII and CETP may modify the FCHL phenotype, they are unlikely to be the primary genetic determinant for FCHL.
26. La Ville A, Turner PR, Pittilo M, Martini S, Marenah CB, Rowles PW, et al. Hereditary hyperlipidemia in the rabbit due to overproduction of lipoproteins Arteriosclerosis 1987; 7:105-112.
27. Valera A, Pelegrin M, Asins G, Fillat C, Sabater J, Pujol A, et al. Overexpression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in transgenic mice causes hepatic hyperketogenesis. J Biol Chem 1994; 269:6267-6270.
28. Thompson GN, Hsu BY, Pitt JJ, Treacy E, Stanley CA. Fasting hypoketotic coma in a child with deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. N Engl J Med 1997; 337:1203-1207.
29. Brunzell JD, Albers JJ, Chait A, Grundy SM, Groszek E, McDonald GB Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. J Lipid Res 1983; 24:147-155.
30. Schonfeld G, Aguilar-Salina C, Elias N. Role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ('statins') in familial combined hyperlipidemia. Am J Cardiol 1998, 81:43B-46B.
31. Beaty TH, Kwiterovich PO, Laville A, Lewis B. Genetic analysis of total cholesterol and triglycerides in a pedigree of St Thomas rabbits. J Lipid Res 1989; 30:387-394.
32. Beaty TH, Prenger VL, Virgil DG, Lewis B, Kwiterovich PO, Bachonk PS. A genetic model for control of hypertriglyceridemia and apolipoprotein B levels in the Johns Hopkins colony of St Thomas Hospital rabbits. Genetics 1992; 132:1095-1104.
33. Purcell-Huynh DA, Weinreb A, Castellani LW, Mehrabian M, Doolittle MH, Lusis AJ. Genetic factors in lipoprotein metabolism. Analysis of a genetic cross between inbred mouse strains NZB/BINJ and SM/J using a complete linkage map approach. J Clin Invest 1995; 96:1845-1858.
34. Welch CL, Xia Y, Shechter I, Farese R, Mehrabian M, Mehdizadeh S, et al. Genetic regulation of cholesterol homeostasis: chromosomal organization of candidate genes. J Lipid Res 1996; 37:1406-1421.
35. Machleder D, Ivandic B, Welch C, Castellani L, Reue K, Lusis AJ. Complex genetic control of HDL levels in mice in response to an atherogenic diet J Clin Invest 1997; 99:1406-1419.
36. Lembertas AV, Perusse L, Chagnon YC, Fisler JS, Warden CH, Purcell-Huynh DA, et al. Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q. J Clin Invest 1997; 100.1240-1247.
37. Gu L, Johnson M, Lusis AJ. Genetic determinants of plasma lipoprotein metabolism: quantitative trait locus mapping of a cross between mouse strains MRL-lpr/lpr and BALB/cJ. Arterioscler Thromb Vasc Biol 1999; 19: 442-453
38. Wilson DE, Emi M, Iverius PH, Hata A, Wu LL, Hillas E, et al Phenotypic expression of heterozygous LPL deficiency in the extended pedigree of a proband homozygous for a misense mutation. J Clin Invest 1990; 86:735-750.
39. Yang WS, Nevin DN, Iwasaki L, Peng R, Brown BG, Brunzell JD, Deeb SS. Regulatory mutations in the human LPL gene in patients with familial combined hyperlipidemia and coronary artery disease. J Lipid Res 1996; 37:2627-2637.
40. Pajukanta P, Porkka KV, Antikainen M, Taskinen MR, Perola M, Murtomaki-Repo S, et al. No evidence of linkage between familial combined hyperlipidemia and genes encoding lipolytic enzymes in Finnish families. Arterioscler Thromb Vase Biol 1997, 17:841-850. Fourteen large FCHL families from a Finnish isolate were selected for study by employing strict ascertainment criteria. Candidate genes LPL, hormone sensitive lipase and hepatic lipase were tested for linkage to the qualitative FCHL trait, A parametric analytic methodology was employed. No evidence for linkage was observed for the recessive, intermediate or dominant inheritance models tested.
41. Aouizerat BE, Allayee H, Dallinga-Thie GM, Cantor RM, Vora HR, Lusis AJ, et al. Evidence for a multilocus contribution to familial combined hyperlipidemia (FCHL). Circulation 1997; 96 (Suppl) 545-546
42. Wojciechowski AP, Farrall M, Cullen P, Wilson TM, Bayliss JD, Farren B, et al. Familial combined hyperlipidemia linked to the apolipoprotein AI-CIII-AIV gene cluster on chromosome 11q23-q24. Nature 1991; 349:161-164.
43. Xu CF, Talmud P, Schuster H, Houlston R, Miller G, Humphries S. Association between genetic variation at the apoAI-GIII-AIV gene cluster and familial combined hyperlipidaemia. Clin Genet 1994; 46:385-397.
44. Dallinga-Thie GM, Bu XD, van Linde-Sibenius Trip M, Rotter JI, Lusis AJ, de Bruin TW. Apolipoprotein AI-CIII-AIV gene cluster in familial combined hyperlipidemia: effects on LDL-cholesterol and apolipoproteins B and CIII. J Lipid Res 1996; 37.136-147.
45. Wijsman EM, Brunzell JD, Jarvik GP, Austin MA, Motulsky AG, Deeb, SS. Evidence against linkage of familial combined hyperlipidemia to the apolipoprotein AI-CIII-AIV gene complex Arterioscler Thromb Vasc Biol 1998; 18:215-226. The potential involvement of the apolipoprotein AI-CIII-AIV gene cluster in FCHL was tested in three large pedigrees. Linkage analysis for the qualitative FCHL trait, total cholesterol and total cholesterol and apolipoprotein B levels revealed strong evidence against linkage of the gene cluster in these families (LOD scores of -787, -8.95 and -2.58, respectively).
46. Tas S. Strong association of a single nucleotide substitution in the 3′-untranslated region of the apolipoprotein-CIII gene with common hypertriglycendemia in Arabs. Clin Chem 1989; 35:256-259.
47. Ito Y, Azrolan N, O'Connell A, Walsh A, Breslow JL. Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. Science 1990, 249:790-793
48. Hayden MR, Kirk H, Clark C, Frohlich J, Rabkin S, McLeod R, Hewitt J. DNA polymorphisms in and around the apoAI-CIII-AIV genes and genetic hyperlipidemias. Am J Hum Genet 1987, 40:421-430.
49. Naganawa S, Ginsberg HN, Glickman RM, Ginsburg GS. Intestinal transcription and synthesis of apolipoprotein AI is regulated by five natural polymorphisms upstream of the apolipoprotein CIII gene. J Clin Invest 1997; 99:1958-1965.
50. Baier LJ, Sacchettini JC, Knowler WC, Eads J, Paolisso G, Tataranni PA, et al. An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance. J Clin Invest 1995, 95:1281-1287.
51. Pihlajarnaki 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.
52. Austin MA, Brunzell JD, Fitch WL, Krauss RM Inheritance of low density lipoprotein subclass patterns in familial combined hyperlipidemia Arteriosclerosis 1990; 10:520-530.
53. Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC, Krauss RM Low density lipoprotein subclass patterns and risk of myocardial infarction, JAMA 1988; 260:1917-1921.
54. Nishina PM, Johnson JP, Naggert JK, Krauss RM. Linkage of atherogenic lipoprotein phenotype to the low density lipoprotein receptor locus on the short arm of chromosome 19. Proc Natl Acad Sci USA 1992; 89.708-717
55. Rotter JI, Bu X, Cantor RM, Warden CH, Brown J, Gray RJ, et al. Multi-locus genetic determinants of LDL particle size in coronary artery disease families. Am J Hum Genet 1996; 58:585-594.
56. Austin MA, Talmud PJ, Luong L-A, Haddad L, Day INM, Newman B, et al. Candidate-gene studies of the atherogenic lipoprotein phenotype: a sib-pair linkage analysis of DZ women twins. Am J Hum Genet 1998, 62:406-419.
57. Hunt SC, Wu LL, Hopkins PN, Stults BM, Kuida H, Ramirez ME, et al. Apolipoprotein, low density lipoprotein subfraction, and insulin associations with familial combined hyperlipidemia. Study of Utah patients with familial dyslipidemic hypertension. Arteriosclerosis 1989; 9:335-344
58. Castro Cabezas M, de Bruin TWA. de Valk HW, Shoulders CC, JansenH, Erkelens DW. Impaired fatty acid metabolism in familial combined hyperlipidemia J Clin Invest 1993; 92:160-168
59. Selby JV, Newman B, Quiroga J, Christian JC, Austin MA, Fabsitz RR. Concordance for dyslipidemic hypertension in mate twins. JAMA 1991; 265:2079-2084
60. Aitman TJ, Godsland IF, Farren B, Crook D, Wong HJ, Scott J. Defects of insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol 1997; 17:748-754. This study provides biochemical evidence that subjects with FCHL are insulin resistant. Insulin action on carbohydrate and fatty acid metabolism in FCHL patients and healthy control individuals was studied by a two-step euglycemic, hyperinsulinemic clamp. Insulin resistance in affecteds resulted in significantly elevated non-esterified free fatty acid levels (P< 0.005) and impaired peripheral glucose disposal when compared with control individuals
61. Bredie SJH, Tack CJJ, Smith P, Stalenhoef AFH. Nonobese patients with familial combined hyperlipidemia are insulin resistant compared with their nonaffected relatives. Arterioscler Thromb Vasc Biol 1997; 17:1465-1471
62. 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. This study provides biochemical evidence that subjects with FCHL are insulin resistant. Insulin action in FCHL family members and controls was investigated by applying hyperinsulinemic euglycemic clamps. FCHL individuals had lower rates of glucose oxidation (P=O 001), higher rates of lipid oxidation and higher levels of serum free fatty acids (P<0.001) compared with control individuals. Interestingly, relatives without dyslipidemia also differed from control individuals with respect to free fatty acid levels. This suggests that the suppressive effect of insulin on free fatty acid levels may precede dyslipidemia in FCHL.
63. Ascaso JF, Sales J, Marchante A, Real J, Lorente R, Martinez-Valls J, et al. Influence of obesity on plasma lipoproteins, glycemia and insulinemia in patients with familial combined hyperlipidemia. Int J Obesity 1997; 21.360-366.
64. Reaven GM Role of insulin resistance in human disease. Diabetes 1998; 37.1595-1607.
65. Laws A, Reaven GM. Evidence for an independent relationship between insulin resistance and fasting plasma HDL-cholesterol, triglyceride and insulin concentrations. J Intern Med 1991; 231:25-30
66. Vakkilainen J, Porkka KVK, Nuotio I, Pajukanta P, Suurinkeroinen L, Ylitalo K, et al., for the EUFAM study group. Glucose intolerance in familial combined hyperlipidemia Eur J Clin Invest 1998: 24-33.
67. Porkka KVK, Nuotio I, Pajukanta P, Ehnholm C, Suurinkeroinen L, Syvanne M, et al. Phenotype expression in familial combined hyperlipidemia. Arteriosclerosis 1997; 133.245-253.
68. Baier LJ, Wiedrich C, Dobberfuhl A, Traurig M, Thuillez P, Bogardus C, Hanson R. Sequence analysis of candidate genes in a region of chromosome 1 linked to type 2 diabetes. Diabetes 1998; 47:A171
69. Elbein SC, Yount PA, Teng K, Hasstedt SJ. Genome-wide search for type 2 diabetes susceptibility genes in Caucasians. evidence for a recessive locus on chromsome 1 Diabetes 1998; 47:A15
70. Cianflone KM, Maslowska MD, Sniderman AD. Impaired response of fibroblasts from patients with hyperapobetalipoproteinemia to acylation stimulation protein J Clin Invest 1990; 85 722-730.
71. Kwiterovich PO, Motevalli M Inhibition of protein tyrosine kinase alters the effect of serum basic protein I on triacylglycerols and cholesterol differently in normal and hyperapoB fibroblasts. Arterioscler Thromb Vasc Biol 1995; 15. 1195-1203.
72. Kwiterovich PO, Motevali M Differential effect of genistein on the stimulation of cholesterol production by basic protein II in normal hyperapoB fibroblasts. Arterioscler Thromb vase Biol 1997, 18:67-64
73. Motevalli M, Goldschmidt-Clermont PJ, Virgil D, Kwiterovich PO Abnormal protein tyrosine phosphorylation in fibroblasts from hyperapobetalipoproteinemia subjects. J Biol Chem 1997; 272:24702-23709. This study provides further evidence for abnormal protein-tyrosine kinase phosphorylation in individuals with hyperapoB, a trait which overlaps in etiology with FCHL. In particular, tyrosine phosphorylated Erk-2, a mitogen-activated protein kinase, appeared significantly decreased in hyperapoB cells. The authors speculate that there may be a possible link between atherosclerotic changes in hyperapoB patients and growth regulation involving mitogen-activated protein kinase signaling pathways.
74. Magana MM, Osborne TF. Two tandem binding sites for sterol regulatory element binding proteins are required for sterol regulation of fatty-acid synthase promoter. J Biol Chem 1996, 271:32689-32694
75. Ericsson J, Jackson SM, Kim JB, Spiegelman BM, Edwards PA. Identification of glycerol-3-phosphate acyltransferase as an adipocyte determination and differentiation factor-1 and sterol regulatory element binding protein responsive gene. J Biol Chem 1997; 272:7298-7305.
76. Blangero J, Almasy L SOLAR: sequential oligogenic linkage analysis routines: technical notes. San Antonio, TX: Population Genetics Laboratory, Southwest Foundation for Biomedical Research; 1996
77. Comuzzie AG, Hixson JE, Almasy L, Mitchell BD, Mahaney MC, Dyer TD, et al. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nature Genet 1997; 15:273-276