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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Aug;63(2):577–585. doi: 10.1086/301983

Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype.

H Allayee 1, B E Aouizerat 1, R M Cantor 1, G M Dallinga-Thie 1, R M Krauss 1, C D Lanning 1, J I Rotter 1, A J Lusis 1, T W de Bruin 1
PMCID: PMC1377323  PMID: 9683614

Abstract

Small, dense LDL particles consistently have been associated with hypertriglyceridemia, premature coronary artery disease (CAD), and familial combined hyperlipidemia (FCH). Previously, we have observed linkage of LDL particle size with four separate candidate-gene loci in a study of families enriched for CAD. These loci contain the genes for manganese superoxide dismutase (MnSOD), on chromosome 6q; for apolipoprotein AI-CIII-AIV, on chromosome 11q; for cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), on chromosome 16q; and for the LDL receptor (LDLR), on chromosome 19p. We have now tested whether these loci also contribute to LDL particle size in families ascertained for FCH. The members of 18 families (481 individuals) were typed for genetic markers at the four loci, and linkage to LDL particle size was assessed by nonparametric sib-pair linkage analysis. The presence of small, dense LDL (pattern B) was much more frequent in the FCH probands (39%) than in the spouse controls (4%). Evidence for linkage was observed at the MnSOD (P=.02), CETP/LCAT (P=.03), and apolipoprotein AI-CIII-AIV loci (P=.005) but not at the LDLR locus. We conclude that there is a genetically based association between FCH and small, dense LDL and that the genetic determinants for LDL particle size are shared, at least in part, among FCH families and the more general population at risk for CAD.

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Selected References

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  1. Amos C. I., Elston R. C., Wilson A. F., Bailey-Wilson J. E. A more powerful robust sib-pair test of linkage for quantitative traits. Genet Epidemiol. 1989;6(3):435–449. doi: 10.1002/gepi.1370060306. [DOI] [PubMed] [Google Scholar]
  2. Austin M. A., Breslow J. L., Hennekens C. H., Buring J. E., Willett W. C., Krauss R. M. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA. 1988 Oct 7;260(13):1917–1921. [PubMed] [Google Scholar]
  3. Austin M. A., Brunzell J. D., Fitch W. L., Krauss R. M. Inheritance of low density lipoprotein subclass patterns in familial combined hyperlipidemia. Arteriosclerosis. 1990 Jul-Aug;10(4):520–530. doi: 10.1161/01.atv.10.4.520. [DOI] [PubMed] [Google Scholar]
  4. Austin M. A., King M. C., Vranizan K. M., Krauss R. M. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation. 1990 Aug;82(2):495–506. doi: 10.1161/01.cir.82.2.495. [DOI] [PubMed] [Google Scholar]
  5. Austin M. A., King M. C., Vranizan K. M., Newman B., Krauss R. M. Inheritance of low-density lipoprotein subclass patterns: results of complex segregation analysis. Am J Hum Genet. 1988 Dec;43(6):838–846. [PMC free article] [PubMed] [Google Scholar]
  6. Bredie S. J., Demacker P. N., Stalenhoef A. F. Metabolic and genetic aspects of familial combined hyperlipidaemia with emphasis on low-density lipoprotein heterogeneity. Eur J Clin Invest. 1997 Oct;27(10):802–811. doi: 10.1046/j.1365-2362.1997.1850734.x. [DOI] [PubMed] [Google Scholar]
  7. Bredie S. J., Kiemeney L. A., de Haan A. F., Demacker P. N., Stalenhoef A. F. Inherited susceptibility determines the distribution of dense low-density lipoprotein subfraction profiles in familial combined hyperlipidemia. Am J Hum Genet. 1996 Apr;58(4):812–822. [PMC free article] [PubMed] [Google Scholar]
  8. 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 Feb;24(2):147–155. [PubMed] [Google Scholar]
  9. Castro Cabezas M., de Bruin T. W., de Valk H. W., Shoulders C. C., Jansen H., Willem Erkelens D. Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating hepatic apolipoprotein B overproduction and insulin resistance. J Clin Invest. 1993 Jul;92(1):160–168. doi: 10.1172/JCI116544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cortner J. A., Coates P. M., Bennett M. J., Cryer D. R., Le N. A. Familial combined hyperlipidaemia: use of stable isotopes to demonstrate overproduction of very low-density lipoprotein apolipoprotein B by the liver. J Inherit Metab Dis. 1991;14(6):915–922. doi: 10.1007/BF01800473. [DOI] [PubMed] [Google Scholar]
  11. 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 Aug;14(8):1233–1249. doi: 10.1161/01.atv.14.8.1233. [DOI] [PubMed] [Google Scholar]
  12. Dallinga-Thie G. M., Bu X. D., van Linde-Sibenius Trip M., Rotter J. I., Lusis A. J., de Bruin T. W. Apolipoprotein A-I/C-III/A-IV gene cluster in familial combined hyperlipidemia: effects on LDL-cholesterol and apolipoproteins B and C-III. J Lipid Res. 1996 Jan;37(1):136–147. [PubMed] [Google Scholar]
  13. Dallinga-Thie G. M., van Linde-Sibenius Trip M., Rotter J. I., Cantor R. M., Bu X., Lusis A. J., de Bruin T. W. Complex genetic contribution of the Apo AI-CIII-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes. J Clin Invest. 1997 Mar 1;99(5):953–961. doi: 10.1172/JCI119260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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 Jul;52(7):1544–1568. doi: 10.1172/JCI107332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Haseman J. K., Elston R. C. The investigation of linkage between a quantitative trait and a marker locus. Behav Genet. 1972 Mar;2(1):3–19. doi: 10.1007/BF01066731. [DOI] [PubMed] [Google Scholar]
  16. 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 Nov;14(11):1687–1694. doi: 10.1161/01.atv.14.11.1687. [DOI] [PubMed] [Google Scholar]
  17. Naggert J. K., Recinos A., 3rd, Lamerdin J. E., Krauss R. M., Nishina P. M. The atherogenic lipoprotein phenotype is not caused by a mutation in the coding region of the low density lipoprotein receptor gene. Clin Genet. 1997 Apr;51(4):236–240. doi: 10.1111/j.1399-0004.1997.tb02461.x. [DOI] [PubMed] [Google Scholar]
  18. Nichols A. V., Krauss R. M., Musliner T. A. Nondenaturing polyacrylamide gradient gel electrophoresis. Methods Enzymol. 1986;128:417–431. doi: 10.1016/0076-6879(86)28084-2. [DOI] [PubMed] [Google Scholar]
  19. Nishina P. M., Johnson J. P., Naggert J. K., Krauss R. M. Linkage of atherogenic lipoprotein phenotype to the low density lipoprotein receptor locus on the short arm of chromosome 19. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):708–712. doi: 10.1073/pnas.89.2.708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rotter J. I., Bu X., Cantor R. M., Warden C. H., Brown J., Gray R. J., Blanche P. J., Krauss R. M., Lusis A. J. Multilocus genetic determinants of LDL particle size in coronary artery disease families. Am J Hum Genet. 1996 Mar;58(3):585–594. [PMC free article] [PubMed] [Google Scholar]
  21. Sakai N., Yamashita S., Hirano K., Menju M., Arai T., Kobayashi K., Ishigami M., Yoshida Y., Hoshino T., Nakajima N. Frequency of exon 15 missense mutation (442D:G) in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic Japanese subjects. Atherosclerosis. 1995 Apr 24;114(2):139–145. doi: 10.1016/0021-9150(94)05477-z. [DOI] [PubMed] [Google Scholar]
  22. Skretting G., Prydz H. An amino acid exchange in exon I of the human lecithin: cholesterol acyltransferase (LCAT) gene is associated with fish eye disease. Biochem Biophys Res Commun. 1992 Jan 31;182(2):583–587. doi: 10.1016/0006-291x(92)91772-i. [DOI] [PubMed] [Google Scholar]
  23. Sniderman A., Shapiro S., Marpole D., Skinner B., Teng B., Kwiterovich P. O., Jr Association of coronary atherosclerosis with hyperapobetalipoproteinemia [increased protein but normal cholesterol levels in human plasma low density (beta) lipoproteins]. Proc Natl Acad Sci U S A. 1980 Jan;77(1):604–608. doi: 10.1073/pnas.77.1.604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Tall A. R. Plasma lipid transfer proteins. J Lipid Res. 1986 Apr;27(4):361–367. [PubMed] [Google Scholar]
  25. Tribble D. L., Holl L. G., Wood P. D., Krauss R. M. Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size. Atherosclerosis. 1992 Apr;93(3):189–199. doi: 10.1016/0021-9150(92)90255-f. [DOI] [PubMed] [Google Scholar]
  26. 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 Jul;13(7):1110–1118. doi: 10.1161/01.atv.13.7.1110. [DOI] [PubMed] [Google Scholar]
  27. Walter M. A., Spillett D. J., Thomas P., Weissenbach J., Goodfellow P. N. A method for constructing radiation hybrid maps of whole genomes. Nat Genet. 1994 May;7(1):22–28. doi: 10.1038/ng0594-22. [DOI] [PubMed] [Google Scholar]
  28. Weinstock P. H., Bisgaier C. L., Hayek T., Aalto-Setala K., Sehayek E., Wu L., Sheiffele P., Merkel M., Essenburg A. D., Breslow J. L. Decreased HDL cholesterol levels but normal lipid absorption, growth, and feeding behavior in apolipoprotein A-IV knockout mice. J Lipid Res. 1997 Sep;38(9):1782–1794. [PubMed] [Google Scholar]
  29. Williams W. R., Lalouel J. M. Complex segregation analysis of hyperlipidemia in a Seattle sample. Hum Hered. 1982;32(1):24–36. doi: 10.1159/000153254. [DOI] [PubMed] [Google Scholar]
  30. Wojciechowski A. P., Farrall M., Cullen P., Wilson T. M., Bayliss J. D., Farren B., Griffin B. A., Caslake M. J., Packard C. J., Shepherd J. Familial combined hyperlipidaemia linked to the apolipoprotein AI-CII-AIV gene cluster on chromosome 11q23-q24. Nature. 1991 Jan 10;349(6305):161–164. doi: 10.1038/349161a0. [DOI] [PubMed] [Google Scholar]
  31. Wong G. H., Elwell J. H., Oberley L. W., Goeddel D. V. Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor. Cell. 1989 Sep 8;58(5):923–931. doi: 10.1016/0092-8674(89)90944-6. [DOI] [PubMed] [Google Scholar]
  32. Zuliani G., Hobbs H. H. Dinucleotide repeat polymorphism at the 3' end of the LDL receptor gene. Nucleic Acids Res. 1990 Jul 25;18(14):4300–4300. doi: 10.1093/nar/18.14.4300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. de Graaf J., Hak-Lemmers H. L., Hectors M. P., Demacker P. N., Hendriks J. C., Stalenhoef A. F. Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects. Arterioscler Thromb. 1991 Mar-Apr;11(2):298–306. doi: 10.1161/01.atv.11.2.298. [DOI] [PubMed] [Google Scholar]

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