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. 1996 Mar;58(3):585–594.

Multilocus genetic determinants of LDL particle size in coronary artery disease families.

J I Rotter 1, X Bu 1, R M Cantor 1, C H Warden 1, J Brown 1, R J Gray 1, P J Blanche 1, R M Krauss 1, A J Lusis 1
PMCID: PMC1914567  PMID: 8644718

Abstract

Recent interest in atherosclerosis has focused on the genetic determinants of low-density lipoprotein (LDL) particle size, because of (i) the association of small dense LDL particles with a three-fold increased risk for coronary artery disease (CAD) and (ii) the recent report of linkage of the trait to the LDL receptor (chromosome 19). By utilizing nonparametric quantitative sib-pair and relative-pair analysis methods in CAD families, we tested for linkage of a gene or genes controlling LDL particle sizes with the genetic loci for the major apolipoproteins and enzymes participating in lipoprotein metabolism. We confirmed evidence for linkage to the LDL receptor locus (P=.008). For six candidate gene loci, including apolipoprotein(apo)B, apoAII, apo(a), apoE-CI-CII, lipoprotein lipase, and high-density lipoprotein-binding protein, no evidence for linkage was observed by sib-pair linkage analyses (P values ranged from .24 to .81). However, in addition, we did find tentative evidence for linkage with the apoAI-CIII-AIV locus (chromosome 11) (P=.06) and significant evidence for linkage of the cholesteryl ester transfer protein locus (chromosome 16) (P=.01) and the manganese superoxide dismutase locus (chromosome 6) (P=.001), thus indicating multilocus determination of this atherogenic trait.

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Selected References

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  1. Adams G. H., Schumaker V. N. Polydispersity of human low-density lipoproteins. Ann N Y Acad Sci. 1969 Nov 7;164(1):130–146. doi: 10.1111/j.1749-6632.1969.tb14036.x. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. 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]
  4. 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]
  5. Austin M. A. Genetic epidemiology of low-density lipoprotein subclass phenotypes. Ann Med. 1992 Dec;24(6):477–481. doi: 10.3109/07853899209166999. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. Austin M. A., Newman B., Selby J. V., Edwards K., Mayer E. J., Krauss R. M. Genetics of LDL subclass phenotypes in women twins. Concordance, heritability, and commingling analysis. Arterioscler Thromb. 1993 May;13(5):687–695. doi: 10.1161/01.atv.13.5.687. [DOI] [PubMed] [Google Scholar]
  9. Barakat H. A., Carpenter J. W., McLendon V. D., Khazanie P., Leggett N., Heath J., Marks R. Influence of obesity, impaired glucose tolerance, and NIDDM on LDL structure and composition. Possible link between hyperinsulinemia and atherosclerosis. Diabetes. 1990 Dec;39(12):1527–1533. doi: 10.2337/diab.39.12.1527. [DOI] [PubMed] [Google Scholar]
  10. Boerwinkle E., Xiong W. J., Fourest E., Chan L. Rapid typing of tandemly repeated hypervariable loci by the polymerase chain reaction: application to the apolipoprotein B 3' hypervariable region. Proc Natl Acad Sci U S A. 1989 Jan;86(1):212–216. doi: 10.1073/pnas.86.1.212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Brown M. S., Goldstein J. L. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986 Apr 4;232(4746):34–47. doi: 10.1126/science.3513311. [DOI] [PubMed] [Google Scholar]
  12. Brown W. V., Baginsky M. L. Inhibition of lipoprotein lipase by an apoprotein of human very low density lipoprotein. Biochem Biophys Res Commun. 1972 Jan 31;46(2):375–382. doi: 10.1016/s0006-291x(72)80149-9. [DOI] [PubMed] [Google Scholar]
  13. Bu X., Warden C. H., Xia Y. R., De Meester C., Puppione D. L., Teruya S., Lokensgard B., Daneshmand S., Brown J., Gray R. J. Linkage analysis of the genetic determinants of high density lipoprotein concentrations and composition: evidence for involvement of the apolipoprotein A-II and cholesteryl ester transfer protein loci. Hum Genet. 1994 Jun;93(6):639–648. doi: 10.1007/BF00201563. [DOI] [PubMed] [Google Scholar]
  14. Campos H., Blijlevens E., McNamara J. R., Ordovas J. M., Posner B. M., Wilson P. W., Castelli W. P., Schaefer E. J. LDL particle size distribution. Results from the Framingham Offspring Study. Arterioscler Thromb. 1992 Dec;12(12):1410–1419. doi: 10.1161/01.atv.12.12.1410. [DOI] [PubMed] [Google Scholar]
  15. Campos H., Genest J. J., Jr, Blijlevens E., McNamara J. R., Jenner J. L., Ordovas J. M., Wilson P. W., Schaefer E. J. Low density lipoprotein particle size and coronary artery disease. Arterioscler Thromb. 1992 Feb;12(2):187–195. doi: 10.1161/01.atv.12.2.187. [DOI] [PubMed] [Google Scholar]
  16. Campos H., Willett W. C., Peterson R. M., Siles X., Bailey S. M., Wilson P. W., Posner B. M., Ordovas J. M., Schaefer E. J. Nutrient intake comparisons between Framingham and rural and Urban Puriscal, Costa Rica. Associations with lipoproteins, apolipoproteins, and low density lipoprotein particle size. Arterioscler Thromb. 1991 Jul-Aug;11(4):1089–1099. doi: 10.1161/01.atv.11.4.1089. [DOI] [PubMed] [Google Scholar]
  17. Castelli W. P., Garrison R. J., Wilson P. W., Abbott R. D., Kalousdian S., Kannel W. B. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA. 1986 Nov 28;256(20):2835–2838. [PubMed] [Google Scholar]
  18. Dammerman M., Sandkuijl L. A., Halaas J. L., Chung W., Breslow J. L. An apolipoprotein CIII haplotype protective against hypertriglyceridemia is specified by promoter and 3' untranslated region polymorphisms. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4562–4566. doi: 10.1073/pnas.90.10.4562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Drayna D., Lawn R. Multiple RFLPs at the human cholesteryl ester transfer protein (CETP) locus. Nucleic Acids Res. 1987 Jun 11;15(11):4698–4698. doi: 10.1093/nar/15.11.4698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Dreon D. M., Fernstrom H. A., Miller B., Krauss R. M. Low-density lipoprotein subclass patterns and lipoprotein response to a reduced-fat diet in men. FASEB J. 1994 Jan;8(1):121–126. [PubMed] [Google Scholar]
  21. Feingold K. R., Grunfeld C., Pang M., Doerrler W., Krauss R. M. LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes. Arterioscler Thromb. 1992 Dec;12(12):1496–1502. doi: 10.1161/01.atv.12.12.1496. [DOI] [PubMed] [Google Scholar]
  22. Fisher W. R., Hammond M. G., Mengel M. C., Warmke G. L. A genetic determinant of the phenotypic variance of the molecular weight of low density lipoprotein. Proc Natl Acad Sci U S A. 1975 Jun;72(6):2347–2351. doi: 10.1073/pnas.72.6.2347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Heiba I. M., DeMeester C. A., Xia Y. R., Diep A., George V. T., Amos C. I., Srinivasan S. R., Berenson G. S., Elston R. C., Lusis A. J. Genetic contributions to quantitative lipoprotein traits associated with coronary artery disease: analysis of a large pedigree from the Bogalusa Heart Study. Am J Med Genet. 1993 Nov 1;47(6):875–883. doi: 10.1002/ajmg.1320470615. [DOI] [PubMed] [Google Scholar]
  25. Heinzmann C., Ladias J., Antonarakis S., Diep A., Schotz M., Lusis A. J. Two polymorphisms for the human hepatic lipase (HL) gene. Nucleic Acids Res. 1988 May 25;16(10):4739–4739. doi: 10.1093/nar/16.10.4739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hudson T. J., Engelstein M., Lee M. K., Ho E. C., Rubenfield M. J., Adams C. P., Housman D. E., Dracopoli N. C. Isolation and chromosomal assignment of 100 highly informative human simple sequence repeat polymorphisms. Genomics. 1992 Jul;13(3):622–629. doi: 10.1016/0888-7543(92)90133-d. [DOI] [PubMed] [Google Scholar]
  27. Ito Y., Azrolan N., O'Connell A., Walsh A., Breslow J. L. Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. Science. 1990 Aug 17;249(4970):790–793. doi: 10.1126/science.2167514. [DOI] [PubMed] [Google Scholar]
  28. Jiao S., Cole T. G., Kitchens R. T., Pfleger B., Schonfeld G. Genetic heterogeneity of plasma lipoproteins in the mouse: control of low density lipoprotein particle sizes by genetic factors. J Lipid Res. 1990 Mar;31(3):467–477. [PubMed] [Google Scholar]
  29. Kamboh M. I., Hamman R. F., Iyengar S., Aston C. E., Ferrell R. E. Apolipoprotein A-IV polymorphism, and its role in determining variation in lipoprotein-lipid, glucose and insulin levels in normal and non-insulin-dependent diabetic individuals. Atherosclerosis. 1991 Nov;91(1-2):25–34. doi: 10.1016/0021-9150(91)90184-5. [DOI] [PubMed] [Google Scholar]
  30. Kannel W. B., Castelli W. P., Gordon T., McNamara P. M. Serum cholesterol, lipoproteins, and the risk of coronary heart disease. The Framingham study. Ann Intern Med. 1971 Jan;74(1):1–12. doi: 10.7326/0003-4819-74-1-1. [DOI] [PubMed] [Google Scholar]
  31. Kondo I., Berg K., Drayna D., Lawn R. DNA polymorphism at the locus for human cholesteryl ester transfer protein (CETP) is associated with high density lipoprotein cholesterol and apolipoprotein levels. Clin Genet. 1989 Jan;35(1):49–56. doi: 10.1111/j.1399-0004.1989.tb02904.x. [DOI] [PubMed] [Google Scholar]
  32. Krauss R. M., Burke D. J. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res. 1982 Jan;23(1):97–104. [PubMed] [Google Scholar]
  33. Krauss R. M., Herbert P. N., Levy R. I., Fredrickson D. S. Further observations on the activation and inhibition of lipoprotein lipase by apolipoproteins. Circ Res. 1973 Oct;33(4):403–411. doi: 10.1161/01.res.33.4.403. [DOI] [PubMed] [Google Scholar]
  34. Krauss R. M. Relationship of intermediate and low-density lipoprotein subspecies to risk of coronary artery disease. Am Heart J. 1987 Feb;113(2 Pt 2):578–582. doi: 10.1016/0002-8703(87)90636-3. [DOI] [PubMed] [Google Scholar]
  35. LaBelle M., Austin M. A., Rubin E., Krauss R. M. Linkage analysis of low-density lipoprotein subclass phenotypes and the apolipoprotein B gene. Genet Epidemiol. 1991;8(4):269–275. doi: 10.1002/gepi.1370080407. [DOI] [PubMed] [Google Scholar]
  36. Lagrost L., Gandjini H., Athias A., Guyard-Dangremont V., Lallemant C., Gambert P. Influence of plasma cholesteryl ester transfer activity on the LDL and HDL distribution profiles in normolipidemic subjects. Arterioscler Thromb. 1993 Jun;13(6):815–825. doi: 10.1161/01.atv.13.6.815. [DOI] [PubMed] [Google Scholar]
  37. Lamon-Fava S., Jimenez D., Christian J. C., Fabsitz R. R., Reed T., Carmelli D., Castelli W. P., Ordovas J. M., Wilson P. W., Schaefer E. J. The NHLBI Twin Study: heritability of apolipoprotein A-I, B, and low density lipoprotein subclasses and concordance for lipoprotein(a). Atherosclerosis. 1991 Nov;91(1-2):97–106. doi: 10.1016/0021-9150(91)90191-5. [DOI] [PubMed] [Google Scholar]
  38. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nakano K., Swindle M. M., Spinale F., Ishihara K., Kanazawa S., Smith A., Biederman R. W., Clamp L., Hamada Y., Zile M. R. Depressed contractile function due to canine mitral regurgitation improves after correction of the volume overload. J Clin Invest. 1991 Jun;87(6):2077–2086. doi: 10.1172/JCI115238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. 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]
  41. Nigon F., Lesnik P., Rouis M., Chapman M. J. Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL receptor. J Lipid Res. 1991 Nov;32(11):1741–1753. [PubMed] [Google Scholar]
  42. 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]
  43. Olson J. M. Some empirical properties of an all-relative-pairs linkage test. Genet Epidemiol. 1994;11(1):41–49. doi: 10.1002/gepi.1370110105. [DOI] [PubMed] [Google Scholar]
  44. Olson J. M., Wijsman E. M. Linkage between quantitative trait and marker loci: methods using all relative pairs. Genet Epidemiol. 1993;10(2):87–102. doi: 10.1002/gepi.1370100202. [DOI] [PubMed] [Google Scholar]
  45. Paul-Hayase H., Rosseneu M., Robinson D., Van Bervliet J. P., Deslypere J. P., Humphries S. E. Polymorphisms in the apolipoprotein (apo) AI-CIII-AIV gene cluster: detection of genetic variation determining plasma apo AI, apo CIII and apo AIV concentrations. Hum Genet. 1992 Feb;88(4):439–446. doi: 10.1007/BF00215679. [DOI] [PubMed] [Google Scholar]
  46. Reaven G. M., Chen Y. D., Jeppesen J., Maheux P., Krauss R. M. Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles. J Clin Invest. 1993 Jul;92(1):141–146. doi: 10.1172/JCI116541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sakai N., Matsuzawa Y., Hirano K., Yamashita S., Nozaki S., Ueyama Y., Kubo M., Tarui S. Detection of two species of low density lipoprotein particles in cholesteryl ester transfer protein deficiency. Arterioscler Thromb. 1991 Jan-Feb;11(1):71–79. doi: 10.1161/01.atv.11.1.71. [DOI] [PubMed] [Google Scholar]
  48. Selby J. V., Austin M. A., Newman B., Zhang D., Quesenberry C. P., Jr, Mayer E. J., Krauss R. M. LDL subclass phenotypes and the insulin resistance syndrome in women. Circulation. 1993 Aug;88(2):381–387. doi: 10.1161/01.cir.88.2.381. [DOI] [PubMed] [Google Scholar]
  49. Shen M. M., Krauss R. M., Lindgren F. T., Forte T. M. Heterogeneity of serum low density lipoproteins in normal human subjects. J Lipid Res. 1981 Feb;22(2):236–244. [PubMed] [Google Scholar]
  50. Terry R. B., Wood P. D., Haskell W. L., Stefanick M. L., Krauss R. M. Regional adiposity patterns in relation to lipids, lipoprotein cholesterol, and lipoprotein subfraction mass in men. J Clin Endocrinol Metab. 1989 Jan;68(1):191–199. doi: 10.1210/jcem-68-1-191. [DOI] [PubMed] [Google Scholar]
  51. 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]
  52. Tribble D. L., van den Berg J. J., Motchnik P. A., Ames B. N., Lewis D. M., Chait A., Krauss R. M. Oxidative susceptibility of low density lipoprotein subfractions is related to their ubiquinol-10 and alpha-tocopherol content. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1183–1187. doi: 10.1073/pnas.91.3.1183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Tybjaerg-Hansen A., Nordestgaard B. G., Gerdes L. U., Faergeman O., Humphries S. E. Genetic markers in the apo AI-CIII-AIV gene cluster for combined hyperlipidemia, hypertriglyceridemia, and predisposition to atherosclerosis. Atherosclerosis. 1993 May;100(2):157–169. doi: 10.1016/0021-9150(93)90202-6. [DOI] [PubMed] [Google Scholar]
  54. Warden C. H., Daluiski A., Bu X., Purcell-Huynh D. A., De Meester C., Shieh B. H., Puppione D. L., Gray R. M., Reaven G. M., Chen Y. D. Evidence for linkage of the apolipoprotein A-II locus to plasma apolipoprotein A-II and free fatty acid levels in mice and humans. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10886–10890. doi: 10.1073/pnas.90.22.10886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Weber J. L., May P. E. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet. 1989 Mar;44(3):388–396. [PMC free article] [PubMed] [Google Scholar]
  56. Windler E., Havel R. J. Inhibitory effects of C apolipoproteins from rats and humans on the uptake of triglyceride-rich lipoproteins and their remnants by the perfused rat liver. J Lipid Res. 1985 May;26(5):556–565. [PubMed] [Google Scholar]
  57. 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]
  58. Wood S., Schertzer M., Hayden M., Ma Y. Support for founder effect for two lipoprotein lipase (LPL) gene mutations in French Canadians by analysis of GT microsatellites flanking the LPL gene. Hum Genet. 1993 May;91(4):312–316. doi: 10.1007/BF00217348. [DOI] [PubMed] [Google Scholar]
  59. Xia Y. R., Klisak I., Sparkes R. S., Oram J., Lusis A. J. Localization of the gene for high-density lipoprotein binding protein (HDLBP) to human chromosome 2q37. Genomics. 1993 May;16(2):524–525. doi: 10.1006/geno.1993.1221. [DOI] [PubMed] [Google Scholar]
  60. Xiang K., Cox N. J., Hallewell R. A., Bell G. I. Multiple Taq I RFLPs at the human manganese superoxide dismutase (S0D2) locus on chromosome 6. Nucleic Acids Res. 1987 Sep 25;15(18):7654–7654. doi: 10.1093/nar/15.18.7654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. 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]
  62. 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]
  63. de Graaf J., Swinkels D. W., de Haan A. F., Demacker P. N., Stalenhoef A. F. Both inherited susceptibility and environmental exposure determine the low-density lipoprotein-subfraction pattern distribution in healthy Dutch families. Am J Hum Genet. 1992 Dec;51(6):1295–1310. [PMC free article] [PubMed] [Google Scholar]

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