Advertisement

Localization of genes that control LDL size fractions in baboons

  • David L Rainwater
    Correspondence
    Corresponding author. Tel.: +1-210-258-9531; fax: +1-210-670-3317
    Affiliations
    Department of Genetics, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245-0549, USA
    Search for articles by this author
  • Candace M Kammerer
    Affiliations
    Department of Physiology and Medicine, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245-0549, USA

    Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Search for articles by this author
  • Michael C Mahaney
    Affiliations
    Department of Genetics, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245-0549, USA
    Search for articles by this author
  • Jeffrey Rogers
    Affiliations
    Department of Genetics, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245-0549, USA

    Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245-0549, USA
    Search for articles by this author
  • Laura A Cox
    Affiliations
    Department of Genetics, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245-0549, USA
    Search for articles by this author
  • Jennifer L Schneider
    Affiliations
    Department of Genetics, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245-0549, USA
    Search for articles by this author
  • John L VandeBerg
    Affiliations
    Department of Genetics, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245-0549, USA

    Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245-0549, USA
    Search for articles by this author

      Abstract

      LDL phenotypes are strongly associated with risk of cardiovascular disease and are heritable, although little is known about individual genes that influence them. We investigated genetic control of LDL size-related phenotypes in 634 pedigreed baboons fed three diets contrasting in levels of fat and cholesterol. On a high-cholesterol high-fat diet, we obtained significant evidence for a quantitative trait locus (QTL) for cholesterol concentrations of lipoproteins between 27 and 28 nm (LOD=4.22, genomic P=0.0047) on the baboon homologue of human chromosome 22. For baboons fed a low-cholesterol high-fat diet, we obtained suggestive evidence for a QTL for cholesterol concentrations between 26 and 27 nm (LOD=2.67) on the baboon homologue of human chromosome 5. We speculate that this QTL influences LDL size distributions because LDL median diameters and other LDL fractions also showed peak LOD scores in this same chromosomal region. On a low-cholesterol low-fat basal diet we obtained suggestive evidence for a QTL for cholesterol concentrations of lipoproteins between 26 and 27 nm in diameter (LOD=2.15) on the baboon homologue of human chromosome 16. Thus, we have evidence for three putative QTLs that influence variation in baboon LDL size phenotypes on different diets.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Gardner C.D
        • Fortmann S.P
        • Krauss R.M
        Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.
        JAMA. 1996; 276: 875-881
        • Stampfer M.J
        • Krauss R.M
        • Ma J
        • Blanche P.J
        • Holl L.G
        • Sacks F.M
        • et al.
        A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.
        JAMA. 1996; 276: 882-888
        • Lamarche B
        • Tchernof A
        • Moorjani S
        • Cantin B
        • Dagenais G.R
        • Lupien P.J
        • et al.
        Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study.
        Circulation. 1997; 95: 69-75
        • Austin M.A
        Genetic epidemiology of low-density lipoprotein subclass phenotypes.
        Ann. Med. 1992; 24: 477-481
        • Austin M.A
        • Edwards K.L
        Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes.
        Curr. Opin. Lipidol. 1996; 7: 167-171
        • Grundy S.M
        Small LDL, atherogenic dyslipidemia, and the metabolic syndrome.
        Circulation. 1997; 95: 1-4
        • Brewer Jr, H.B
        Hypertriglyceridemia: changes in the plasma lipoproteins associated with an increased risk of cardiovascular disease.
        Am. J. Cardiol. 1999; 83: 3F-12F
        • Hasstedt S.J
        • Wu L
        • Williams R.R
        Major locus inheritance of apolipoprotein B in Utah pedigrees.
        Genet. Epidemiol. 1987; 4: 67-76
        • Pairitz G
        • Davignon J
        • Mailloux H
        • Sing C.F
        Sources of interindividual variation in the quantitative levels of apolipoprotein B in pedigrees ascertained through a lipid clinic.
        Am. J. Hum. Genet. 1988; 43: 311-321
        • Juo S.H
        • Beaty T.H
        • Kwiterovich Jr, P.O
        Etiologic heterogeneity of hyperapobetalipoproteinemia (hyperapoB). Results from segregation analysis in families with premature coronary artery disease.
        Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2729-2736
        • Coon H
        • Leppert M.F
        • Kronenberg F
        • Province M.A
        • Myers R.H
        • Arnett D.K
        • et al.
        Evidence for a major gene accounting for mild elevation in LDL cholesterol: the NHLBI family heart study.
        Ann. Hum. Genet. 1999; 63: 401-412
        • 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; 43: 838-846
        • De Graaf J
        • Swinkels D.W
        • De Haan A.F.J
        • Demacker P.N.M
        • Stalenhoef A.F.H
        Both inherited susceptibility and environmental exposure determine the low-density lipoprotein-subfraction pattern distribution in healthy Dutch families.
        Am. J. Hum. Genet. 1992; 51: 1295-1310
        • Austin M.A
        • Jarvik G.P
        • Hokanson J.E
        • Edwards K
        Complex segregation analysis of LDL peak particle diameter.
        Genet. Epidemiol. 1993; 10: 599-604
        • Friedlander Y
        • Kark J.D
        • Sinnreich R
        • Edwards K.L
        • Austin M.A
        Inheritance of LDL peak particle diameter: results from a segregation analysis in Israeli families.
        Genet. Epidemiol. 1999; 16: 382-396
        • Austin M.A
        • Stephens K
        • Walden C.E
        • Wijsman E
        Linkage analysis of candidate genes and the small, dense low-density lipoprotein phenotype.
        Atherosclerosis. 1999; 142: 79-87
        • 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. USA. 1992; 89: 708-712
        • Rotter J.I
        • Bu X
        • Cantor R.M
        • Warden C.H
        • Brown J
        • Gray R.J
        • et al.
        Multilocus genetic determinants of LDL particle size in coronary artery disease families.
        Am. J. Hum. Genet. 1996; 58: 585-594
        • Austin M.A
        • Talmud P.J
        • Luong L.-A
        • Haddad L
        • Day I.N.M
        • 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
        • Allayee H
        • Aouizerat B.E
        • Cantor R.M
        • Dallinga-Thie G.M
        • Krauss R.M
        • Lanning C.D
        • et al.
        Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype.
        Am. J. Hum. Genet. 1998; 63: 577-585
        • Rainwater D.L
        • Almasy L
        • Blangero J
        • Cole S.A
        • VandeBerg J.L
        • MacCluer J.W
        • et al.
        A genome search identifies major quantitative trait loci on human chromosomes 3 and 4 that influence cholesterol concentrations in small LDL particles.
        Arterioscler. Thromb. Vasc. Biol. 1999; 19: 777-783
        • Allayee H
        • Dominguez K.M
        • Aouizerat B.E
        • Krauss R.M
        • Rotter J.I
        • Lu J
        • et al.
        Contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype in familial combined hyperlipidemia.
        J. Lipid Res. 2000; 41: 245-252
        • Talmud P.J
        • Edwards K.L
        • Turner C.M
        • Newman B
        • Palmen J.M
        • Humphries S.E
        • et al.
        Linkage of the cholesteryl ester transfer protein (CETP) gene to LDL particle size: use of a novel tetranucleotide repeat within the CETP promoter.
        Circulation. 2000; 101: 2461-2466
        • Rainwater D.L
        • Kammerer C.M
        • Hixson J.E
        • Carey K.D
        • Rice K.S
        • Dyke B
        • et al.
        Two major loci control variation in β-lipoprotein cholesterol and response to dietary fat and cholesterol in baboons.
        Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1061-1068
        • Kammerer C.M
        • Rainwater D.L
        • Cox L.A
        • Schneider J.L
        • Mahaney M.C
        • Rogers J
        • VandeBerg J.L
        Locus controlling LDL cholesterol response to dietary cholesterol is on baboon homologue of human chromosome 6.
        Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1720-1725
        • Singh A.T.K
        • Rainwater D.L
        • Kammerer C.M
        • Sharp R.M
        • Poushesh M
        • Shelledy W.R
        • et al.
        Dietary and genetic effects on LDL size measures in baboons.
        Arterioscler. Thromb. Vasc. Biol. 1996; 16: 1448-1453
        • Cheng M.-L
        • Woodford S.C
        • Hilburn J.L
        • VandeBerg J.L
        A novel system for storage of sera frozen in small aliquots.
        J. Biochem. Biophys. Methods. 1986; 13: 47-51
        • Allain C.C
        • Poon L.S
        • Chan C.S.G
        • Richmond W
        • Fu P.C
        Enzymatic determination of total serum cholesterol.
        Clin. Chem. 1974; 20: 470-475
      1. Lipid Research Clinics Program. Manual of Laboratory Operations. Volume 1: Lipid and Lipoprotein Analysis. (DHEW Publ. No. (NIH) 75–628). US Government Printing Office: Washington D.C., 1974. p. 56.

        • Cheng M.-L
        • Kammerer C.M
        • Lowe W.F
        • Dyke B
        • VandeBerg J.L
        Method for quantitating cholesterol in subfractions of serum lipoproteins separated by gradient gel electrophoresis.
        Biochem. Genet. 1988; 26: 657-681
        • Rainwater D.L
        • Moore Jr., P.H
        • Shelledy W.R
        • Dyer T.D
        • Slifer S.H
        Characterization of a composite gradient gel for the electrophoretic separation of lipoproteins.
        J. Lipid Res. 1997; 38: 1261-1266
        • Singh A.T.K
        • Rainwater D.L
        • Haffner S.M
        • VandeBerg J.L
        • Shelledy W.R
        • Moore Jr., P.H
        • et al.
        Effect of diabetes on lipoprotein size.
        Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1805-1811
        • Schjeide O.A
        • Rivin A.U
        • Yoshino J
        Uptake of lipid stains by lipids and serum lipoproteins.
        Am. J. Clin. Pathol. 1963; 39: 329-341
        • Callais F
        • Roche D
        • Andreux J.P
        Value of polyacrylamide gradient gel electrophoresis of lipoproteins for determining HDL cholesterol.
        Clin. Chem. 1987; 33: 1266
        • Gambert P
        • Farnier M
        • Bouzerand C
        • Athias A
        • Lallemant C
        Direct quantitation of serum high density lipoprotein subfractions separated by gradient gel electrophoresis.
        Clin. Chim. Acta. 1988; 172: 183-190
        • Bojanovski D
        • Alaupovic P
        • Kelley J.L
        • Stout C
        Isolation and characterization of the major lipoprotein density classes of normal and diabetic baboon (Papio anubis) plasma.
        Atherosclerosis. 1978; 31: 481-487
        • Rogers J
        • Mahaney M.C
        • Witte S.M
        • Nair S
        • Newman D
        • Wedel S
        • et al.
        A genetic linkage map of the baboon (Papio hamadryas) genome based on human microsatellite polymorphisms.
        Genomics. 2000; 67: 237-247
        • Lange K
        • Weeks D
        • Boehnke M
        Programs for pedigree analysis: MENDEL, FISHER, and dGENE.
        Genet. Epidemiol. 1988; 5: 471-472
        • Hasstedt S.J
        Variance components/major locus likelihood approximation for quantitative, polychotomous, and multivariate data.
        Genet. Epidemiol. 1993; 10: 145-158
        • Mahaney M.C
        • Blangero J
        • Comuzzie A.G
        • VandeBerg J.L
        • Stern M.P
        • MacCluer J.W
        Plasma HDL cholesterol, triglycerides, and adiposity. A quantitative genetic test of the conjoint trait hypothesis in the San Antonio Family Heart Study.
        Circulation. 1995; 92: 3240-3248
        • Almasy L
        • Blangero J
        Multipoint quantitative-trait linkage analysis in general pedigrees.
        Am. J. Hum. Genet. 1998; 62: 1198-1211
        • Allison D.B
        • Neale M.C
        • Zannolli R
        • Schork N.J
        • Amos C.I
        • Blangero J
        Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure.
        Am. J. Hum. Genet. 1999; 65: 531-544
        • Blangero J
        • Williams J.T
        • Almasy L
        Variance component methods for detecting complex trait loci.
        Adv. Genet. 2001; 42: 151-181
        • Lander E
        • Kruglyak L
        Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.
        Nature Genet. 1995; 11: 241-247
        • Martin L.J
        • Mahaney M.C
        • Almasy L
        • Hixson J.E
        • Cole S.A
        • MacCluer J.W
        • et al.
        A quantitative trait locus on chromosome 22 for serum leptin levels adjusted for serum testosterone.
        Obes. Res. 2002; 10: 602-607
        • Williams P.T
        • Krauss R.M
        Associations of age, adiposity, menopause, and alcohol intake with low-density lipoprotein subclasses.
        Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1082-1090
        • Rainwater D.L
        • Mitchell B.D
        • Comuzzie A.G
        • Haffner S.M
        Relationship of low-density lipoprotein particle size and measures of adiposity.
        Int. J. Obes. Relat. Metab. Disord. 1999; 23: 180-189
        • Clifton P.M
        • Noakes M
        • Nestel P.J
        LDL particle size and LDL and HDL cholesterol changes with dietary fat and cholesterol in healthy subjects.
        J. Lipid Res. 1998; 39: 1799-1804
        • Comuzzie A.G
        • Funahashi T
        • Sonnenberg G
        • Martin L.J
        • Jacob H.J
        • Black A.E
        • et al.
        The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome.
        J. Clin. Endocrinol. Metab. 2001; 86: 4321-4325
        • Peacock J.M
        • Arnet D.K
        • Atwood L.D
        • Myers R.H
        • Coon H
        • Rich S.S
        • et al.
        Genome scan for quantitative trait loci linked to high-density lipoprotein cholesterol: the NHLBI Family Heart Study.
        Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1823-1828
        • Coon H
        • Leppert M.F
        • Eckfeldt J.H
        • Oberman A
        • Myers R.H
        • Peacock J.M
        • et al.
        Genome-wide linkage analysis of lipids in the Hypertension Genetic Epidemiology Network (HyperGEN) Blood Pressure Study.
        Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1969-1976
        • Mehrabian M
        • Callaway K.A
        • Clarke C.F
        • Tanaka R.D
        • Greenspan M
        • Lusis A.J
        • et al.
        Regulation of rat liver 3-hydroxy-3-methylglutaryl coenzyme A synthase and the chromosomal localization of the human gene.
        J. Biol. Chem. 1986; 261: 16249-16255
        • Hixson J.E
        • Borenstein S
        • Cox L.A
        PvuII RFLP for the lecithin-cholesterol acyltransferase gene (LCAT) in baboons.
        Nucleic Acids Res. 1990; 18: 384
        • Rainwater D.L
        • Blangero J
        • Hixson J.E
        • Birnbaum S
        • Mott G.E
        • VandeBerg J.L
        A DNA polymorphism for LCAT is associated with altered LCAT activity and high density lipoprotein size distributions in baboons.
        Arterioscler. Thromb. 1992; 12: 682-690
        • Ohta T
        • Saku K
        • Takata K
        • Nagata N
        • Maung K.K
        • Matsuda I
        Fractional esterification rate of cholesterol in high density lipoprotein (HDL) can predict the particle size of low density lipoprotein and HDL in patients with coronary heart disease.
        Atherosclerosis. 1997; 135: 205-212