Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 2000 Apr 17;66(6):1845–1856. doi: 10.1086/302945

Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23.

E N Kort 1, D G Ballinger 1, W Ding 1, S C Hunt 1, B R Bowen 1, V Abkevich 1, K Bulka 1, B Campbell 1, C Capener 1, A Gutin 1, K Harshman 1, M McDermott 1, T Thorne 1, H Wang 1, B Wardell 1, J Wong 1, P N Hopkins 1, M Skolnick 1, M Samuels 1
PMCID: PMC1378041  PMID: 10775531

Abstract

Coronary heart disease (CHD) accounts for half of the 1 million deaths annually ascribed to cardiovascular disease and for almost all of the 1.5 million acute myocardial infarctions. Within families affected by early and apparently heritable CHD, dyslipidemias have a much higher prevalence than in the general population; 20%-30% of early familial CHD has been ascribed to primary hypoalphalipoproteinemia (low HDL-C). This study assesses the evidence for linkage of low HDL-C to chromosomal region 11q23 in 105 large Utah pedigrees ascertained with closely related clusters of early CHD and expanded on the basis of dyslipidemia. Linkage analysis was performed by use of 22 STRP markers in a 55-cM region of chromosome 11. Two-point analysis based on a general, dominant-phenotype model yielded LODs of 2.9 for full pedigrees and 3.5 for 167 four-generation split pedigrees. To define a localization region, model optimization was performed using the heterogeneity, multipoint LOD score (mpHLOD). This linkage defines a region on 11q23.3 that is approximately 10 cM distal to-and apparently distinct from-the ApoAI/CIII/AIV gene cluster and thus represents a putative novel localization for the low HDL-C phenotype.

Full Text

The Full Text of this article is available as a PDF (224.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Acton S., Osgood D., Donoghue M., Corella D., Pocovi M., Cenarro A., Mozas P., Keilty J., Squazzo S., Woolf E. A. Association of polymorphisms at the SR-BI gene locus with plasma lipid levels and body mass index in a white population. Arterioscler Thromb Vasc Biol. 1999 Jul;19(7):1734–1743. doi: 10.1161/01.atv.19.7.1734. [DOI] [PubMed] [Google Scholar]
  2. Adams T. D., Hunt S. C., Mason L. A., Ramirez M. E., Fisher A. G., Williams R. R. Familial aggregation of morbid obesity. Obes Res. 1993 Jul;1(4):261–270. doi: 10.1002/j.1550-8528.1993.tb00620.x. [DOI] [PubMed] [Google Scholar]
  3. Almasy L., Hixson J. E., Rainwater D. L., Cole S., Williams J. T., Mahaney M. C., VandeBerg J. L., Stern M. P., MacCluer J. W., Blangero J. Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism. Am J Hum Genet. 1999 Jun;64(6):1686–1693. doi: 10.1086/302425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bodzioch M., Orsó E., Klucken J., Langmann T., Böttcher A., Diederich W., Drobnik W., Barlage S., Büchler C., Porsch-Ozcürümez M. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet. 1999 Aug;22(4):347–351. doi: 10.1038/11914. [DOI] [PubMed] [Google Scholar]
  5. Boright A. P., Connelly P. W., Brunt J. H., Scherer S. W., Tsui L. C., Hegele R. A. Genetic variation in paraoxonase-1 and paraoxonase-2 is associated with variation in plasma lipoproteins in Alberta Hutterites. Atherosclerosis. 1998 Jul;139(1):131–136. doi: 10.1016/s0021-9150(98)00071-9. [DOI] [PubMed] [Google Scholar]
  6. Broman K. W., Murray J. C., Sheffield V. C., White R. L., Weber J. L. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet. 1998 Sep;63(3):861–869. doi: 10.1086/302011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brooks-Wilson A., Marcil M., Clee S. M., Zhang L. H., Roomp K., van Dam M., Yu L., Brewer C., Collins J. A., Molhuizen H. O. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999 Aug;22(4):336–345. doi: 10.1038/11905. [DOI] [PubMed] [Google Scholar]
  8. Brownstein M. J., Carpten J. D., Smith J. R. Modulation of non-templated nucleotide addition by Taq DNA polymerase: primer modifications that facilitate genotyping. Biotechniques. 1996 Jun;20(6):1004-6, 1008-10. doi: 10.2144/96206st01. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Clerget-Darpoux F., Bonaïti-Pellié C., Hochez J. Effects of misspecifying genetic parameters in lod score analysis. Biometrics. 1986 Jun;42(2):393–399. [PubMed] [Google Scholar]
  11. Cohen J. C., Wang Z., Grundy S. M., Stoesz M. R., Guerra R. Variation at the hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation in plasma HDL cholesterol levels. J Clin Invest. 1994 Dec;94(6):2377–2384. doi: 10.1172/JCI117603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Conneally P. M., Edwards J. H., Kidd K. K., Lalouel J. M., Morton N. E., Ott J., White R. Report of the Committee on Methods of Linkage Analysis and Reporting. Cytogenet Cell Genet. 1985;40(1-4):356–359. doi: 10.1159/000132186. [DOI] [PubMed] [Google Scholar]
  13. Connelly P. W., Hegele R. A. Hepatic lipase deficiency. Crit Rev Clin Lab Sci. 1998 Dec;35(6):547–572. doi: 10.1080/10408369891234273. [DOI] [PubMed] [Google Scholar]
  14. Cottingham R. W., Jr, Idury R. M., Schäffer A. A. Faster sequential genetic linkage computations. Am J Hum Genet. 1993 Jul;53(1):252–263. [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
  17. Fisher R. M., Humphries S. E., Talmud P. J. Common variation in the lipoprotein lipase gene: effects on plasma lipids and risk of atherosclerosis. Atherosclerosis. 1997 Dec;135(2):145–159. doi: 10.1016/s0021-9150(97)00199-8. [DOI] [PubMed] [Google Scholar]
  18. Franceschini G., Sirtori C. R., Capurso A., 2nd, Weisgraber K. H., Mahley R. W. A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. J Clin Invest. 1980 Nov;66(5):892–900. doi: 10.1172/JCI109956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Friedlander Y., Kark J. D., Stein Y. Biological and environmental sources of variation in plasma lipids and lipoproteins: the Jerusalem Lipid Research Clinic. Hum Hered. 1986;36(3):143–153. doi: 10.1159/000153618. [DOI] [PubMed] [Google Scholar]
  20. Funke H., von Eckardstein A., Pritchard P. H., Karas M., Albers J. J., Assmann G. A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol-acyltransferase deficiency, and corneal opacities. J Clin Invest. 1991 Jan;87(1):371–376. doi: 10.1172/JCI114997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Genest J. J., Jr, Martin-Munley S. S., McNamara J. R., Ordovas J. M., Jenner J., Myers R. H., Silberman S. R., Wilson P. W., Salem D. N., Schaefer E. J. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation. 1992 Jun;85(6):2025–2033. doi: 10.1161/01.cir.85.6.2025. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Hanson R. L., Ehm M. G., Pettitt D. J., Prochazka M., Thompson D. B., Timberlake D., Foroud T., Kobes S., Baier L., Burns D. K. An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet. 1998 Oct;63(4):1130–1138. doi: 10.1086/302061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Huang W., Sasaki J., Matsunaga A., Nanimatsu H., Moriyama K., Han H., Kugi M., Koga T., Yamaguchi K., Arakawa K. A novel homozygous missense mutation in the apo A-I gene with apo A-I deficiency. Arterioscler Thromb Vasc Biol. 1998 Mar;18(3):389–396. doi: 10.1161/01.atv.18.3.389. [DOI] [PubMed] [Google Scholar]
  25. Hunt S. C., Hasstedt S. J., Kuida H., Stults B. M., Hopkins P. N., Williams R. R. Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in Utah pedigrees and twins. Am J Epidemiol. 1989 Mar;129(3):625–638. doi: 10.1093/oxfordjournals.aje.a115175. [DOI] [PubMed] [Google Scholar]
  26. Kamboh M. I., Bunker C. H., Aston C. E., Nestlerode C. S., McAllister A. E., Ukoli F. A. Genetic association of five apolipoprotein polymorphisms with serum lipoprotein-lipid levels in African blacks. Genet Epidemiol. 1999;16(2):205–222. doi: 10.1002/(SICI)1098-2272(1999)16:2<205::AID-GEPI7>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]
  27. Kaprio J., Ferrell R. E., Kottke B. A., Kamboh M. I., Sing C. F. Effects of polymorphisms in apolipoproteins E, A-IV, and H on quantitative traits related to risk for cardiovascular disease. Arterioscler Thromb. 1991 Sep-Oct;11(5):1330–1348. doi: 10.1161/01.atv.11.5.1330. [DOI] [PubMed] [Google Scholar]
  28. Kuivenhoven J. A., Pritchard H., Hill J., Frohlich J., Assmann G., Kastelein J. The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res. 1997 Feb;38(2):191–205. [PubMed] [Google Scholar]
  29. Lander E. S., Green P. Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2363–2367. doi: 10.1073/pnas.84.8.2363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995 Nov;11(3):241–247. doi: 10.1038/ng1195-241. [DOI] [PubMed] [Google Scholar]
  31. Lathrop G. M., Lalouel J. M. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984 Mar;36(2):460–465. [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Lathrop G. M., Lalouel J. M., White R. L. Construction of human linkage maps: likelihood calculations for multilocus linkage analysis. Genet Epidemiol. 1986;3(1):39–52. doi: 10.1002/gepi.1370030105. [DOI] [PubMed] [Google Scholar]
  34. Lawn R. M., Wade D. P., Garvin M. R., Wang X., Schwartz K., Porter J. G., Seilhamer J. J., Vaughan A. M., Oram J. F. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest. 1999 Oct;104(8):R25–R31. doi: 10.1172/JCI8119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Litt M., Kramer P., Kort E., Fain P., Cox S., Root D., White R., Weissenbach J., Donis-Keller H., Gatti R. The CEPH consortium linkage map of human chromosome 11. Genomics. 1995 May 1;27(1):101–112. doi: 10.1006/geno.1995.1011. [DOI] [PubMed] [Google Scholar]
  36. Mahaney M. C., Blangero J., Rainwater D. L., Comuzzie A. G., VandeBerg J. L., Stern M. P., MacCluer J. W., Hixson J. E. A major locus influencing plasma high-density lipoprotein cholesterol levels in the San Antonio Family Heart Study. Segregation and linkage analyses. Arterioscler Thromb Vasc Biol. 1995 Oct;15(10):1730–1739. doi: 10.1161/01.atv.15.10.1730. [DOI] [PubMed] [Google Scholar]
  37. Nestlerode C. S., Bunker C. H., Sanghera D. K., Aston C. E., Ukoli F. A., Kamboh M. I. Apolipoprotein J polymorphisms and serum HDL cholesterol levels in African blacks. Hum Biol. 1999 Apr;71(2):197–218. [PubMed] [Google Scholar]
  38. O'Connell J. R., Weeks D. E. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet. 1998 Jul;63(1):259–266. doi: 10.1086/301904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ott J. Linkage analysis with misclassification at one locus. Clin Genet. 1977 Aug;12(2):119–124. doi: 10.1111/j.1399-0004.1977.tb00913.x. [DOI] [PubMed] [Google Scholar]
  40. Pajukanta P., Terwilliger J. D., Perola M., Hiekkalinna T., Nuotio I., Ellonen P., Parkkonen M., Hartiala J., Ylitalo K., Pihlajamäki J. 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 May;64(5):1453–1463. doi: 10.1086/302365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Peacock R. E., Hamsten A., Johansson J., Nilsson-Ehle P., Humphries S. E. Associations of genotypes at the apolipoprotein AI-CIII-AIV, apolipoprotein B and lipoprotein lipase gene loci with coronary atherosclerosis and high density lipoprotein subclasses. Clin Genet. 1994 Oct;46(4):273–282. doi: 10.1111/j.1399-0004.1994.tb04159.x. [DOI] [PubMed] [Google Scholar]
  42. Pocovi M., Cenarro A., Civeira F., Torralba M. A., Perez-Calvo J. I., Mozas P., Giraldo P., Giralt M., Myers R. H., Cupples L. A. Beta-glucocerebrosidase gene locus as a link for Gaucher's disease and familial hypo-alpha-lipoproteinaemia. Lancet. 1998 Jun 27;351(9120):1919–1923. doi: 10.1016/S0140-6736(97)09490-7. [DOI] [PubMed] [Google Scholar]
  43. Prenger V. L., Beaty T. H., Kwiterovich P. O. Genetic determination of high-density lipoprotein-cholesterol and apolipoprotein A-1 plasma levels in a family study of cardiac catheterization patients. Am J Hum Genet. 1992 Nov;51(5):1047–1057. [PMC free article] [PubMed] [Google Scholar]
  44. Pérusse L., Després J. P., Tremblay A., Leblanc C., Talbot J., Allard C., Bouchard C. Genetic and environmental determinants of serum lipids and lipoproteins in French Canadian families. Arteriosclerosis. 1989 May-Jun;9(3):308–318. doi: 10.1161/01.atv.9.3.308. [DOI] [PubMed] [Google Scholar]
  45. Risch N., Giuffra L. Model misspecification and multipoint linkage analysis. Hum Hered. 1992;42(1):77–92. doi: 10.1159/000154047. [DOI] [PubMed] [Google Scholar]
  46. Rust S., Rosier M., Funke H., Real J., Amoura Z., Piette J. C., Deleuze J. F., Brewer H. B., Duverger N., Denèfle P. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet. 1999 Aug;22(4):352–355. doi: 10.1038/11921. [DOI] [PubMed] [Google Scholar]
  47. Römling R., von Eckardstein A., Funke H., Motti C., Fragiacomo G. C., Noseda G., Assmann G. A nonsense mutation in the apolipoprotein A-I gene is associated with high-density lipoprotein deficiency and periorbital xanthelasmas. Arterioscler Thromb. 1994 Dec;14(12):1915–1922. doi: 10.1161/01.atv.14.12.1915. [DOI] [PubMed] [Google Scholar]
  48. Schäffer A. A., Gupta S. K., Shriram K., Cottingham R. W., Jr Avoiding recomputation in linkage analysis. Hum Hered. 1994 Jul-Aug;44(4):225–237. doi: 10.1159/000154222. [DOI] [PubMed] [Google Scholar]
  49. Utermann G., Steinmetz A., Paetzold R., Wilk J., Feussner G., Kaffarnik H., Mueller-Eckhardt C., Seidel D., Vogelberg K. H., Zimmer F. Apolipoprotein AIMarburg: studies on two kindreds with a mutant of human apolipoprotein AI. Hum Genet. 1982;61(4):329–337. doi: 10.1007/BF00276597. [DOI] [PubMed] [Google Scholar]
  50. Warnick G. R., Wood P. D. National Cholesterol Education Program recommendations for measurement of high-density lipoprotein cholesterol: executive summary. The National Cholesterol Education Program Working Group on Lipoprotein Measurement. Clin Chem. 1995 Oct;41(10):1427–1433. [PubMed] [Google Scholar]
  51. Wijsman E. M., Brunzell J. D., Jarvik G. P., Austin M. A., Motulsky A. G., Deeb S. S. Evidence against linkage of familial combined hyperlipidemia to the apolipoprotein AI-CIII-AIV gene complex. Arterioscler Thromb Vasc Biol. 1998 Feb;18(2):215–226. doi: 10.1161/01.atv.18.2.215. [DOI] [PubMed] [Google Scholar]
  52. Williams R. R., Hopkins P. N., Hunt S. C., Wu L. L., Hasstedt S. J., Lalouel J. M., Ash K. O., Stults B. M., Kuida H. Population-based frequency of dyslipidemia syndromes in coronary-prone families in Utah. Arch Intern Med. 1990 Mar;150(3):582–588. [PubMed] [Google Scholar]
  53. 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]
  54. Wu L. L., Warnick G. R., Wu J. T., Williams R. R., Lalouel J. M. A rapid micro-scale procedure for determination of the total lipid profile. Clin Chem. 1989 Jul;35(7):1486–1491. [PubMed] [Google Scholar]
  55. Yamakawa-Kobayashi K., Yanagi H., Fukayama H., Hirano C., Shimakura Y., Yamamoto N., Arinami T., Tsuchiya S., Hamaguchi H. Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey. Hum Mol Genet. 1999 Feb;8(2):331–336. doi: 10.1093/hmg/8.2.331. [DOI] [PubMed] [Google Scholar]
  56. Yamashita S., Arai T., Hirano K., Sakai N., Ishigami M., Nakajima N., Matsuzawa Y. Molecular disorders of cholesteryl ester transfer protein. J Atheroscler Thromb. 1996;3(1):1–11. doi: 10.5551/jat1994.3.1. [DOI] [PubMed] [Google Scholar]
  57. von Eckardstein A., Funke H., Henke A., Altland K., Benninghoven A., Assmann G. Apolipoprotein A-I variants. Naturally occurring substitutions of proline residues affect plasma concentration of apolipoprotein A-I. J Clin Invest. 1989 Dec;84(6):1722–1730. doi: 10.1172/JCI114355. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES