Hum Hered 2004;57:80–89

Familial Aggregation and Genome-Wide Linkage Analysis of Carotid Artery Plaque: The NHLBI Family Heart Study

Pankow J.S.a · Heiss G.b · Evans G.W.d · Sholinsky P.e · Province M.A.f · Coon H.g · Ellison R.C.h · Miller M.B.a · Qaqish B.c
aDivision of Epidemiology, University of Minnesota, Minneapolis, Minn., Departments of bEpidemiology and cBiostatistics, University of North Carolina, Chapel Hill, N.C., dDepartment of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, N.C., eEpidemiology and Biometry Program, National Heart, Lung and Blood Institute, Bethesda, Md., fDivision of Biostatistics, Washington University, St. Louis, Mo., gDepartment of Psychiatry, University of Utah, Salt Lake City, Utah, hSection of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Mass., USA
email Corresponding Author

 goto top of outline Key Words

  • Carotid artery plaque
  • Genome-wide scan
  • Heritability
  • Atherosclerosis
  • Linkage analysis

 goto top of outline Abstract

Objective: To evaluate familial and genetic influences on carotid artery plaque, a qualitative marker of the systemic burden of atherosclerosis. Methods: The design was a cross-sectional study of 2,223 members of 525 randomly-ascertained families and 2,514 members of 589 high coronary heart disease (CHD) risk families from 4 U.S. communities. Results: The prevalence of plaque was 33, 36, and 47%, respectively, among probands with 0, 1, and 2 or more first-degree relatives with a history of CHD. There was evidence of sibling aggregation of plaque in random families (OR = 1.89; 95% CI: 1.44, 2.48), but associations were substantially attenuated when adjusted for major cardiovascular disease risk factors. A genome scan with 420 microsatellite markers revealed no regions of significant or suggestive linkage for plaque in 342 affected sibling pairs, although suggestive linkage (LOD score: 2.43) was found on chromosome 2p11.2 (D2S1790) in pairs aged 55 years or younger. Other markers with nominal evidence for linkage (p < 0.05) were found on chromosomes 2p25, 2q24-q32, 6q21-q23, 7p12-p21, 7q11-q21, 8q24, 12q12-q13, 18p11, 21q21 and Xp11, Xq12, and Xq24. Conclusions: There was modest familial aggregation of carotid artery plaque, but a genome-wide scan indicated no regions of significant or suggestive linkage.

Copyright © 2004 S. Karger AG, Basel

 goto top of outline References
  1. Li R, Bensen JT, Hutchinson RG, Province MA, Hertz-Picciotto I, Sprafka JM, Tyroler HA: Family risk score of coronary heart disease (CHD) as a predictor of CHD: the Atherosclerosis Risk in Communities (ARIC) study and the NHLBI family heart study. Genet Epidemiol 2000;18:236–250.
  2. Morrison AC, Fornage M, Liao D, Boerwinkle E: Parental history of stroke predicts subclinical but not clinical stroke: the Atherosclerosis Risk in Communities Study. Stroke 2000;31:2098–2102.
  3. Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U: Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994;330:1041–1046.
  4. Williams RR, Hunt SC, Heiss G, Province MA, Bensen JT, Higgins M, Chamberlain RM, Ware J, Hopkins PN: Usefulness of cardiovascular family history data for population-based preventive medicine and medical research (the Health Family Tree Study and the NHLBI Family Heart Study). Am J Cardiol 2001;87:129–135.

    External Resources

  5. Swan L, Birnie DH, Inglis G, Connell JM, Hillis WS: The determination of carotid intima medial thickness in adults-a population-based twin study. Atherosclerosis 2003;166:137–141.
  6. North KE, MacCluer JW, Devereux RB, Howard BV, Welty TK, Best LG, Lee ET, Fabsitz RR, Roman MJ: Heritability of carotid artery structure and function: The Strong Heart Family Study. Arterioscler Thromb Vasc Biol 2002;22:1698–1703.
  7. Duggirala R, Gonzalez Villalpando C, O’Leary DH, Stern MP, Blangero J: Genetic basis of variation in carotid artery wall thickness. Stroke 1996;27:833–837.
  8. Fox C, Polak JF, Chazaro I, Cupples A, Wolf P, D’Agostino R, O’Donnell CJ: Carotid intimal medial thickness is a heritable phenotype: The Framingham Heart Study. Circulation 2002;105:26.
  9. Lange LA, Bowden DW, Langefeld CD, Wagenknecht LE, Carr JJ, Rich SS, Riley WA, Freedman BI: Heritability of carotid artery intima-medial thickness in type 2 diabetes. Stroke 2002;33:1876–1881.

    External Resources

  10. Zannad F, Visvikis S, Gueguen R, Sass C, Chapet O, Herbeth B, Siest G: Genetics strongly determines the wall thickness of the left and right carotid arteries. Hum Genet 1998;103:183–188.
  11. Peyser PA, Bielak LF, Chu JS, Turner ST, Ellsworth DL, Boerwinkle E, Sheedy PF, 2nd: Heritability of coronary artery calcium quantity measured by electron beam computed tomography in asymptomatic adults. Circulation 2002;106:304–308.

    External Resources

  12. Wagenknecht LE, Bowden DW, Carr JJ, Langefeld CD, Freedman BI, Rich SS: Familial aggregation of coronary artery calcium in families with type 2 diabetes. Diabetes 2001;50:861–866.
  13. O’Donnell CJ, Chazaro I, Wilson PW, Fox C, Hannan MT, Kiel DP, Cupples LA: Evidence for heritability of abdominal aortic calcific deposits in the Framingham Heart Study. Circulation 2002;106:337–341.

    External Resources

  14. Li R, Duncan BB, Metcalf PA, Crouse JR, 3rd, Sharrett AR, Tyroler HA, Barnes R, Heiss G: B-mode-detected carotid artery plaque in a general population. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Stroke 1994;25:2377–2383.
  15. Hillen T, Nieczaj R, Munzberg H, Schaub R, Borchelt M, Steinhagen-Thiessen E: Carotid atherosclerosis, vascular risk profile and mortality in a population-based sample of functionally healthy elderly subjects: the Berlin ageing study. J Intern Med 2000;247:679–688.
  16. Ebrahim S, Papacosta O, Whincup P, Wannamethee G, Walker M, Nicolaides AN, Dhanjil S, Griffin M, Belcaro G, Rumley A, Lowe GD: Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999;30:841–850.
  17. Duncan BB, Metcalf P, Crouse JR 3rd, Li R, Sharrett AR, Tegeler C, Tyroler HA, Heiss G: Risk factors differ for carotid artery plaque with and without acoustic shadowing. Atherosclerosis Risk in Communities Study Investigators. J Neuroimaging 1997;7:28–34.
  18. Bonithon-Kopp C, Touboul PJ, Berr C, Leroux C, Mainard F, Courbon D, Ducimetiere P: Relation of intima-media thickness to atherosclerotic plaques in carotid arteries. The Vascular Aging (EVA) Study. Arterioscler Thromb Vasc Biol 1996;16:310–316.
  19. Zureik M, Touboul PJ, Bonithon-Kopp C, Courbon D, Ruelland I, Ducimetiere P: Differential association of common carotid intima-media thickness and carotid atherosclerotic plaques with parental history of premature death from coronary heart disease : the EVA study. Arterioscler Thromb Vasc Biol 1999;19:366–371.
  20. Hunt KJ, Duggirala R, Goring HH, Williams JT, Almasy L, Blangero J, O’Leary DH, Stern MP: Genetic basis of variation in carotid artery plaque in the San Antonio family heart study. Stroke 2002;33:2775–2780.

    External Resources

  21. Higgins M, Province M, Heiss G, Eckfeldt J, Ellison RC, Folsom AR, Rao DC, Sprafka JM, Williams R: NHLBI Family Heart Study: objectives and design. Am J Epidemiol 1996;143:1219–1228.
  22. Hunt SC, Williams RR, Barlow GK: A comparison of positive family history definitions for defining risk of future disease. J Chronic Dis 1986;39:809–821.
  23. ARIC Investigators: The Atherosclerosis Risk in Communities (ARIC) Study: Design and objectives. Am J Epidemiol 1989;129:687–702.
  24. Riley WA, Barnes RW, Bond MG, Evans GW, Chambless LE, Heiss G: High-resolution B-mode ultrasound reading methods in the Atherosclerosis Risk in Communities (ARIC) cohort. The ARIC Study Group. J Neuroimaging 1991;1:168–172.
  25. Bond MG, Barnes RW, Riley WA, Wilmoth SK, Chambless LE, Howard G, Owens B: High-resolution B-mode ultrasound scanning methods in the Atherosclerosis Risk in Communities Study (ARIC). The ARIC Study Group. J Neuroimaging 1991;1:68–73.
  26. Feitosa MF, Borecki IB, Rich SS, Arnett DK, Sholinsky P, Myers RH, Leppert M, Province MA: Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13:The National Heart, Lung, and Blood Institute Family Heart Study. Am J Hum Genet 2002;70:72–82.
  27. Hinds DA, Risch N: The ASPEX package: affected sib-pair exclusion mapping, ASPEX source code, executables, and documentation are available at, 1999.
  28. Kruglyak L, Lander ES: Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet 1995;57:439–454.
  29. SAS/STAT®User’s Guide. Cary, NC, SAS Institute Inc., 1999.
  30. Hunt SC, Hasstedt SJ, Williams RR: Testing for familial aggregation of a dichotomous trait. Genet Epidemiol 1986;3:299–312.
  31. Liang KY, Beaty TH: Measuring familial aggregation by using odds-ratio regression models. Genet Epidemiol 1991;8:361–370.
  32. Qaqish BF, Liang KY: Marginal models for correlated binary responses with multiple classes and multiple levels of nesting. Biometrics 1992;48:939–950.
  33. Almasy L, Blangero J: Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Gen 1998;62:1198–1211.
  34. Abecasis GR, Cherny SS, Cookson WO, Cardon LR: Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002;30:97–101.
  35. Whittemore AS, Halpern J: A class of tests for linkage using affected pedigree members. Biometrics 1994;50:118–127.
  36. Kong A, Cox NJ: Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 1997;61:1179–1188.
  37. Lander E, Kruglyak L: Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nat Genet 1995;11:241–247.
  38. Hunt KJ, Sharrett AR, Chambless LE, Folsom AR, Evans GW, Heiss G: Acoustic shadowing on B-mode ultrasound of the carotid artery predicts CHD. Ultrasound Med Biol 2001;27:357–365.
  39. Hollander M, Bots ML, Del Sol AI, Koudstaal PJ, Witteman JC, Grobbee DE, Hofman A, Breteler MM: Carotid plaques increase the risk of stroke and subtypes of cerebral infarction in asymptomatic elderly: the Rotterdam study. Circulation 2002;105:2872–2877.

    External Resources

  40. Polak JF, Shemanski L, O’Leary DH, Lefkowitz D, Price TR, Savage PJ, Brant WE, Reid C: Hypoechoic plaque at US of the carotid artery: An independent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study. Radiology 1998;208:649–654.
  41. Hunt KJ, Evans GW, Folsom AR, Sharrett AR, Chambless LE, Tegeler CH, Heiss G: Acoustic shadowing on B-mode ultrasound of the carotid artery predicts ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2001;32:1120–1126.
  42. Bensen JT, Li R, Hutchinson RG, Province MA, Tyroler HA: Family history of coronary heart disease and pre-clinical carotid artery atherosclerosis in African-Americans and whites: The ARIC study: Atherosclerosis Risk in Communities. Genet Epidemiol 1999;16:165–178.
  43. Arad Y, Newstein D, Cadet F, Roth M, Guerci AD: Association of multiple risk factors and insulin resistance with increased prevalence of asymptomatic coronary artery disease by an electron-beam computed tomographic study. Arterioscler Thromb Vasc Biol 2001;21:2051–2058.
  44. Pajukanta P, Cargill M, Viitanen L, Nuotio I, Kareinen A, Perola M, Terwilliger JD, Kempas E, Daly M, Lilja H, Rioux JD, Brettin T, Viikari JS, Ronnemaa T, Laakso M, Lander ES, Peltonen L: Two loci on chromosomes 2 and X for premature coronary heart disease identified in early- and late-settlement populations of Finland. Am J Hum Genet 2000;67:1481–1493.
  45. Lange LA, Lange EM, Bielak LF, Langefeld CD, Kardia SL, Royston P, Turner ST, Sheedy PF, 2nd, Boerwinkle E, Peyser PA: Autosomal genome-wide scan for coronary artery calcification loci in sibships at high risk for hypertension. Arterioscler Thromb Vasc Biol 2002;22:418–423.
  46. Broeckel U, Hengstenberg C, Mayer B, Holmer S, Martin LJ, Comuzzie AG, Blangero J, Nurnberg P, Reis A, Riegger GA, Jacob HJ, Schunkert H: A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nat Genet 2002;30:210–214.
  47. Gretarsdottir S, Sveinbjornsdottir S, Jonsson HH, Jakobsson F, Einarsdottir E, Agnarsson U, Shkolny D, Einarsson G, Gudjonsdottir HM, Valdimarsson EM, Einarsson OB, Thorgeirsson G, Hadzic R, Jonsdottir S, Reynisdottir ST, Bjarnadottir SM, Gudmundsdottir T, Gudlaugsdottir GJ, Gill R, Lindpaintner K, Sainz J, Hannesson HH, Sigurdsson GT, Frigge ML, Kong A, Gudnason V, Stefansson K, Gulcher JR: Localization of a susceptibility gene for common forms of stroke to 5q12. Am J Hum Genet 2002;70:593–603.
  48. Harrap SB, Zammit KS, Wong ZY, Williams FM, Bahlo M, Tonkin AM, Anderson ST: Genome-wide linkage analysis of the acute coronary syndrome suggests a locus on chromosome 2. Arterioscler Thromb Vasc Biol 2002;22:874–878.
  49. Francke S, Manraj M, Lacquemant C, Lecoeur C, Lepretre F, Passa P, Hebe A, Corset L, Yan SL, Lahmidi S, Jankee S, Gunness TK, Ramjuttun US, Balgobin V, Dina C, Froguel P: A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27. Hum Mol Genet 2001;10:2751–2765.
  50. Dale M, Nicklin MJ: Interleukin-1 receptor cluster: gene organization of IL1R2, IL1R1, IL1RL2 (IL-1Rrp2), IL1RL1 (T1/ST2), and IL18R1 (IL-1Rrp) on human chromosome 2q. Genomics 1999;57:177–179.
  51. Strong JP, Malcom GT, McMahan CA, Tracy RE, Newman WP, 3rd, Herderick EE, Cornhill JF: Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study. JAMA 1999;281:727–735.
  52. Tejada C, Strong JP, Montenegro MR, Restrepo C, Solberg LA: Distribution of coronary and aortic atherosclerosis by geographic location, race, and sex. Lab Invest 1968;18:509–526.
  53. Cueto-Garcia L, Restrepo C, Guzman MA, Barrios-del Valle R, Garcia GC, Strong JP: Is atherosclerosis increasing in Mexico City? Mod Pathol 1989;2:295–300.
  54. Newman WP, 3rd, Guzman MA, Strong JP, Tracy RE, Oalmann MC: Secular trends in atherosclerotic lesions: comparison of two studies of autopsied men conducted in different time periods. Mod Pathol 1988;1:109–113.
  55. Bensen JT, Liese AD, Rushing JT, Province M, Folsom AR, Rich SS, Higgins M: Accuracy of proband reported family history: The NHLBI Family Heart Study (FHS). Genet Epidemiol 1999;17:141–150.
  56. Sollberg LA, McGarry PA, Moossy J, Strong JP, Tejada C, Loken AC: Severity of atherosclerosis in cerebral arteries, coronary arteries, and aortas. Ann N Y Acad Sci 1968;149:956–973.
  57. Joakimsen O, Bonaa KH, Stensland-Bugge E: Reproducibility of ultrasound assessment of carotid plaque occurrence, thickness, and morphology. The Tromso Study. Stroke 1997;28:2201–2207.

 goto top of outline Author Contacts

James S. Pankow, PhD, MPH
Division of Epidemiology, University of Minnesota
1300 South Second Street, Suite 300
Minneapolis, MN 55454 (USA)
Tel. +1 612 624 2883, Fax +1 612 624 0315, E-Mail

 goto top of outline Article Information

Received: November 3, 2003
Accepted after revision: January 16, 2004
Number of Print Pages : 10
Number of Figures : 2, Number of Tables : 4, Number of References : 57

 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)
Founded 1950 as Acta Genetica et Statistica Medica by Gunnar Dahlberg; Continued by M. Hauge (1965–1983)

Vol. 57, No. 2, Year 2004 (Cover Date: Released June 2004)

Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information:

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.