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Table of Contents
Vol. 60, No. 2, 2005
Issue release date: 2005
Hum Hered 2005;60:63–72
(DOI:10.1159/000087971)

The Impact of Pedigree Structure on Heritability Estimates for Pulse Pressure in Three Studies

Hsu F.-C.a · Zaccaro D.J.a · Lange L.A.e · Arnett D.K.f · Langefeld C.D.a · Wagenknecht L.E.a · Herrington D.M.b · Beck S.R.a · Freedman B.I.b · Bowden D.W.b, c, d · Rich S.S.a
Departments of aPublic Health Sciences, bInternal Medicine and cBiochemistry, and dCenter for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, N.C., eDepartment of Genetics, School of Medicine, University of North Carolina, Chapel Hill, N.C., fDivision of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minn., USA
email Corresponding Author

Abstract

Objectives: Pulse pressure (PP) is a measure of large artery stiffness and has been shown to be an important predictor of cardiovascular morbidity and mortality. The aims of the present study were to investigate the heritability of PP in three studies, the Diabetes Heart Study (DHS), the Insulin Resistance Atherosclerosis Family Study (IRAS FS), and the NHLBI Family Heart Study (FHS), to estimate the residual heritability after inclusion of a common set of covariates, and to investigate the impact of pedigree structure on estimating heritability. Methods and Results: DHS is primarily a sibling pair nuclear family study design, while both IRAS FS and FHS have large pedigrees. Heritability estimates of log-transformed PP were obtained using variance component models. After adjusting for age, gender, ethnicity/center, height, diabetes status, and mean arterial pressure (MAP), heritability estimates of PP were 0.40 ± 0.08 , 0.22 ± 0.05, and 0.19 ± 0.03 in DHS, IRAS FS, and FHS, respectively. The heritability estimate from DHS was significantly different from both IRAS FS and FHS (both p values <0.05). A random re-sampling technique (modified bootstrap) was used to explore the heritability in the IRAS FS and FHS data when these pedigrees were trimmed to mimic the DHS pedigree structure. The re-sampling method (mimicking a sibling pair nuclear family design in all studies) yielded PP heritability estimates of 0.37, 0.34, and 0.27 in DHS, IRAS FS, and FHS, respectively. There was no significant difference among the heritability estimates from the three studies based on the re-sampling method. Conclusion: We have shown that PP has a moderately heritable component in three different studies. These data illustrate the influence of pedigree structure can have on estimating heritability. Thoughtful comparisons of heritability estimates must consider study design factors such as pedigree structure.


 goto top of outline Key Words

  • Pulse pressure
  • Heritability
  • Pedigree structure
  • Genetics
  • Cardiovascular disease

 goto top of outline Abstract

Objectives: Pulse pressure (PP) is a measure of large artery stiffness and has been shown to be an important predictor of cardiovascular morbidity and mortality. The aims of the present study were to investigate the heritability of PP in three studies, the Diabetes Heart Study (DHS), the Insulin Resistance Atherosclerosis Family Study (IRAS FS), and the NHLBI Family Heart Study (FHS), to estimate the residual heritability after inclusion of a common set of covariates, and to investigate the impact of pedigree structure on estimating heritability. Methods and Results: DHS is primarily a sibling pair nuclear family study design, while both IRAS FS and FHS have large pedigrees. Heritability estimates of log-transformed PP were obtained using variance component models. After adjusting for age, gender, ethnicity/center, height, diabetes status, and mean arterial pressure (MAP), heritability estimates of PP were 0.40 ± 0.08 , 0.22 ± 0.05, and 0.19 ± 0.03 in DHS, IRAS FS, and FHS, respectively. The heritability estimate from DHS was significantly different from both IRAS FS and FHS (both p values <0.05). A random re-sampling technique (modified bootstrap) was used to explore the heritability in the IRAS FS and FHS data when these pedigrees were trimmed to mimic the DHS pedigree structure. The re-sampling method (mimicking a sibling pair nuclear family design in all studies) yielded PP heritability estimates of 0.37, 0.34, and 0.27 in DHS, IRAS FS, and FHS, respectively. There was no significant difference among the heritability estimates from the three studies based on the re-sampling method. Conclusion: We have shown that PP has a moderately heritable component in three different studies. These data illustrate the influence of pedigree structure can have on estimating heritability. Thoughtful comparisons of heritability estimates must consider study design factors such as pedigree structure.

Copyright © 2005 S. Karger AG, Basel


 goto top of outline References
  1. Mitchell GF, Moye LA, Braunwald E, Rouleau JL, Bernstein V, Geltman EM, Flaker GC, Pfeffer MA: Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function. Circulation 1997;96:4254–4260.
  2. Vaccarino V, Berger AK, Abramson J, Black HR, Setaro JF, Davey JA, Krumholz HM: Pulse pressure and risk of cardiovascular events in the systolic hypertension in the elderly program. Am J Cardiol 2001;88:980–986.
  3. Chae CU, Pfeffer MA, Glynn RJ, Mitchell GF, Taylor JO, Hennekens CH: Increased pulse pressure and risk of heart failure in the elderly. JAMA 1999;281:634–639.
  4. Vaccarino V, Holford TR, Krumholz HM: Pulse pressure and risk for myocardial infarction and heart failure in the elderly. J Am Coll Cardiol 2000;36:130–138.
  5. Domanski M, Norman J, Wolz M, Mitchell G, Pfeffer M: Cardiovascular risk assessment using pulse pressure in the first national health and nutrition examination survey (NHANES I). Hypertension 2001;38:793–797.
  6. Levy D, DeStefano AL, Larson MG, O’Donnell CJ, Lifton RP, Gavras H, Cupples LA, Myers RH: Evidence for a gene influencing blood pressure on chromosome 17. Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the Framingham heart study. Hypertension 2000;36:477–483.
  7. Rice T, Rao R, Perusse L, Bouchard C, Rao DC: Tracking of familial resemblance for resting blood pressure over time in the Quebec Family Study. Hum Biol 2000;72:415–431.
  8. Adeyemo AA, Omotade OO, Rotimi CN, Luke AH, Tayo BO, Cooper RS: Heritability of blood pressure in Nigerian families. J Hypertens 2002;20:859–863.
  9. Snieder H, Harshfield GA, Treiber FA: Heritability of blood pressure and hemodynamics in African- and European-American youth. Hypertension 2003;41:1196–1201.
  10. Atwood LD, Samollow PB, Hixson JE, Stern MP, MacCluer JW: Genome-wide linkage analysis of pulse pressure in Mexican Americans. Hypertension 2001;37:425–428.
  11. Sham P: Statistics in human genetics. New York, John Wiley & Sons, 1998.
  12. Blangero J: Multivariate oligogenic linkage analysis of quantitative traits in general pedigrees. Am J Hum Genet 1995;57:A11.
  13. Wijsman EM, Amos CI: Genetic analysis of simulated oligogenic traits in nuclear and extended pedigrees: summary of GAW10 contributions. Genet Epidemiol 1997;14:719–735.
  14. Williams JT, Duggirala R, Blangero J: Statistical properties of a variance components method for quantitative trait linkage analysis in nuclear families and extended pedigrees. Genet Epidemiol 1997;14:1065–1070.
  15. Xiang AH, Azen SP, Buchanan TA, Raffel LJ, Tan S, Cheng LS, Diaz J, Toscano E, Quinonnes M, Liu CR, Liu CH, Castellani LW, Hsueh WA, Rotter JI, Hodis HN: Heritability of subclinical atherosclerosis in Latino families ascertained through a hypertensive parent. Arterioscler Thromb Vasc Biol 2002;22:843–848.
  16. Efron B, Tibshirani RJ: An introduction to the bootstrap. Boca Raton, CRC Press. 1993.
  17. 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.
  18. 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.
  19. Henkin L, Bergman RN, Bowden DW, Ellsworth DL, Haffner SM, Langefeld CD, Mitchell BD, Norris JM, Rewers M, Saad MF, Stamm E, Wagenknecht LE, Rich SS: Genetic Epidemiology of Insulin Resistance and Visceral Obesity. The IRAS Family Study Design and Methods. Ann Epidemiol 2003;13:211–217.
  20. 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.
  21. Almasy L, Blangero J: Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998;62:1198–1211.
  22. Jeanclos E, Schork NJ, Kyvik KO, Kimura M, Skurnick JH, Aviv A: Telomere length inversely correlates with pulse pressure and is highly familial. Hypertension 2000;36:195–200.

 goto top of outline Author Contacts

Fang-Chi Hsu
Department of Public Health Sciences, Wake Forest University School of Medicine
Medical Center Blvd
Winston-Salem, NC 27157 (USA)
Tel. +1 336 716 8457, Fax +1 336 716 6427, E-Mail fhsu@wfubmc.edu


 goto top of outline Article Information

Received: August 23, 2004
Accepted after revision: July 13, 2005
Published online: September 8, 2005
Number of Print Pages : 10
Number of Figures : 1, Number of Tables : 4, Number of References : 22


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 60, No. 2, Year 2005 (Cover Date: 2005)

Journal Editor: Devoto, M. (Wilmington, Del.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.com/hhe


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.

Abstract

Objectives: Pulse pressure (PP) is a measure of large artery stiffness and has been shown to be an important predictor of cardiovascular morbidity and mortality. The aims of the present study were to investigate the heritability of PP in three studies, the Diabetes Heart Study (DHS), the Insulin Resistance Atherosclerosis Family Study (IRAS FS), and the NHLBI Family Heart Study (FHS), to estimate the residual heritability after inclusion of a common set of covariates, and to investigate the impact of pedigree structure on estimating heritability. Methods and Results: DHS is primarily a sibling pair nuclear family study design, while both IRAS FS and FHS have large pedigrees. Heritability estimates of log-transformed PP were obtained using variance component models. After adjusting for age, gender, ethnicity/center, height, diabetes status, and mean arterial pressure (MAP), heritability estimates of PP were 0.40 ± 0.08 , 0.22 ± 0.05, and 0.19 ± 0.03 in DHS, IRAS FS, and FHS, respectively. The heritability estimate from DHS was significantly different from both IRAS FS and FHS (both p values <0.05). A random re-sampling technique (modified bootstrap) was used to explore the heritability in the IRAS FS and FHS data when these pedigrees were trimmed to mimic the DHS pedigree structure. The re-sampling method (mimicking a sibling pair nuclear family design in all studies) yielded PP heritability estimates of 0.37, 0.34, and 0.27 in DHS, IRAS FS, and FHS, respectively. There was no significant difference among the heritability estimates from the three studies based on the re-sampling method. Conclusion: We have shown that PP has a moderately heritable component in three different studies. These data illustrate the influence of pedigree structure can have on estimating heritability. Thoughtful comparisons of heritability estimates must consider study design factors such as pedigree structure.



 goto top of outline Author Contacts

Fang-Chi Hsu
Department of Public Health Sciences, Wake Forest University School of Medicine
Medical Center Blvd
Winston-Salem, NC 27157 (USA)
Tel. +1 336 716 8457, Fax +1 336 716 6427, E-Mail fhsu@wfubmc.edu


 goto top of outline Article Information

Received: August 23, 2004
Accepted after revision: July 13, 2005
Published online: September 8, 2005
Number of Print Pages : 10
Number of Figures : 1, Number of Tables : 4, Number of References : 22


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 60, No. 2, Year 2005 (Cover Date: 2005)

Journal Editor: Devoto, M. (Wilmington, Del.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.com/hhe


Copyright / Drug Dosage

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.

References

  1. Mitchell GF, Moye LA, Braunwald E, Rouleau JL, Bernstein V, Geltman EM, Flaker GC, Pfeffer MA: Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function. Circulation 1997;96:4254–4260.
  2. Vaccarino V, Berger AK, Abramson J, Black HR, Setaro JF, Davey JA, Krumholz HM: Pulse pressure and risk of cardiovascular events in the systolic hypertension in the elderly program. Am J Cardiol 2001;88:980–986.
  3. Chae CU, Pfeffer MA, Glynn RJ, Mitchell GF, Taylor JO, Hennekens CH: Increased pulse pressure and risk of heart failure in the elderly. JAMA 1999;281:634–639.
  4. Vaccarino V, Holford TR, Krumholz HM: Pulse pressure and risk for myocardial infarction and heart failure in the elderly. J Am Coll Cardiol 2000;36:130–138.
  5. Domanski M, Norman J, Wolz M, Mitchell G, Pfeffer M: Cardiovascular risk assessment using pulse pressure in the first national health and nutrition examination survey (NHANES I). Hypertension 2001;38:793–797.
  6. Levy D, DeStefano AL, Larson MG, O’Donnell CJ, Lifton RP, Gavras H, Cupples LA, Myers RH: Evidence for a gene influencing blood pressure on chromosome 17. Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the Framingham heart study. Hypertension 2000;36:477–483.
  7. Rice T, Rao R, Perusse L, Bouchard C, Rao DC: Tracking of familial resemblance for resting blood pressure over time in the Quebec Family Study. Hum Biol 2000;72:415–431.
  8. Adeyemo AA, Omotade OO, Rotimi CN, Luke AH, Tayo BO, Cooper RS: Heritability of blood pressure in Nigerian families. J Hypertens 2002;20:859–863.
  9. Snieder H, Harshfield GA, Treiber FA: Heritability of blood pressure and hemodynamics in African- and European-American youth. Hypertension 2003;41:1196–1201.
  10. Atwood LD, Samollow PB, Hixson JE, Stern MP, MacCluer JW: Genome-wide linkage analysis of pulse pressure in Mexican Americans. Hypertension 2001;37:425–428.
  11. Sham P: Statistics in human genetics. New York, John Wiley & Sons, 1998.
  12. Blangero J: Multivariate oligogenic linkage analysis of quantitative traits in general pedigrees. Am J Hum Genet 1995;57:A11.
  13. Wijsman EM, Amos CI: Genetic analysis of simulated oligogenic traits in nuclear and extended pedigrees: summary of GAW10 contributions. Genet Epidemiol 1997;14:719–735.
  14. Williams JT, Duggirala R, Blangero J: Statistical properties of a variance components method for quantitative trait linkage analysis in nuclear families and extended pedigrees. Genet Epidemiol 1997;14:1065–1070.
  15. Xiang AH, Azen SP, Buchanan TA, Raffel LJ, Tan S, Cheng LS, Diaz J, Toscano E, Quinonnes M, Liu CR, Liu CH, Castellani LW, Hsueh WA, Rotter JI, Hodis HN: Heritability of subclinical atherosclerosis in Latino families ascertained through a hypertensive parent. Arterioscler Thromb Vasc Biol 2002;22:843–848.
  16. Efron B, Tibshirani RJ: An introduction to the bootstrap. Boca Raton, CRC Press. 1993.
  17. 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.
  18. 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.
  19. Henkin L, Bergman RN, Bowden DW, Ellsworth DL, Haffner SM, Langefeld CD, Mitchell BD, Norris JM, Rewers M, Saad MF, Stamm E, Wagenknecht LE, Rich SS: Genetic Epidemiology of Insulin Resistance and Visceral Obesity. The IRAS Family Study Design and Methods. Ann Epidemiol 2003;13:211–217.
  20. 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.
  21. Almasy L, Blangero J: Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998;62:1198–1211.
  22. Jeanclos E, Schork NJ, Kyvik KO, Kimura M, Skurnick JH, Aviv A: Telomere length inversely correlates with pulse pressure and is highly familial. Hypertension 2000;36:195–200.