Polymorphic variation in choline transporter gene (CHT1) is associated with early, subclinical measures of carotid atherosclerosis in humans

  • Serina A. Neumann
  • Katherine J. Linder
  • Matthew F. Muldoon
  • Kimberly Sutton-Tyrrell
  • Christopher Kline
  • Catherine J. Shrader
  • Elizabeth C. Lawrence
  • Robert E. Ferrell
  • Stephen B. Manuck
Original Paper


Atherosclerosis is a heritable trait with little known about specific genetic influences on preclinical measures of plaque formation. Based on relations of parasympathetic-cholinergic function to atherosclerosis and to a choline transporter gene [CHT1 (G/T)] polymorphism, we investigated whether the same allelic variant predicts variation in carotid intima-media thickness (IMT) and plaque formation. Carotid IMT and plaque occurrence as well as genotyping for the CHT1 (G/T) variant were measured in a sample (N = 264) of generally healthy adults (age 30–55) of European ancestry. CHT1 GG homozygotes had greater IMT (P < 0.005) and plaque occurrence (P < 0.020) than T allele carriers. This is the first study showing polymorphic variation in the CHT1 gene to predict early, subclinical measures of carotid atherosclerosis which may aid in understanding cholinergic-vagal processes potentially underlying atherosclerotic risk.


Atherosclerosis Intima-media thickness Plaque Cholinergic function Choline transport Acetylcholine 



This research supported by NIH grants K01 MH 074766 (SAN), P01 HL 40962 (SBM) and HL 07560.


  1. 1.
    O’Donnell CJ, Cupples LA, D’Agostino RB, Fox CS, Hoffmann U, Hwang SJ et al (2007) Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study. BMC Med Genet 8(Suppl 1):S4PubMedCrossRefGoogle Scholar
  2. 2.
    Roy H, Bhardwaj S, Yla-Herttuala S (2009, March 20) Molecular genetics of atherosclerosis. Hum Genet 125:467–491Google Scholar
  3. 3.
    Kleiger RE, Bigger JT, Moss AJ (1997) Decreased heart rate variability and its association with increased mortality after myocardial infraction. Am J Cardiol 73:845–849Google Scholar
  4. 4.
    Tsuji H, Larson MG, Venditti FJ, Manders ES, Evans JC, Feldman CL et al (1996) Impact of reduced heart rate variability on risk for cardiac events—the Framingham Heart Study. Circulation 94(11):2850–2855PubMedGoogle Scholar
  5. 5.
    Carney RM, Freedland KE, Veith RC (2005) Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med 67:S29–S33PubMedCrossRefGoogle Scholar
  6. 6.
    Eller NH, Malmberg B, Bruhn P (2006) Heart rate variability and intima media thickness. Int J Behav Med 13(3):201–213PubMedCrossRefGoogle Scholar
  7. 7.
    Singh JP, Larson MG, O’Donnell CJ, Tsuji H, Evans JC, Levy D (1999) Heritability of heart rate variability—the Framingham Heart Study. Circulation 99(17):2251–2254PubMedGoogle Scholar
  8. 8.
    Antelmi I, de Paula RS, Shinzato AR, Peres CA, Mansur AJ, Grupi CJ (2004) Influence of age, gender, body mass index, and functional capacity on heart rate variability in a cohort of subjects without heart disease. Am J Cardiol 93(3):381–385PubMedCrossRefGoogle Scholar
  9. 9.
    Reims HM, Sevre K, Fossum E, Hoieggen A, Mellem H, Kjeldsen SE (2004) Relations between insulin sensitivity, fitness and autonomic cardiac regulation in healthy, young men. J Hypertens 22(10):2007–2015PubMedCrossRefGoogle Scholar
  10. 10.
    Gottsater A, Ahlgren AR, Taimour S, Sundkvist G (2006) Decreased heart rate variability may predict the progression of carotid atherosclerosis in type 2 diabetes. Clin Auton Res 16(3):228–234PubMedCrossRefGoogle Scholar
  11. 11.
    Schroeder EB, Chambless LE, Liao D, Prineas RJ, Evans GW, Rosamond WD et al (2005) Diabetes, glucose, insulin, and heart rate variability: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care 28(3):668–674PubMedCrossRefGoogle Scholar
  12. 12.
    Clarkson TB, Kaplan JR, Adams MR, Manuck SB (1987) Psychosocial influences on the pathogenesis of atherosclerosis among nonhuman primates. Circulation 76(1 Pt 2):I29–I40PubMedGoogle Scholar
  13. 13.
    Marsland AL, Gianaros PJ, Prather AA, Jennings JR, Neumann SA, Manuck SB (2007) Stimulated production of proinflammatory cytokines covaries inversely with heart rate variability. Psychosom Med 69(8):709–716PubMedCrossRefGoogle Scholar
  14. 14.
    Sheps DS, Sheffield D (2001) Depression, anxiety, and the cardiovascular system: the cardiologist’s perspective. J Clin Psychiatry 62(Suppl 8):12–16PubMedGoogle Scholar
  15. 15.
    Singh JP, Larson MG, O’Donnell CJ, Levy D (2001) Genetic factors contribute to the variance in frequency domain measures of heart rate variability. Auton Neurosci Basic Clin 90(1–2):122–126CrossRefGoogle Scholar
  16. 16.
    Busjahn A, Voss A, Knoblauch H, Knoblauch M, Jeschke E, Wessel N et al (1998) Angiotensin-converting enzyme and angiotensinogen gene polymorphisms and heart rate variability in twins. Am J Cardiol 81(6):755–760PubMedCrossRefGoogle Scholar
  17. 17.
    Kupper NH, Willemsen G, van den Berg M, de Boer D, Posthuma D, Boomsma DI et al (2004) Heritability of ambulatory heart rate variability. Circulation 110(18):2792–2796PubMedCrossRefGoogle Scholar
  18. 18.
    Snieder H, van Doornen LJ, Boomsma DI, Thayer JF (2007) Sex differences and heritability of two indices of heart rate dynamics: a twin study. Twin Res Hum Genet 10(2):364–372PubMedCrossRefGoogle Scholar
  19. 19.
    Sinnreich R, Friedlander Y, Luria MH, Sapoznikov D, Kark JD (1999) Inheritance of heart rate variability: the kibbutzim family study. Hum Genet 105(6):654–661PubMedCrossRefGoogle Scholar
  20. 20.
    Uusitalo AL, Vanninen E, Levalahti E, Battie MC, Videman T, Kaprio J (2007) Role of genetic and environmental influences on heart rate variability in middle-aged men. Am J Physiol Heart Circul Physiol 293(2):H1013–H1022CrossRefGoogle Scholar
  21. 21.
    Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996) Heart rate variability—standards of measurement, physiological interpretation, and clinical use. Circulation 93(5):1043–1065CrossRefGoogle Scholar
  22. 22.
    Okuda T, Okamura M, Kaitsuka C, Haga T, Gurwitz D (2002) Single nucleotide polymorphism of the human high affinity choline transporter alters transport rate. J Biol Chem 277(47):45315–45322PubMedCrossRefGoogle Scholar
  23. 23.
    Lips KS, Pfeil U, Reiners K, Rimasch C, Kuchelmeister K, Braun-Dullaeus RC et al (2003) Expression of the high-affinity choline transporter CHT1 in rat and human arteries. J Histochem Cytochem 51(12):1645–1654PubMedCrossRefGoogle Scholar
  24. 24.
    Neumann SA, Lawrence EC, Jennings JR, Ferrell RE, Manuck SB (2005) Heart rate variability is associated with polymorphic variation in the choline transporter gene. Psychosom Med 67(2):168–171PubMedCrossRefGoogle Scholar
  25. 25.
    Spence JD, Hegele RA (2004) Noninvasive phenotypes of atherosclerosis. Arterioscler Thromb Vasc Biol 24(11):e188–e189PubMedCrossRefGoogle Scholar
  26. 26.
    Spence JD (2006) Measurement of intima-media thickness vs. carotid plaque: uses in patient care, genetic research and evaluation of new therapies. Int J Stroke 1(4):216–221PubMedCrossRefGoogle Scholar
  27. 27.
    Finn AV, Kolodgie FD, Virmani R (2010) Correlation between carotid intimal/medial thickness and atherosclerosis: a point of view from pathology. Arterioscler Thromb Vasc Biol 30(2):177–181PubMedCrossRefGoogle Scholar
  28. 28.
    Miller S, Dykes D, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 16:12–15Google Scholar
  29. 29.
    Chen XN, Levine L, Kwok PY (1999) Fluorescence polarization in homogeneous nucleic acid analysis. Genome Res 9(5):492–498PubMedGoogle Scholar
  30. 30.
    Veller MG, Fisher CM, Nicolaides AN, Renton S, Geroulakos G, Stafford NJ et al (1993) Measurement of the ultrasonic intima-media complex thickness in normal subjects. J Vasc Surg 17(4):719–725PubMedCrossRefGoogle Scholar
  31. 31.
    Tracey K (2002) The inflammatory reflex. Nature 40:853–859CrossRefGoogle Scholar
  32. 32.
    Kirkpatrick CJ, Bittinger F, Unger RE, Kriegsmann J, Kilbinger H, Wessler I (2001) The non-neuronal cholinergic system in the endothelium: evidence and possible pathobiological significance. Jpn J Pharmacol 85(1):24–28PubMedCrossRefGoogle Scholar
  33. 33.
    Neumann SA, Flory JD, Ferrell RE, Manuck SB (2005) Depression is related to polymorphic variation in the choline transporter gene. Psychosom Med 67:A38CrossRefGoogle Scholar
  34. 34.
    Rozanski A, Blumenthal JA, Kaplan J (1999) Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 99(16):2192–2217PubMedGoogle Scholar
  35. 35.
    Burmeister M (2007) Basic concepts in the study of disease with complex genetics. Biol Psychiatry 45:522–532CrossRefGoogle Scholar
  36. 36.
    Allison D (1997) Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet 60:676–690PubMedGoogle Scholar
  37. 37.
    Devlin B, Roeder K, Wasserman L (2000) Genomic control for association studies: a semiparametric test to detect excess-haplotype sharing. Biostatistics 1:369–387PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, B.V. 2011

Authors and Affiliations

  • Serina A. Neumann
    • 1
  • Katherine J. Linder
    • 1
  • Matthew F. Muldoon
    • 2
  • Kimberly Sutton-Tyrrell
    • 3
  • Christopher Kline
    • 4
  • Catherine J. Shrader
    • 1
  • Elizabeth C. Lawrence
    • 4
  • Robert E. Ferrell
    • 4
  • Stephen B. Manuck
    • 5
  1. 1.Department of Psychiatry and Behavioral SciencesEastern Virginia Medical SchoolNorfolkUSA
  2. 2.Center for Clinical Pharmacology, School of MedicineUniversity of PittsburghPittsburghUSA
  3. 3.Graduate School of Public HealthUniversity of PittsburghPittsburghUSA
  4. 4.Department of Human Genetics, Graduate School of Public HealthUniversity of PittsburghPittsburghUSA
  5. 5.Department of PsychologyUniversity of PittsburghPittsburghUSA

Personalised recommendations