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The International Journal of Cardiovascular Imaging

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01-02-2012 | Original Paper

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

Authors: 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

Published in: The International Journal of Cardiovascular Imaging | Issue 2/2012

Abstract

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.

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):S4PubMedCrossRef

Roy H, Bhardwaj S, Yla-Herttuala S (2009, March 20) Molecular genetics of atherosclerosis. Hum Genet 125:467–491

Kleiger RE, Bigger JT, Moss AJ (1997) Decreased heart rate variability and its association with increased mortality after myocardial infraction. Am J Cardiol 73:845–849

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):2850–2855PubMed

Carney RM, Freedland KE, Veith RC (2005) Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med 67:S29–S33PubMedCrossRef

Eller NH, Malmberg B, Bruhn P (2006) Heart rate variability and intima media thickness. Int J Behav Med 13(3):201–213PubMedCrossRef

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):2251–2254PubMed

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):381–385PubMedCrossRef

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):2007–2015PubMedCrossRef

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):228–234PubMedCrossRef

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):668–674PubMedCrossRef

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–I40PubMed

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):709–716PubMedCrossRef

14.

Sheps DS, Sheffield D (2001) Depression, anxiety, and the cardiovascular system: the cardiologist’s perspective. J Clin Psychiatry 62(Suppl 8):12–16PubMed

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):122–126CrossRef

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):755–760PubMedCrossRef

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):2792–2796PubMedCrossRef

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):364–372PubMedCrossRef

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):654–661PubMedCrossRef

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–H1022CrossRef

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):1043–1065CrossRef

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):45315–45322PubMedCrossRef

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):1645–1654PubMedCrossRef

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):168–171PubMedCrossRef

25.

Spence JD, Hegele RA (2004) Noninvasive phenotypes of atherosclerosis. Arterioscler Thromb Vasc Biol 24(11):e188–e189PubMedCrossRef

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):216–221PubMedCrossRef

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):177–181PubMedCrossRef

28.

Miller S, Dykes D, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 16:12–15

29.

Chen XN, Levine L, Kwok PY (1999) Fluorescence polarization in homogeneous nucleic acid analysis. Genome Res 9(5):492–498PubMed

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):719–725PubMedCrossRef

31.

Tracey K (2002) The inflammatory reflex. Nature 40:853–859CrossRef

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):24–28PubMedCrossRef

33.

Neumann SA, Flory JD, Ferrell RE, Manuck SB (2005) Depression is related to polymorphic variation in the choline transporter gene. Psychosom Med 67:A38CrossRef

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):2192–2217PubMed

35.

Burmeister M (2007) Basic concepts in the study of disease with complex genetics. Biol Psychiatry 45:522–532CrossRef

36.

Allison D (1997) Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet 60:676–690PubMed

37.

Devlin B, Roeder K, Wasserman L (2000) Genomic control for association studies: a semiparametric test to detect excess-haplotype sharing. Biostatistics 1:369–387PubMedCrossRef

Title: Polymorphic variation in choline transporter gene (CHT1) is associated with early, subclinical measures of carotid atherosclerosis in humans
Authors: 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
Publication date: 01-02-2012
Publisher: Springer Netherlands
Published in: The International Journal of Cardiovascular Imaging / Issue 2/2012
Print ISSN: 1569-5794
Electronic ISSN: 1875-8312
DOI: https://doi.org/10.1007/s10554-011-9831-4

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

Abstract

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Abstract

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