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Gender-Dependent Correlations of Carotid Intima–Media Thickness with Gene Expression in Blood

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Abstract

The mechanisms underlying gender differences in stroke incidence, risk, and outcome are uncertain. We sought to determine whether transcriptional profiles of circulating blood cells of men and women differentially correlated with carotid artery intima–media thickness (CIMT), a predictor of atherosclerosis and stroke risk. Gene expression in whole blood was measured using Affymetrix expression arrays in men (n = 17) and women (n = 35), aged 45–64 years, with at least one risk factor for stroke. Mean average CIMT was measured using B-mode ultrasound. Expression levels of 746 genes positively and 292 genes negatively correlated with CIMT only in women (p < 0.05); 881 genes positively and 597 genes negatively correlated with CIMT only in men (p < 0.05). Forty-one genes correlated with CIMT in men and women, but in opposite directions. These genes were associated with estrogen, cholesterol and lipid metabolism, inflammation, coagulation, and vasoreactivity. This pilot study provides the first proof of principle that gene expression in blood cells correlates with CIMT. These results point to potential pathophysiological mechanisms underlying sex differences in stroke risk. Since the sample size is small, the findings are preliminary and need to be confirmed in independent, larger studies.

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References

  1. Gargano J, Reeves M. Sex differences in stroke recovery and stroke-specific quality of life. Stroke. 2007;38:2541–8.

    Article  PubMed  Google Scholar 

  2. Reeves M, Bushnell C, Howard G, Gargano J, Duncan P, Lynch G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008;7:915–26.

    Article  PubMed  Google Scholar 

  3. Kapral MK, Fang J, Hill MD, Silver F, Richars J, Jaigobin C, et al. Sex differences in stroke care and outcomes. Results from the registry of the Canadian Stroke Network. Stroke. 2005;36:809–14.

    Article  PubMed  Google Scholar 

  4. Di Carlo A, Lamassa M, Baldreschi M, Pracucci G, Basile AM, Wolfe CD, et al. Sex differences in the clinical presentation, resource use, and 3-month outcome of acute stroke in Europe. Data from a Multicenter Multinational Hospital-Based Registry. Stroke. 2003;34:1114–9.

    Article  PubMed  Google Scholar 

  5. Smith D, Murphy P, Santos P, Phillips M, Wilde M. Gender differences in the Colorado Stroke Registry. Stroke. 2009;40:1078–81.

    Article  PubMed  Google Scholar 

  6. Grewal J, Anand S, Islam S, Lonn E. Prevalence and predictors of subclinical atherosclerosis among asymptomatic "low risk" individuals in a multiethnic population. Atherosclerosis. 2008;197:435–42.

    Article  PubMed  CAS  Google Scholar 

  7. Folsom A, Kronmal R, Detrano R, O’Leary D, Bild D, Bluemke D, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence. The Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med. 2008;168:1333–9.

    Article  PubMed  Google Scholar 

  8. Lloyd-Jones D, Adams R, Brown T, Carnethon M, Dai S, De Simone G, et al. Heart Disease and Stroke Statistics 2010 Update. A report from the American Heart Association. Circulation. 2009. doi:10.1161/CIRCULATIONAHA.109.192667.

    Google Scholar 

  9. de Groot E, van Leuven S, Duivenvoorden R, Meuwese M, Akdim F, Bots M, et al. Measurement of carotid intima-media thickness to assess progression and regression of atherosclerosis. Nat Clin Pract Cardiovasc Med. 2008;5:280–8.

    Article  PubMed  Google Scholar 

  10. O’Leary D, Polak J, Kronmal R, Manolio T, Burke GL, Wolfson S. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med. 1999;340:14–22.

    Article  PubMed  Google Scholar 

  11. Lanktree M, Hegele R, Yusuf S, Anand S. Multi-ethnic genetic association study of carotid intima-media thickness using a targeted cardiovascular SNP microarray. Stroke. 2009;40:3173–9.

    Article  PubMed  Google Scholar 

  12. Elosua R, Ordovas J, Cupples L, Fox C, Polak J, Wolf P, et al. Association of APOE genotype with carotid atherosclerosis in men and women: the Framingham Heart Study. J Lipid Res. 2004;45:1868–75.

    Article  PubMed  CAS  Google Scholar 

  13. Paternoster L, Anani N, Gonzalez M, Lewis S, Sudlow C. Association between apolipoprotein E genotype and carotid intima-media thickness may suggest a specific effect on large artery atherothrombotic stroke. Stroke. 2008;39:48–54.

    Article  PubMed  Google Scholar 

  14. Wingrove J, Daniels S, Sehnert A, Tingley W, Elashoff M, Rosenberg S, et al. Correlation of peripheral blood gene expression with the extent of coronary artery stenosis. Circulation Cardiovascular Genetics. 2008;1:31–8.

    Article  PubMed  CAS  Google Scholar 

  15. Sex Differences in Vascular Markers of Stroke Risk (SAVVY) [database on the Internet]. U.S. National Institutes of Health. 2008 [cited November 27, 2010].

  16. Xu H, Tang Y, Liu D-Z, Ran R, Ander B, Apperson M, et al. Gene expression in peripheral blood differs after cardioembolic compared with large-vessel atherosclerotic stroke: biomarkers for the etiology of ischemic stroke. J Cerebral Blood Flow and Metabolism. 2008. doi:10.1038/jcbfm.2008.22.

    Google Scholar 

  17. Mandel C, Bai Y, Tong L. Protein factors in pre-mRNA 3′-end processing. Cell Mol Life Sci. 2008;65:1099–122.

    Article  PubMed  CAS  Google Scholar 

  18. Waterham H. Defects of cholesterol biosynthesis. FEBS Lett. 2006;580:5442–9.

    Article  PubMed  CAS  Google Scholar 

  19. Karabina S, Gora S, Atout R, Ninio E. Extracellular phospholipases in athersclerosis. Biochimie. 2010;92:594–600.

    Article  PubMed  CAS  Google Scholar 

  20. Wasserthiel-Smoller S, Kooperberg C, McGinn A, Kaplan R, Hsia J, Hendrix S, et al. Lipoprotein-associated phospholipase A2, hormone use, and the risk of ischemic stroke in postmenopausal women. Hypertension. 2008;51:1115–22.

    Article  Google Scholar 

  21. Tabas I, Seimon T, Timmins J, LI G, Lim W. Macrophage apoptosis in advanced atherosclerosis. Ann NY Acad Sci. 2009;1173 Suppl 1:E40–5.

    Article  PubMed  CAS  Google Scholar 

  22. Hasdemir C, Aydin H, Celik H, Simsek E, Payzin S, Kayikcioglu M, et al. Transcriptional profiling of septal wall of the right ventricular outflow tract in patients with idiopathic ventricular arrhythmias. Pacing Clin Electrophysiol. 2010;33:159–67.

    Article  PubMed  Google Scholar 

  23. Mizuno K, Ris L, Sánchez-Capelo A, Godaux E, Giese K. Ca2+/calmodulin kinase kinase alpha is dispensable for brain development but is required for distinct memories in male, though not in female, mice. Mol Cell Biol. 2006;26:9094–104.

    Article  PubMed  CAS  Google Scholar 

  24. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, et al. Adiponectin and AdipoR1 regulate PGC-1-alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature. 2010;464:1313–9.

    Article  PubMed  CAS  Google Scholar 

  25. Barillari G, Iovane A, Bonuglia M, Albonici L, Garofano P, Di Campli E, et al. Fibroblast growth factor-2 transiently activates the p53 oncosuppressor protein in human primary vascular smooth muscle cells: implications for atherogenesis. Atherosclerosis. 2010;210:400–6.

    Article  PubMed  CAS  Google Scholar 

  26. Cucina A, Scavo M, Muzzoli L, Coluccia P, Ceccarini S, Fuso A, et al. High density lipoproteins downregulate basic fibroblast growth factor production and release in minimally oxidated-LDL treated smooth muscle cells. Atherosclerosis. 2006;189:303–9.

    Article  PubMed  CAS  Google Scholar 

  27. Liao S, Bodmer J, Pietras D, Azhar M, Doetschman T, Schultz J. Biological functions of the low and high molecular weight protein isoforms of fibroblast growth factor-2 in cardiovascular development and disease. Dev Dyn. 2009;238:249–64.

    Article  PubMed  CAS  Google Scholar 

  28. Sobrino A, Mata M, Laguna-Fernandez A, Novella S, Oviedo P, Garcia-Perez M, et al. Estradiol stimulates vasodilatory and metabolic pathways in cultured human endothelial cells. PLoS ONE. 2009;4:e8242.

    Article  PubMed  Google Scholar 

  29. Holm P, Slart R, Zeebregts C, Hillebrands J, Tio R. Atherosclerotic plaque development and instability: a dual role for VEGF. Ann Med. 2009;41:257–64.

    Article  PubMed  CAS  Google Scholar 

  30. Burton D, Giles P, Sheerin A, Smith S, Lawton J, Ostler E, et al. Microarray analysis of senescent vascular smooth muscle cells: a link to atherosclerosis and vascular calcification. Exp Gerontol. 2009;44:659–65.

    Article  PubMed  CAS  Google Scholar 

  31. Hellings W, Pasterkamp G, Verhoeven B, De Kleijn D, de Vries J, Seldenrijk C, et al. Differences between men and women in the composition of atherosclerotic plaque, as an explanation for the lower success rate of carotid endarterectomy in women. Ned Tijdschr Geneeskd. 2008;152:2624–31.

    PubMed  CAS  Google Scholar 

  32. Barton M, d’Uscio L, Shaw S, Meyer P, Moreau P, Luscher T. ETA receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension. Hypertension. 1998;31:499–504.

    PubMed  CAS  Google Scholar 

  33. Sayama H, Nakamura Y, Saito N, Konoshita M. Does the plasma endothelin-1 concentration reflect atherosclerosis in the elderly? Gerontology. 1999;45:312–6.

    Article  PubMed  CAS  Google Scholar 

  34. David F, Carvalho M, Cobra A, Nigro D, Fortes Z, Reboucas N, et al. Ovarian hormones modulate endothelin-1 vascular reactivity and mRNA expression in DOCA-salt hypertensive rats. Hypertension. 2001;38:692–6.

    PubMed  CAS  Google Scholar 

  35. Wang X, Barber D, Lewis D, McGregor C, Seick G, Fitzpatrick L, et al. Gender and transcriptional regulation of NO synthase and ET-1 in porcine aortic endothelial cells. Am J Physiol. 1997;273:H1962–7.

    PubMed  CAS  Google Scholar 

  36. Stamova B, Xu H, Jickling G, Bushnell C, Tian Y, Ander B, et al. Gene expression profiling of blood for the prediction of ischemic stroke. Stroke. 2010;41:2171–7.

    Article  PubMed  Google Scholar 

  37. Jickling G, Xu H, Stamova B, Ander B, Zhan X, Tian Y, et al. Signatures of cardioembolic and large-vessel ischemic stroke. Ann Neurol. 2010;68:681–92.

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Ryan Davis and Jeff Gregg of the UC Davis Genomics Core for processing the microarrays. We also thank the many individuals in the Sharp group who helped teach the skills needed to do the analyses.

Sources of Funding

RJT is supported by a National Health and Medical Research Council (Australia; 519365) Postdoctoral fellowship. CDB and the SAVVY study are supported by NIH/NINDS K02 NS058760. FRS is supported by NIH/NINDS-NS056302 and the American Heart Association Bugher Foundation.

Conflict of Interests

None.

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Correspondence to Cheryl D. Bushnell.

Electronic Supplementary Materials

Below is the link to the electronic supplementary material.

Online Table 1

Genes positively correlated with CIMT in women. (XLS 270 kb)

Online Table 2

Genes positively correlated with CIMT in men. (XLS 380 kb)

Online Table 3

Genes negatively correlated with CIMT in women. (XLS 175 kb)

Online Table 4

Genes negatively correlated with CIMT in men. (XLS 251 kb)

Online Table 5

Genes negatively correlated with CIMT in both men and women. (XLS 21 kb)

Online Table 6

Genes positively correlated with CIMT in both men and women. (XLS 35 kb)

Online Table 7

Canonical pathway analysis of genes posititvely correlated with CIMT in both men and women. (XLS 30 kb)

Online Table 8

Canonical pathway analysis of genes negatviely correlated with CIMT in men and women. (XLS 26 kb)

Online Table 9

Canonical pathway analysis of genes differnentially correlated between men and women. (XLS 35 kb)

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Turner, R.J., Bushnell, C.D., Register, T.C. et al. Gender-Dependent Correlations of Carotid Intima–Media Thickness with Gene Expression in Blood. Transl. Stroke Res. 2, 171–178 (2011). https://doi.org/10.1007/s12975-011-0066-4

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  • DOI: https://doi.org/10.1007/s12975-011-0066-4

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