Abstract
Atherosclerosis was an important pathophysiological basis of atherothrombotic stroke, and phosphodiesterase 4D (PDE4D) polymorphism (SNP83/rs966221) was reported to be associated with the susceptibility to atherothrombotic stroke. Aim of the present study was to explore the potential association between SNP83 and carotid atherosclerosis (CAS). 204 southern Chinese Han participants were divided into two groups according to the carotid intima-media thickness (IMT) of the carotid artery: CAS group (carotid IMT ≥ 1.0 mm) and non-CAS group (carotid IMT < 1.0 mm). Carotid IMT was measured by color Doppler ultrasound. The PDE4D SNP83 polymorphism was determined by SNaPshot technique. Our study found that SNP83 was associated significantly with CAS susceptibility under the dominant, overdominant and codominant models. After adjusting for age, gender, low-density lipoprotein cholesterol, Hemoglobin A1c, cigarette smoking, hypertension history, and diabetes mellitus history, the association still remained significant (dominant model: crude OR = 2.373, 95% CI: 1.268–4.442, P = 0.007; adjusted OR = 3.129, 95% CI: 1.104–8.866, P = 0.032; overdominant model: crude OR = 1.968, 95% CI: 1.043–3.714, P = 0.037; adjusted OR = 2.854, 95% CI: 1.005–8.108, P = 0.049; codominant: crude OR = 2.102, 95% CI: 1.110–3.979, P = 0.023; adjusted OR = 2.984, 95% CI: 1.047–8.502, P = 0.041). Carotid IMT of carriers with CT + CC genotypes was higher than carriers with TT genotype (P = 0.016). Our results indicated that the SNP83/rs966221 located on PDE4D gene was significantly associated between CAS susceptibility and carotid IMT independently of conventional risk factors in a southern Chinese Han population.
Similar content being viewed by others
Data availability
All the datasets supporting the conclusions of this article have been included in the article.
Code availability
Not applicable.
References
Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35–41. https://doi.org/10.1161/01.STR.24.1.35
Baillie G, MacKenzie SJ, Houslay MD (2001) Phorbol 12-myristate 13-acetate triggers the protein kinase A-mediated phosphorylation and activation of the PDE4D5 cAMP phosphodiesterase in human aortic smooth muscle cells through a route involving extracellular signal regulated kinase (ERK). Mol Pharmacol 60:1100–1111. https://doi.org/10.1124/mol.60.5.1100
Banner KH, Trevethick MA (2004) PDE4 inhibition: a novel approach for the treatment of inflammatory bowel disease. Trends Pharmacol Sci 25:430–436. https://doi.org/10.1016/j.tips.2004.06.008
Ebrahim S, Papacosta O, Whincup P, Wannamethee G, Walker M, Nicolaides AN, Dhanjil S, Griffin M, Belcaro G, Rumley A, Lowe GD (1999) Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 30:841–850. https://doi.org/10.1161/01.STR.30.4.841
Fukumoto S, Koyama H, Hosoi M, Yamakawa K, Tanaka S, Morii H, Nishizawa Y (1999) Distinct role of cAMP and cGMP in the cell cycle control of vascular smooth muscle cells: cGMP delays cell cycle transition through suppression of cyclin D1 and cyclin-dependent kinase 4 activation. Circ Res 85:985–991. https://doi.org/10.1161/01.RES.85.11.985
Gretarsdottir S, Sveinbjörnsdottir S, Jonsson HH et al (2002) Localization of a susceptibility gene for common forms of stroke to 5q12. Am J Hum Genet 70:593–603. https://doi.org/10.1086/339252
Gretarsdottir S, Thorleifsson G, Reynisdottir ST et al (2003) The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 35:131–138. https://doi.org/10.1038/ng1245
Indolfi C, Di Lorenzo E, Rapacciuolo A, Stingone AM, Stabile E, Leccia A, Torella D, Caputo R, Ciardiello F, Tortora G, Chiariello M (2000) 8-chloro-cAMP inhibits smooth muscle cell proliferation in vitro and neointima formation induced by balloon injury in vivo. J Am Coll Cardiol 36:288–293. https://doi.org/10.1016/s0735-1097(00)00679-3
Jin SL, Conti M (2002) Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses. Proceedings of the National Academy of Sciences of the United States of America 99(11):7628–7633. https://doi.org/10.1073/pnas.122041599
Kawamoto R, Tomita H, Inoue A, Ohtsuka N, Kamitani A (2007) Metabolic syndrome may be a risk factor for early carotid atherosclerosis in women but not in men. Journal of atherosclerosis and thrombosis 14:36–43. https://doi.org/10.5551/jat.14.36
Kumar A, Misra S, Kumar P, Sagar R, Gulati A, Prasad K (2017) Relationship of phosphodiesterase 4D (PDE4D) gene polymorphisms with risk of ischemic stroke: a hospital based case-control study. Neurol Res 39:689–694. https://doi.org/10.1080/01616412.2017.1333975
Landells LJ, Szilagy CM, Jones NA, Banner KH, Allen JM, Doherty A, O’Connor BJ, Spina D, Page CP (2001) Identification and quantification of phosphodiesterase 4 subtypes in CD4 and CD8 lymphocytes from healthy and asthmatic subjects. Br J Pharmacol 133:722–729. https://doi.org/10.1038/sj.bjp.0704120
Li D, Budoff MJ (2016) Genetics paired with CT angiography in the setting of atherosclerosis. Clin Imaging 40:917–925. https://doi.org/10.1016/j.clinimag.2016.04.005
Li W, Hu B, Li GL, Zhao XQ, Xin BZ, Lin JX., Shen Y, Liang XH, Liu GF, Gao HQ, Liao XL, Liang ZG, Wang YJ (2012) Heterozygote genotypes at rs2222823 and rs2811712 SNP loci are associated with cerebral small vessel disease in Han Chinese population. CNS Neurosci Ther 18(7):558–565. https://doi.org/10.1111/j.1755-5949.2012.00322.x
Liao YC, Lin HF, Rundek T, Cheng R, Guo YC, Sacco RL, Juo SH (2008) Segment-specific genetic effects on carotid intima-media thickness: the Northern Manhattan study. Stroke 39(12):3159–3165. https://doi.org/10.1161/STROKEAHA.108.522789
Liu H, Maurice DH (1999) Phosphorylation-mediated activation and translocation of the cyclic AMP-specific phosphodiesterase PDE4D3 by cyclic AMP-dependent protein kinase and mitogen-activated protein kinases. A potential mechanism allowing for the coordinated regulation of PDE4D activity and targeting. The Journal of biological chemistry 274:10557–10565. https://doi.org/10.1074/jbc.274.15.10557
Liu H, Palmer D, Jimmo SL, Tilley DG, Dunkerley HA, Pang SC, Maurice DH (2000) Expression of phosphodiesterase 4D (PDE4D) is regulated by both the cyclic AMP-dependent protein kinase and mitogen-activated protein kinase signaling pathways. A potential mechanism allowing for the coordinated regulation of PDE4D activity and expression in cells. The Journal of biological chemistry 275:26615–26624. https://doi.org/10.1074/jbc.M001634200
Liu X, Zhu R, Li L, Deng S, Li Q, He Z (2013) Genetic polymorphism in PDE4D gene and risk of ischemic stroke in Chinese population: a meta-analysis. PLoS ONE. https://doi.org/10.1371/journal.pone.0066374
Lv S, Qiu X, Li J, Liang J, Li W, Zhang C, Zhang ZN, Luan B (2017) Glucagon-induced extracellular cAMP regulates hepatic lipid metabolism. The Journal of endocrinology 234:73–87. https://doi.org/10.1530/JOE-16-0649
Muo IM, Park SJ, Smith A, Springer A, D, Allen MD, Hagen TJ, Chung JH, (2018) Compound D159687, a phosphodiesterase 4D inhibitor, induces weight and fat mass loss in aged mice without changing lean mass, physical and cognitive function. Biochem Biophys Res Commun 506:1059–1064. https://doi.org/10.1016/j.bbrc.2018.10.180
Ricciarelli R, Fedele E (2015) Phosphodiesterase 4D: an enzyme to remember. Br J Pharmacol 172:4785–4789. https://doi.org/10.1111/bph.13257
Sacco RL, Blanton SH, Slifer S, Beecham A, Glover K, Gardener H, Wang L, Sabala E, Juo SH, Rundek T (2009) Heritability and linkage analysis for carotid intima-media thickness: the family study of stroke risk and carotid atherosclerosis. Stroke 40:2307–2312. https://doi.org/10.1161/STROKEAHA.109.554121
Sayed-Tabatabaei FA, Van Rijn MJ, Schut AF, Aulchenko YS, Croes EA, Zillikens MC, Pols HA, Witteman JC, Oostra BA, Van Duijn CM (2005) Heritability of the function and structure of the arterial wall: findings of the Erasmus Rucphen Family (ERF) study. Stroke 36:2351–2356. https://doi.org/10.1161/01.STR.0000185719.66735.dd
Song Y, Wang C, Wu Y et al (2017) Phosphodiesterase 4D polymorphisms associate with the short-term outcome in ischemic stroke. Scientific Reports. https://doi.org/10.1038/srep42914
Wang P, Chen YM, He LP, Chen CG, Zhang B, Xue WQ, Su YX (2012) Association of natural intake of dietary plant sterols with carotid intima-media thickness and blood lipids in Chinese adults: a cross-section study. PLoS ONE. https://doi.org/10.1371/journal.pone.0032736
Xu Y, Zeng FF, He LP, Ling WH, Chen WQ, Chen YM (2014) Comparison of predictive value of cardiometabolic indices for subclinical atherosclerosis in Chinese adults. PLoS One 9(4):e93538. https://doi.org/10.1371/journal.pone.0093538
Xue H, Wang H, Song X, Li W, Sun K, Zhang W, Wang X, Wang Y, Hui R (2009) Phosphodiesterase 4D gene polymorphism is associated with ischaemic and haemorrhagic stroke. Clin Sci 116:335–340. https://doi.org/10.1042/CS20080162
Yan Y, Luo XP, Zhang JL, Su L, Liang WJ, Huang GF, Wu GL, Huang GH, Gu L (2014) Association between phosphodiesterase 4D polymorphism SNP83 and ischemic stroke. J Neurol Sci 338:3–11. https://doi.org/10.1016/j.jns.2013.12.012
Yun S, Budatha M, Dahlman J, Coon B, Cameron R, Langer R, Anderson D, Baillie G, Schwartz M (2016) Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling. Nat Cell Biol 18(10):1043–1053. https://doi.org/10.1038/ncb3405
Zhao J, Cheema FA, Bremner JD, Goldberg J, Su S, Snieder H, Maisano C, Jones L, Javed F, Murrah N, Le NA, Vaccarino V (2008) Heritability of carotid intima-media thickness: a twin study. Atherosclerosis 197:814–820. https://doi.org/10.1016/j.atherosclerosis.2007.07.030
Acknowledgements
We would like to thank all participants who agreed to participate in the study, the grants from Natural Science Foundation of Guangxi Province (2013GXNSFBA019131, 2015GXNSFAA139171, 2020GXNSFAA259053), Guangxi Scholarship Fund of Guangxi Education Department and National Natural Science Foundation of China for Young Scientists Fund (81701142).
Funding
This work was supported by the grants from Natural Science Foundation of Guangxi Province (2013GXNSFBA019131, 2015GXNSFAA139171, 2020GXNSFAA259053), Guangxi Scholarship Fund of Guangxi Education Department and National Natural Science Foundation of China for Young Scientists Fund (81701142).
Author information
Authors and Affiliations
Contributions
Man Luo and Jiao-xing Li designed the study and revised the manuscript. Liu-yu Liu and Dong-can Mo performed experiments, conducted data statistics and drafted the manuscript. Jian-li Li, Yi-ying Jiang, Guo-qiu Zhou, Dong-dong Jiang Li-jie Chen and Xiao-ju Wu assisted in the experiment and the collection of data. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University.
Consent to participate
All participants received informed consent and agreed to participate in the study.
Consent for publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Liu, Ly., Mo, Dc., Li, Jl. et al. Associations between SNP83 of phosphodiesterase 4D gene and carotid atherosclerosis in a southern Chinese Han population: a case–control study. Mamm Genome 32, 115–122 (2021). https://doi.org/10.1007/s00335-021-09857-5
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-021-09857-5