Association of the RYR3 gene polymorphisms with atherosclerosis in elderly Japanese population

BMC Cardiovascular Disorders

Motoji Sawabe²  Masaaki Muramatsu³  Noriko Sato³  Makiko Naka-Mieno⁴  Tomio Arai¹  Shinobu Ikeda³  Chenxi Zhao³ 

[1] Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan;Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan;Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan;Department of Medical Informatics, Center of Information, Jichii Medical University, Tochigi, Japan

关键词: Japanese;    Ryanodine receptor 3;    Polymorphism;    Atherosclerosis;   

Others  :  855510
DOI  :  10.1186/1471-2261-14-6

 received in 2013-08-05, accepted in 2013-12-31,  发布年份 2014

【 摘 要 】

Background

The Ryanodine receptor 3 gene (RYR3) encodes an intracellular calcium channel that mediates the efflux of Ca²⁺ from intracellular stores. Two single-nucleotide polymorphisms (SNPs) in the RYR3 gene have been shown to associate with stroke (rs877087) and carotid intima-media thickness (rs2229116) in two independent genome-wide association studies (GWAS) in Caucasian. We investigated the effect of these two SNPs as well as the 31.1 kilobases spanning region on atherosclerosis in Japanese population.

Methods

Atherosclerotic severity was assessed by carotid artery (n = 1374) and pathological atherosclerosis index (PAI) (n = 1262), which is a macroscopic examination of the luminal surfaces of 8 systemic arteries in consecutive autopsy samples. 4 tag SNPs in the 31.1 Kb region, rs877087, rs2132207, rs658750 and rs2229116, were genotyped and haplotypes were inferred to study the association with atherosclerotic indices.

Results

rs877087 and rs2229116 were associated with PAI (OR = 2.07 [1.04-4.12] (95% CI), p = 0.038; and OR = 1.38 [1.02-1.86], p = 0.035, respectively). rs2229116 was also associated with common carotid atherosclerosis (OR = 1.45 [1.13-1.86], p = 0.003). The risk allele of rs2229116 was opposite from the original report. The haplotype block of this 31.1 Kb region was different between Caucasian and Japanese. Haplotype analysis revealed that only TAGG haplotype was associated with PAI (OR = 0.67 [0.48-0.94], p = 0.020) and atherosclerosis of common carotid artery (OR = 0.75 [0.58-0.98], p = 0.034).

Conclusion

rs877087 and rs2229116 of RYR3 gene are associated with atherosclerosis severity in Japanese. The functional difference caused by rs2229116 needs to be investigated.

【 授权许可】

   
2014 Zhao et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Ross R: Atherosclerosis–an inflammatory disease. N Engl J Med 1999, 340(2):115-126.
• [2]Hansson GK: Atherosclerosis–an immune disease: the anitschkov lecture 2007. Atherosclerosis 2009, 202(1):2-10.
• [3]Libby P: Inflammation in atherosclerosis. Nature 2002, 420(6917):868-874.
• [4]Falk E: Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983, 50(2):127-134.
• [5]Jackson SP: Arterial thrombosis--insidious, unpredictable and deadly. Nat Med 2011, 7;17(11):1423-1436.
• [6]Singh RB, Mengi SA, Xu YJ, Arneja AS, Dhalla NS: Pathogenesis of atherosclerosis: a multifactorial process. Exp Clin Cardiol 2002, 7(1):40-53.
• [7]Fox CS, Polak JF, Chazaro I, Cupples A, Wolf PA, D’Agostino RA, O’Donnell CJ: Genetic and environmental contributions to atherosclerosis phenotypes in men and women: heritability of carotid intima-media thickness in the Framingham Heart Study. Stoke 2003, 34:397-401.
• [8]Blanco-Colio LM, Martín-Ventura JL, Vivanco F, Michel JB, Meilhac O, Egido J: Biology of atherosclerotic plaques: what we are learning from proteomic analysis. Cardiovasc Res 2006, 1;72(1):18-29.
• [9]Stylianou IM, Bauer RC, Reilly MP, Rader DJ: Genetic basis of atherosclerosis: insights from mice and humans. Circ Res 2012, 20;110(2):337-355.
• [10]Maouche S, Schunkert H: Strategies beyond genome-wide association studies for atherosclerosis. Arterioscler Thromb Vasc Biol 2012, 32(2):170-181.
• [11]Ikram MA, Seshadri S, Bis JC, Fornage M, DeStefano AL, Aulchenko YS, Debette S, Lumley T, Folsom AR, van den Herik EG, Bos MJ, Beiser A, Cushman M, Launer LJ, Shahar E, Struchalin M, Du Y, Glazer NL, Rosamond WD, Rivadeneira F, Kelly-Hayes M, Lopez OL, Coresh J, Hofman A, DeCarli C, Heckbert SR, Koudstaal PJ, Yang Q, Smith NL, Kase CS, et al.: Genomewide association studies of stroke. N Engl J Med 2009, 23;360(17):1718-1728.
• [12]Shrestha S, Irvin MR, Taylor KD, Wiener HW, Pajewski NM, Haritunians T, Delaney JA, Schambelan M, Polak JF, Arnett DK, Chen YD, Grunfeld C: A genome-wide association study of carotid atherosclerosis in HIV-infected men. AIDS 2010, 24(4):583-592.
• [13]Sorrentino V, Giannini G, Malzac P, Mattei MG: Localization of a novel ryanodine receptor gene (RYR3) to human chromosome 15q14-q15 by in situ hybridization. Genomics 1993, 18(1):163-165.
• [14]Nakashima Y, Nishimura S, Maeda A, Barsoumian EL, Hakamata Y, Nakai J, Allen PD, Imoto K, Kita T: Molecular cloning and characterization of a human brain ryanodine receptor. FEBS Lett 1997, 417:157-162.
• [15]Leeb T, Brenig B: cDNA cloning and sequencing of the human ryanodine receptor type 3 (RYR3) reveals a novel alternative splice site in the RYR3 gene. FEBS Lett 1998, 423(3):367-370.
• [16]Jeyakumar LH, Copello JA, O’Malley AM, Wu GM, Grassucci R, Wagenknecht T, Fleischer S: Purification and characterization of ryanodine receptor 3 from mammalian tissue. J Biol Chem 1998, 273(26):16011-16020.
• [17]Lanner JT, Georgiou DK, Joshi AD, Hamilton SL: Ryanodine receptors: structure, expression, molecular details, and function in calcium release. Cold Spring Harb Perspect Biol 2010, 2(11):a003996.
• [18]Löhn M, Jessner W, Fürstenau M, Wellner M, Sorrentino V, Haller H, Luft FC, Gollasch M: Regulation of calcium sparks and spontaneous transient outward currents by RyR3 in arterial vascular smooth muscle cells. Circ Res 2001, 89(11):1051-1057.
• [19]Köhler R, Brakemeier S, Kühn M, Degenhardt C, Buhr H, Pries A, Hoyer J: Expression of ryanodine receptor type 3 and TRP channels in endothelial cells: comparison of in situ and cultured human endothelial cells. Cardiovasc Res 2001, 51(1):160-168.
• [20]Finn AV, Kolodgie FD, Virmani R: Correlation between carotid intimal/medial thickness and atherosclerosis: a point of view from pathology. Arterioscler Thromb Vasc Biol 2010, 30(2):177-181.
• [21]Sawabe M, Arai T, Kasahara I, Esaki Y, Nakahara K, Hosoi T, Orimo H, Takubo K, Murayama S, Tanaka N: Developments of geriatric autopsy database and Internet-based database of Japanese single nucleotide polymorphisms for geriatric research (JG-SNP). Mech Ageing Dev 2004, 125(8):547-552.
• [22]Oda K, Tanaka N, Arai T, Araki J, Song Y, Zhang L, Kuchiba A, Hosoi T, Shirasawa T, Muramatsu M, Sawabe M: Polymorphisms in pro- and anti-inflammatory cytokine genes and susceptibility to atherosclerosis: a pathological study of 1503 consecutive autopsy cases. Hum Mol Genet 2007, 16(6):592-599.
• [23]Sawabe M, Arai T, Kasahara I, Hamamatsu A, Esaki Y, Nakahara K, Harada K, Chida K, Yamanouchi H, Ozawa T, Takubo K, Murayama S, Tanaka N: Sustained progression and loss of the gender-related difference in atherosclerosis in the very old: a pathological study of 1074 consecutive autopsy cases. Atherosclerosis 2006, 186(2):374-379.
• [24]Song Y, Araki J, Zhang L, Froehlich T, Sawabe M, Arai T, Shirasawa T, Muramatsu M: Haplotyping of TNFalpha gene promoter using melting temperature analysis: detection of a novel −856(G/A) mutation. Tissue Antigens 2005, 66(4):284-290.
• [25]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC: PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet 2007, 81(3):559-575.
• [26]Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005, 21(2):263-265.
• [27]Emeson EE, Robertson AL Jr: T lymphocytes in aortic and coronary intimas. Their potential role in atherogenesis. Am J Pathol 1988, 130(2):369-376.
• [28]Kleindienst R, Xu Q, Willeit J, Waldenberger FR, Weimann S, Wick G: Immunology of atherosclerosis. Demonstration of heat shock protein 60 expression and T lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions. Am J Pathol 1993, 142(6):1927-1937.
• [29]Schwarzmann N, Kunerth S, Weber K, Mayr GW, Guse AH: Knock-down of the type 3 ryanodine receptor impairs sustained Ca2+ signaling via the T cell receptor/CD3 complex. J Biol Chem 2002, 277(52):50636-50642.
• [30]Boubali S, Liopeta K, Virgilio L, Thyphronitis G, Mavrothalassitis G, Dimitracopoulos G, Paliogianni F: Calcium/calmodulin-dependent protein kinase II regulates IL-10 production by human T lymphocytes: a distinct target in the calcium dependent pathway. Mol Immunol 2012, 52(2):51-60.
• [31]Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, Xue X, Parrinello CM, Hunt P, Deeks SG, Hodis HN: T cell activation predicts carotid artery stiffness among HIV-infected women. Atherosclerosis 2011, 217(1):207-213.