Korean Circ J.  2012 Jun;42(6):406-413. 10.4070/kcj.2012.42.6.406.

Rho-Associated Kinase 2 Polymorphism in Patients With Vasospastic Angina

• Yoo SY
• Kim J
• Cheong S
• Shin DH
• Jang J
• Lee C
• Tahk SJ
• Shin JH
• Choi SY
• Yoon MH

• KMID: 1433860
• DOI: http://doi.org/10.4070/kcj.2012.42.6.406

Abstract

BACKGROUND AND OBJECTIVES
Recent studies indicate that in response to vasoconstrictor stimuli, the small GTPase RhoA and its down-stream effector, Rho-associated kinase 2 (ROCK)/Rho-kinase, are associated with hypercontraction of the vascular smooth muscle of coronary arteries through augmentation of myosin light chain phosphorylation and Ca2+ sensitization. Expression of ROCK/Rho-kinase mRNA was significantly increased and up-regulated in the spastic coronary artery in a porcine model, and a specific inhibitor of ROCK/Rho-kinase inhibited coronary artery spasm in humans. We therefore explored the role of ROCK2 polymorphisms in the pathogenesis of vasospastic angina (VA).
SUBJECTS AND METHODS
We studied 106 patients with VA who exhibited spontaneous or provoked coronary spasm during coronary angiography and compared the prevalence of ROCK2 polymorphisms between this group of patients with VA and controls whose angiograms were normal, and in whom the ergonovine test did not cause spasm (n=107). Five single nucleotide polymorphisms (SNPs) of the ROCK2 gene were selected. SNPs were genotyped by high-resolution melting. Linkage disequilibrium and haplotype analyses were performed using the SHEsis program.
RESULTS
The prevalence of genotypes of the 5 interesting SNPs in patients with VA was not different from that in the control group. In haplotype analysis, the haplotype G-T-C-T-G (in order of rs978906, rs2271621, rs2230774, rs1515210, and rs3771106) was significantly associated with a decreased risk of VA (p=0.007).
CONCLUSION
The haplotype G-T-C-T-G in the ROCK2 gene had a protective effect against VA, suggesting the involvement of ROCK2 in VA pathogenesis.

Keyword

Coronary vasospasm; Rho-associated kinase 2; Polymorphsm, genetic; Haplotypes

MeSH Terms

Coronary Angiography
Coronary Vasospasm
Coronary Vessels
Ergonovine
Freezing
Genotype
GTP Phosphohydrolases
Haplotypes
Humans
Linkage Disequilibrium
Muscle Spasticity
Muscle, Smooth, Vascular
Myosin Light Chains
Phosphorylation
Polymorphism, Single Nucleotide
Prevalence
rho-Associated Kinases
RNA, Messenger
Spasm
Ergonovine
GTP Phosphohydrolases
Myosin Light Chains
RNA, Messenger
rho-Associated Kinases

Figure

• 

  Fig. 1 Representative example of ergonovine provocation testing during diagnostic coronary angiography in a 49-year-old man with vasospastic angina. Intravenous injection of ergonovine (E3) provoked subtotal occlusion of the mid-portion of the left anterior descending artery (arrow) (A), and the angiogram after injection of nitroglycerin showed near normal left coronary artery and relief of total occlusion (B).

• 

  Fig. 2 Normalized high resolution melting (HRM) curves of the 3 possible genotypes for the 5 single-nucleotide polymorphisms of the ROCK2 gene. Triplicate HRM data were captured for the ROCK2 gene in SNP genotyping. Each category of SNP genotype can be readily discriminated prior to thermal shifting normalization. A: rs978906. B: rs2271621. C: rs2230774. D: rs1515219. E: rs3771106. SNP: single nucleotide polymorphism.

• 

  Fig. 3 Linkage disequilibrium status of the 5 single-nucleotide polymorphisms (SNPs) of the ROCK2 gene. In this plot, each square represents a pair-wise comparison between 2 SNPs and the respective D' is given within each square. Darker square colors of red indicate higher values of D', up to a maximum of 1.

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