ARHGAP42 rs604723 Gen Polimorfizmi Hipertansiyon Tanısı Konulan Kişilerde Nabız Dalga Hızı ile İlişkilidir

Abstract

Giriş: Hipertansiyon, yüksek tansiyonla karakterize sistemik bir hastalık olup yaygın olması ve ciddi komplikasyonlara neden olabilmesi nedeniyle toplum için önemli bir tehdit oluşturmaktadır. Gelişiminde, Rho GTPase aktive edici protein 42'yi kodlayan ve yakın zamanda tanımlanan genetik risk faktörü ARHGAP42 gibi genetik ve çevresel faktörler rol oynamaktadır. Çalışmada ARHGAP42'nin intronik rs604723 (C/T) gen polimorfizminin arteriyel sertlik ile ilişkisi araştırılmıştır. Yöntemler: Çalışma grubundaki 63 hipertansiyonlu birey ve 100 sağlıklı kontrol grubundan alınan periferik kan örnekleri, DNA izolasyonunu takiben real time PCR yöntemi ile ARHGAP42 rs604723 gen polimorfizmi varlığı açısından analiz edildi. Çalışma grubundaki deneklerin demografik verileri kaydedilerek kan basıncı, ambulatuvar kan basıncı ve arteriyel sertlik değerleri ölçüldü. Bulgular: Heterozigot polimorfik CT (~2-kat) ve homozigot polimorfik TT (~1,6-kat) genotiplerinin çalışma grubundaki deneklerde kontrol grubuna göre daha yüksek olduğu, CT genotipindeki artışın istatistiksel olarak anlamlı olduğu görüldü (p = 0,006). Benzer şekilde çalışma grubundaki deneklerde polimorfik T alelinin sıklığı daha yüksek (~1,9-kat) ve istatistiksel olarak anlamlı bulunmuştur (p=0,003). Ayrıca heterozigot polimorfik CT ve homozigot polimorfik TT genotiplerinin arteriyel sertliğin bir ölçüsü olan karotis-femoral nabız hızı ile ilişkili olduğu bulunmuştur (p = 0,025). Sonuç: Bu çalışmada ARHGAP42 rs604723 (C/T) gen polimorfizminin hipertansiyonlu bireylerde nabız dalga hızı ile ilişkili olduğu belirlendi. Anti-hipertansif tedavide yaygın olarak kullanılan herhangi bir spesifik ilaç veya ilaçlarla ilişkisinin araştırılması ilgi çekici olacaktır. Böylece gelecekte kişiselleştirilmiş tıp uygulamaları için hipertansif bireylerin genotipine göre uygun ilaç veya ilaçların seçilmesi mümkün olabilecektir.

Keywords

• hipertansiyon
• kan basıncı
• arteriyel sertlik
• ARHGAP42
• rs604723
• gen polimorfizmi.

ARHGAP42 rs604723 Gene Polymorphism Is Associated With Pulse Wave Speed In Hypertension Diagnosed Subjects

Abstract

Introduction: Hypertension is a systemic disease characterized by high blood pressure and an important threat for the population, as it is common and can cause serious complications. Genetic and environmental factors are involved in its development like the recently defined genetic risk factor ARHGAP42 that encodes the Rho GTPase activating protein 42. In the study, the intronic rs604723 (C/T) gene polymorphism of ARHGAP42 was investigated in relation to arterial stiffness. Methods: Peripheral blood samples, taken from 63 study group subjects with hypertension and 100 healthy subject as control, were analyzed for the presence of the ARHGAP42 rs604723 gene polymorphism by a real-time PCR method following DNA isolation. Demographic data of the study group subjects were recorded and blood pressure, ambulatory blood pressure and arterial stiffness values were measured. Results: The heterozygous polymorphic CT (~2-fold) and homozygous polymorphic TT (~1.6-fold) genotypes were found to be higher in study group subjects when compared to the control group subjects, whereby the increase of the CT genotype was statistically significant (p = 0.006). Similarly, the frequency of the polymorphic T allele was found to be higher (~1.9-fold) and statistically significant (p = 0.003) in the study group subjects. In addition, the heterozygous polymorphic CT and homozygous polymorphic TT genotypes were found to be associated with carotid-femoral pulse velocity, which is a measure of arterial stiffness (p = 0.025). Conclusion: In this study, the ARHGAP42 rs604723 (C/T) gene polymorphism was found to be associated with pulse wave speed in subjects with hypertension. It will be of interest, to investigate its association with any specific drug or drugs commonly used in anti-hypertensive therapy. Thus, it would be possible to select the appropriate drug or drugs according to the hypertensive subjects’ genotype to carry out personalized medicine in future.

Keywords

• hypertension
• blood pressure
• arterial stiffness
• ARHGAP42
• rs604723
• gene polymorphism.

References

1. 1. Li C, He J, Chen J, Zhao J, Gu D, Hixson JE, et al. Genome-wide gene–sodium interaction analyses on blood pressure: the genetic epidemiology network of salt-sensitivity study. Hypertension. 2016;68(2):348-55.
2. 2. Bai X, Lenhart KC, Bird KE, Suen AA, Rojas M, Kakoki M, et al. The smooth muscle-selective RhoGAP GRAF3 is a criti-cal regulator of vascular tone and hypertension. Nature communications. 2013; 13:4(1):2910.
3. 3. Bai X, Mangum K, Kakoki M, Smithies O, Mack CP, Taylor JM. GRAF3 serves as a blood volume-sensitive rheostat to control smooth muscle contractility and blood pressure. Small GTPases. 2020; 11(3): p. 194-203.
4. 4. Bai X, Mangum KD, Dee RA, Stouffer GA, Lee CR, Oni-Orisan A, et al. Blood pressure–associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding. The Journal of clinical investigation. 2017;127(2):670-80.
5. 5. Oh YS. Arterial stiffness and hypertension. Clin Hypertens. 2018; 24: p.17.
6. 6. Wagenseil JE, Mecham RP. Elastin in large artery stiffness and hypertension. J Cardiovasc Transl Res. 2012; 5(3): p. 264-73.
7. 7. Dudenbostel T, Glasser SP. Effects of antihypertensive drugs on arterial stiffness. Cardiol Rev. 2012; 20(5): p. 259-63.
8. 8. Tatar E, Demirci MS, Kircelli F, Gungor O, Turan MN, Sevinc Ok E, et al. Association of insulin resistance with arterial stiffness in nondiabetic peritoneal dialysis patients. Inter-national urology and nephrology. 2012; 44:255-62.

9. 9. Taylor JM, Hildebrand JD, Mack CP, Cox ME, Parsons JT. Characterization of graf, the GTPase-activating protein for rho associated with focal adhesion kinase. Phosphorylation and possible regulation by mitogen-activated protein ki-nase. J Biol Chem. 1998; 273(14): p. 8063-70.
10. 10. Dee RA, Bai X, Mack CP, Taylor JM. Molecular Regulation of the RhoGAP GRAF3 and Its Capacity to Limit Blood Pres-sure In Vivo. Cells. 2020; 9(4).
11. 11. Luo W, Janostiak R, Tolde O, Ryzhova L.M, Koudelková L, Dibus M, et al. ARHGAP42 is activated by Src-mediated ty-rosine phosphorylation to promote cell motility. J Cell Sci. 2017; 130(14): p. 2382-2393.
12. 12. Azam AB, Azizan EAB. Brief Overview of a Decade of Genome-Wide Association Studies on Primary Hyperten-sion. Int J Endocrinol. 2018; 2018: p. 7259704.
13. 13. Consortium GT. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regula-tion in humans. Science. 2015; 348(6235): p. 648-60.
14. 14. Mangum KD, Freeman EJ, Magin JC, Taylor JM, Mack CP. Transcriptional and posttranscriptional regulation of the SMC-selective blood pressure-associated gene, ARHGAP42. Am J Physiol Heart Circ Physiol. 2020; 318(2): p. H413-H424.
15. 15. Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA. 2012; 308(9): p. 875-81.
16. 16. Ruppert V, Maisch B. Genetics of human hypertension. Herz. 2003; 28(8): p. 655-62.
17. 17. Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, et al. Clinical practice guidelines for the management of hypertension in the community: a state-ment by the American Society of Hypertension and the In-ternational Society of Hypertension. J Clin Hypertens (Greenwich). 2014; 16(1): p. 14-26.
18. 18. Kunes J, Zicha J. The interaction of genetic and environ-mental factors in the etiology of hypertension. Physiol Res. 2009; 58 Suppl 2: p. S33-S42.
19. 19. Chung CM, Cheng HW, Chang JJ, Lin YS, Hsiao JF, Chang ST, et al. Relationship between resistant hypertension and ar-terial stiffness assessed by brachial-ankle pulse wave ve-locity in the older patient. Clin Interv Aging. 2014; 9: p. 1495-502.
20. 20. Rossi GP, Ceolotto G, Caroccia B, Lenzini L. Genetic screening in arterial hypertension. Nat Rev Endocrinol. 2017; 13(5): p. 289-298.
21. 21. McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmo-nary arterial hypertension. J Clin Invest. 2005; 115(6): p. 1479-91.
22. 22. Phillips MI. Gene therapy for hypertension: sense and antisense strategies. Expert Opin Biol Ther. 2001; 1(4): p. 655-62.
23. 23. Bai X, Dee R, Mangum KD, Mack CP, Taylor JM. RhoA sig-naling and blood pressure: The consequence of failing to “Tone it Down”. World Journal of Hypertension. 2016; 6(1).
24. 24. Dee RA, Mangum KD, Bai X, Mack CP, Taylor JM. Druggable targets in the Rho pathway and their promise for therapeu-tic control of blood pressure. Pharmacol Ther. 2019; 193: p. 121-134.