Yıl: 2022 Cilt: 50 Sayı: 1 Sayfa Aralığı: 22 - 33 Metin Dili: İngilizce DOI: 10.5543/tkda.2022.17203 İndeks Tarihi: 17-06-2022

Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease

Öz:
Objective: Coronary artery disease (CAD) is an important public health problem worldwide. Therefore, it is important to identify the molecular mechanisms and the candidate gene polymorphisms involved in the development of CAD. In this study, we focused on 2 polymorphisms of the atherosclerosis-related genes, ESR1 and CYP19A1. Methods: Unselected 339 individuals who underwent coronary angiography were divided into 2 groups: those with normal coronary arteries (≤30% stenosis) and those with critical disease (≥50% stenosis). Individuals were genotyped for CYP19A1 rs10046 C/T and ESR1 rs2175898 A/G polymorphisms using hybridization probes in real-time PCR. In addition, Gensini and SYNTAX scores were assessed. Results: ESR1 polymorphism was significantly associated with CAD in men (p=0.036) via G allele carriage. Multiple logistic regression analyses showed that ESR1 rare allele carriage was associated with CAD presence (Odds ratio=2.12, 95% confidence interval 1.01–4.1, p=0.025), adjusted for age, HDL-C, LDL-C and smoking status in the male group. CYP19A1 rs10046 T allele carriers had a 2.84-fold increased risk for complex CAD in multiple logistic regression analysis (p=0.016). Furthermore, the univariate analysis of variance indicated that T allele carriage of rs10046 polymorphism was associated with increased SYNTAX and Gensini scores (p<0.05). Female patients who were ESR1 G allele carriers with CAD had higher adiponectin levels (p=0.005), whereas HbA1c levels were associated with T allele of CYP19A1 in the CAD group (p=0.004) and male CAD group (p=0.018). Conclusion: The CYP19A1 and ESR1 polymorphisms were associated with the presence and severity of CAD. These gene polymorphisms warrant further studies for the elucidation of their contribution to CAD development.
Anahtar Kelime:

Cinsiyet hormonu genlerindeki polimorfizmlerin koroner arter hastalığı ve ciddiyeti ile ilişkisi

Öz:
Amaç: Koroner arter hastalığı (KAH) dünyada önemli bir halk sağlığı sorunudur. Hastalığın etiyolojisinin altında yatan klasik risk faktörleri tanımlanmış olsa da bu faktörleri etkileyen moleküler mekanizmalar tamamen aydınlatılamamıştır. Bu nedenle, hastalığın gelişimi ve tedavisinde rol oynayabilecek aday gen polimorfizmlerinin tanımlanması önem taşımaktadır. Bu bilgiler ışığında, bu çalışmada ateroskleroz ile ilişkili iki gen olan ESR1 ve CYP19A1 gen polimorfizmleri araştırılmıştır. Yöntemler: 339 KAH ve KAH olmayan bireye ait periferik kan örneğinden DNA izolasyonu yapılmış ve çalışmaya katılan bireyler CYP19A1 rs10046 (C/T) ve ESR1 rs2175898 (A/G) polimorfizmleri için hibridizasyon probları kullanılarak genotiplenmiştir. Kan örnekleri koroner anjiyografiden önce alınarak biyokimyasal analizler yapılmıştır. Bunun yanında, çalışmaya katılan bireylerin koroner anjiyografi sonuçlarına göre Gensini ve SYNTAX skorları belirlenmiştir. Bulgular: ESR1 polimorfizmi G allel taşıyıcılığı erkeklerde KAH ile ilişkili bulunmuştur (p=0.036). Yaş, HDL-K, LDL-K düzeyleri ve sigara içme durumuna göre ayarlama yapılan lojistik regresyon analizinde, ESR1 G allel taşıyıcılığının erkeklerde KAH ile ilişkili olduğu gösterilmiştir (OR=2.12, [%95 GA 1.01–4.1] p=0.025). Yapılan lojistik regresyon analizlerinde, CYP19A1 rs10046 T allel taşıyıcısı bireylerde kompleks KAH riskinin 2.84 kat arttığı görülmüştür (p=0.016). Buna ek olarak, CYP19A1 rs10046 T alel taşıyıcılığı, SYNTAX ve Gensini skorları ile ilişkili bulunmuştur (p<0.05). ESR1 G allel taşıyıcılığı kadın hastalarda yüksek adiponektin düzeyi (p=0.005) ile ilişkili bulunurken CYP19A1 T alleli, HbA1c düzeyleri ile KAH hastalarında (p=0.004) ve erkek KAH hastalarında (p=0.018) ilişkili bulunmuştur. Sonuç: CYP19A1 ve ESR1 polimorfizmleri KAH şiddeti ve KAH varlığı ile ilişkili bulunmuştur. Çalışılan gen polimorfizmlerin KAH gelişimindeki etkilerinin belirlenebilmesi için daha çok çalışmaya ihtiyaç bulunmaktadır.
Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
  • 1. Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nat Rev Dis Primers 2019;5:56. [Crossref]
  • 2. Arnold AP, Cassis LA, Eghbali M, Reue K, Sandberg K. Sex Hormones and Sex Chromosomes Cause Sex Differences in the Development of Cardiovascular Diseases. Arterioscler Thromb Vasc Biol 2017;37:746-56. [Crossref]
  • 3. Boese AC, Kim SC, Yin KJ, Lee JP, Hamblin MH. Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. Am J Physiol Heart Circ Physiol 2017;313:H524-h45. [Crossref]
  • 4. Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 2005;308:1583-7. [Crossref]
  • 5. Losordo DW, Kearney M, Kim EA, Jekanowski J, Isner JM. Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation 1994;89:1501-10. [Crossref]
  • 6. Liu H, Pedram A, Kim JK. Oestrogen prevents cardiomyocyte apoptosis by suppressing p38α-mediated activation of p53 and by down-regulating p53 inhibition on p38β. Cardiovasc Res 2011;89:119-28. [Crossref]
  • 7. Figtree GA, McDonald D, Watkins H, Channon KM. Truncated estrogen receptor α 46-kDa isoform in human endothelial cells: Relationship to acute activation of nitric oxide synthase. Circulation 2003;107:120-6. [Crossref]
  • 8. Hodgin JB, Krege JH, Reddick RL, Korach KS, Smithies O, Maeda N. Estrogen receptor alpha is a major mediator of 17beta-estradiol’s atheroprotective effects on lesion size in Apoe-/- mice. J Clin Invest 2001;107:333-40. [Crossref]
  • 9. Gallagher CJ, Langefeld CD, Gordon CJ, Campbell JK, Mychaleckyj JC, Bryer-Ash M, et al. Association of the estrogen receptor-alpha gene with the metabolic syndrome and its component traits in African-American families: the Insulin Resistance Atherosclerosis Family Study. Diabetes 2007;56:2135-41. [Crossref]
  • 10. Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 2012;22:1790-7. [Crossref]
  • 11. Bulun SE, Sebastian S, Takayama K, Suzuki T, Sasano H, Shozu M. The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters. J Steroid Biochem Mol Biol 2003;86:219-24. [Crossref]
  • 12. Ziv-Gal A, Gallicchio L, Miller SR, Zacur HA, Flaws JA. A genetic polymorphism in the CYP19A1 gene and the risk of hypertension among midlife women. Maturitas 2012;71:70-5. [Crossref]
  • 13. Desautels DN, Blanchette PS, Pritchard KI. Do aromatase inhibitors increase cardiovascular risk? Piecing together the evidence. Eur J Cancer 2016;68:176-8. [Crossref]
  • 14. Paynter RA, Hankinson SE, Colditz GA, Kraft P, Hunter DJ, De Vivo I. CYP19 (aromatase) haplotypes and endometrial cancer risk. Int J Cancer 2005;116:267-74. [Crossref]
  • 15. Haiman CA, Hankinson SE, Spiegelman D, Brown M, Hunter DJ. No association between a single nucleotide polymorphism in CYP19 and breast cancer risk. Cancer Epidemiol Biomarkers Prev 2002;11:215-6.
  • 16. Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd E, et al. Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 2004;96:936-45. [Crossref]
  • 17. Peter I, Shearman AM, Zucker DR, Schmid CH, Demissie S, Cupples LA, et al. Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study. J Hypertens 2005;23:2193-200. [Crossref]
  • 18. Ryan TJ, Faxon DP, Gunnar RM, Kennedy JW, King SB, 3rd, Loop FD, et al. Guidelines for percutaneous transluminal coronary angioplasty. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty). Circulation 1988;78:486-502. [Crossref]
  • 19. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 1983;51:606. [Crossref]
  • 20. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961-72. [Crossref]
  • 21. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021-104. [Crossref]
  • 22. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215. [Crossref]
  • 23. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation 2020;141:e139-e596. [Crossref]
  • 24. Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev 1994;15:342-55. [Crossref]
  • 25. Paradisi G, Steinberg HO, Hempfling A, Cronin J, Hook G, Shepard MK, et al. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation 2001;103:1410-5. [Crossref]
  • 26. Shaw LJ, Bairey Merz CN, Azziz R, Stanczyk FZ, Sopko G, Braunstein GD, et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health--National Heart, Lung, and Blood Institute sponsored Women’s Ischemia Syndrome Evaluation. J Clin Endocrinol Metab 2008;93:1276-84. [Crossref]
  • 27. Roberts KE, Fallon MB, Krowka MJ, Brown RS, Trotter JF, Peter I, et al. Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease. Am J Respir Crit Care Med 2009;179:835-42. [Crossref]
  • 28. Shimodaira M, Nakayama T, Sato N, Saito K, Morita A, Sato I, et al. Association study of aromatase gene (CYP19A1) in essential hypertension. Int J Med Sci 2008;5:29-35. [Crossref]
  • 29. Ramirez-Lorca R, Grilo A, Martinez-Larrad MT, Manzano L, Serrano-Hernando FJ, Moron FJ, et al. Sex and body mass index specific regulation of blood pressure by CYP19A1 gene variants. Hypertension 2007;50:884-90. [Crossref]
  • 30. Yang Y, Wang P. Association of CYP19A1 and CYP1A2 genetic polymorphisms with type 2 diabetes mellitus risk in the Chinese Han population. Lipids Health Dis 2020;19:187. [Crossref]
  • 31. Coban N, Onat A, Guclu-Geyik F, Can G, Erginel-Unaltuna N. Sex- and Obesity-specific Association of Aromatase (CYP19A1) Gene Variant with Apolipoprotein B and Hypertension. Arch Med Res 2015;46:564-71. [Crossref]
  • 32. Meng Y, Adi D, Wu Y, Wang Y, Abudoukelimu M, Huang D, et al. CYP19A1 polymorphisms associated with coronary artery disease and circulating sex hormone levels in a Chinese population. Oncotarget 2017;8:97101-13. [Crossref]
  • 33. Bampali K, Grassos C, Mouzarou A, Liakos C, Mertzanos G, Lamnissou K, et al. Genetic Variant in the CYP19A1 Gene Associated with Coronary Artery Disease. Genet Res Int 2015;2015:820323. [Crossref]
  • 34. Wang B, Fu ZY, Ma YT, Huang D, Liu F, Dong CL, et al. Identification of a CYP19 Gene Single-Nucleotide Polymorphism Associated with a Reduced Risk of Coronary Heart Disease. Genet Test Mol Biomarkers 2016;20:2-10. [Crossref]
  • 35. Pollak A, Rokach A, Blumenfeld A, Rosen LJ, Resnik L, Dresner Pollak R. Association of oestrogen receptor alpha gene polymorphism with the angiographic extent of coronary artery disease. Eur Heart J 2004;25:240-5. [Crossref]
  • 36. Lehtimäki T, Kunnas TA, Mattila KM, Perola M, Penttilä A, Koivula T, et al. Coronary artery wall atherosclerosis in relation to the estrogen receptor 1 gene polymorphism: an autopsy study. J Mol Med (Berl) 2002;80:176-80. [Crossref]
  • 37. Kjaergaard AD, Ellervik C, Tybjærg-Hansen A, Axelsson CK, Grønholdt MLM, Grande P, et al. Estrogen receptor α polymorphism and risk of cardiovascular disease, cancer, and hip fracture: Cross-sectional, cohort, and case-control studies and a meta-analysis. Circulation 2007;115:861-71. [Crossref]
  • 38. Almeida S, Hutz MH. Genetic variation of estrogen metabolism and the risks of cardiovascular disease. Curr Opin Investig Drugs 2007;8:814-20.
  • 39. Yilmaz A, Menevse S, Erkan AF, Ergun MA, Ilhan MN, Cengel A, et al. The relationship of the ESR1 gene polymorphisms with the presence of coronary artery disease determined by coronary angiography. Genet Test 2007;11:367-71. [Crossref]
  • 40. Ding J, Xu H, Yin X, Zhang FR, Pan XP, Gu YA, et al. Estrogen receptor α gene PvuII polymorphism and coronary artery disease: a meta-analysis of 21 studies. J Zhejiang Univ Sci B 2014;15:243-55. [Crossref]
  • 41. Koch W, Hoppmann P, Pfeufer A, Mueller JC, Schömig A, Kastrati A. No replication of association between estrogen receptor α gene polymorphisms and susceptibility to myocardial infarction in a large sample of patients of European descent. Circulation 2005;112:2138-42. [Crossref]
  • 42. Guclu-Geyik F, Coban N, Can G, Erginel-Unaltuna N. The rs2175898 Polymorphism in the ESR1 Gene has a Significant Sex-Specific Effect on Obesity. Biochem Genet 2020;58:935-52. [Crossref]
  • 43. Kelly TN, Rebholz CM, Gu D, Hixson JE, Rice TK, Cao J, et al. Analysis of sex hormone genes reveals gender differences in the genetic etiology of blood pressure salt sensitivity: the GenSalt study. Am J Hypertens 2013;26:191-200. [Crossref]
  • 44. Shearman AM, Cupples LA, Demissie S, Peter I, Schmid CH, Karas RH, et al. Association between estrogen receptor alpha gene variation and cardiovascular disease. JAMA 2003;290:2263-70. [Crossref]
  • 45. Hayashi K, Maeda S, Iemitsu M, Otsuki T, Sugawara J, Tanabe T, et al. Sex differences in the relationship between estrogen receptor alpha gene polymorphisms and arterial stiffness in older humans. Am J Hypertens 2007;20:650-6. [Crossref]
  • 46. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001;86:1930-5. [Crossref]
  • 47. Zhang H, Mo X, Hao Y, Huang J, Lu X, Cao J, et al. Adiponectin levels and risk of coronary heart disease: a meta-analysis of prospective studies. Am J Med Sci 2013;345:455-61. [Crossref]
  • 48. Yoshihara R, Utsunomiya K, Gojo A, Ishizawa S, Kanazawa Y, Matoba K, et al. Association of polymorphism of estrogen receptor-alpha gene with circulating levels of adiponectin in postmenopausal women with type 2 diabetes. J Atheroscler Thromb 2009;16:250-5. [Crossref]
  • 49. Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA, et al. Common Estrogen Receptor Polymorphism Augments Effects of Hormone Replacement Therapy on E-Selectin but Not C-Reactive Protein. Circulation 2002;105:1879-82. [Crossref]
APA coban n, Ozuynuk-Ertugrul A, Erkan A, KAYA A, Ekici B, Guclu-Geyik F, Ademoglu E, CAN G, Erginel-Unaltuna N (2022). Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease. , 22 - 33. 10.5543/tkda.2022.17203
Chicago coban neslihan,Ozuynuk-Ertugrul Aybike Sena,Erkan Aycan Fahri,KAYA AYŞEM,Ekici Berkay,Guclu-Geyik Filiz,Ademoglu Evin,CAN GÜNAY,Erginel-Unaltuna Nihan Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease. (2022): 22 - 33. 10.5543/tkda.2022.17203
MLA coban neslihan,Ozuynuk-Ertugrul Aybike Sena,Erkan Aycan Fahri,KAYA AYŞEM,Ekici Berkay,Guclu-Geyik Filiz,Ademoglu Evin,CAN GÜNAY,Erginel-Unaltuna Nihan Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease. , 2022, ss.22 - 33. 10.5543/tkda.2022.17203
AMA coban n,Ozuynuk-Ertugrul A,Erkan A,KAYA A,Ekici B,Guclu-Geyik F,Ademoglu E,CAN G,Erginel-Unaltuna N Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease. . 2022; 22 - 33. 10.5543/tkda.2022.17203
Vancouver coban n,Ozuynuk-Ertugrul A,Erkan A,KAYA A,Ekici B,Guclu-Geyik F,Ademoglu E,CAN G,Erginel-Unaltuna N Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease. . 2022; 22 - 33. 10.5543/tkda.2022.17203
IEEE coban n,Ozuynuk-Ertugrul A,Erkan A,KAYA A,Ekici B,Guclu-Geyik F,Ademoglu E,CAN G,Erginel-Unaltuna N "Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease." , ss.22 - 33, 2022. 10.5543/tkda.2022.17203
ISNAD coban, neslihan vd. "Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease". (2022), 22-33. https://doi.org/10.5543/tkda.2022.17203
APA coban n, Ozuynuk-Ertugrul A, Erkan A, KAYA A, Ekici B, Guclu-Geyik F, Ademoglu E, CAN G, Erginel-Unaltuna N (2022). Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease. Türk Kardiyoloji Derneği Arşivi, 50(1), 22 - 33. 10.5543/tkda.2022.17203
Chicago coban neslihan,Ozuynuk-Ertugrul Aybike Sena,Erkan Aycan Fahri,KAYA AYŞEM,Ekici Berkay,Guclu-Geyik Filiz,Ademoglu Evin,CAN GÜNAY,Erginel-Unaltuna Nihan Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease. Türk Kardiyoloji Derneği Arşivi 50, no.1 (2022): 22 - 33. 10.5543/tkda.2022.17203
MLA coban neslihan,Ozuynuk-Ertugrul Aybike Sena,Erkan Aycan Fahri,KAYA AYŞEM,Ekici Berkay,Guclu-Geyik Filiz,Ademoglu Evin,CAN GÜNAY,Erginel-Unaltuna Nihan Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease. Türk Kardiyoloji Derneği Arşivi, vol.50, no.1, 2022, ss.22 - 33. 10.5543/tkda.2022.17203
AMA coban n,Ozuynuk-Ertugrul A,Erkan A,KAYA A,Ekici B,Guclu-Geyik F,Ademoglu E,CAN G,Erginel-Unaltuna N Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease. Türk Kardiyoloji Derneği Arşivi. 2022; 50(1): 22 - 33. 10.5543/tkda.2022.17203
Vancouver coban n,Ozuynuk-Ertugrul A,Erkan A,KAYA A,Ekici B,Guclu-Geyik F,Ademoglu E,CAN G,Erginel-Unaltuna N Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease. Türk Kardiyoloji Derneği Arşivi. 2022; 50(1): 22 - 33. 10.5543/tkda.2022.17203
IEEE coban n,Ozuynuk-Ertugrul A,Erkan A,KAYA A,Ekici B,Guclu-Geyik F,Ademoglu E,CAN G,Erginel-Unaltuna N "Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease." Türk Kardiyoloji Derneği Arşivi, 50, ss.22 - 33, 2022. 10.5543/tkda.2022.17203
ISNAD coban, neslihan vd. "Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease". Türk Kardiyoloji Derneği Arşivi 50/1 (2022), 22-33. https://doi.org/10.5543/tkda.2022.17203