Identification of variations in genes encoding ATP-dependent potassium channel proteins in patients with primary Raynaud's phenomenon
Öz
Purpose: Primary Raynaud’s phenomenon (PRP) is a vascular disorder characterized by recurrent vasospastic response of the fingers and toes to cold or stress. ATP-sensitive potassium (KATP) channels are widely distributed in vasculatures, and play an important role in the vascular tone regulation. The major vascular isoform of KATP channels is composed of Kir6.1/SUR2 (KCNJ8/ABCC9). It would be important to determine whether variations of KATP genes related to PRP is thought to be associated with vasospasm. It is believed that the studies describing mechanisms involved in the pathogenesis of inherited vascular disorders offers the best opportunity for investigation of the early stages of pathogenicity and diagnosis of PRP and associated other diseases. In this study we aim to investigate possible association between genetic variations observed in KATP channel coding genes and vasospasm associated with PRP.
Materials and Methods: In our study; the cases with PRP, the relation between the variation in the KCNJ8/ABCC9 genes (S422L/V734I or rs72554071/rs61688134) was examined. 50 subjects who were diagnosed with PRP (patient group) and 50 healthy subjects (control group) were included in the study. Variations were determined using the Tetra-Primer Amplification Refractory Mutation System-Polymerase Chain Reaction (T-ARMS PCR) method.
Results: Of the individuals in the patient and control group included in the study, 21 were male and 29 were female. The mean age of the patients was 25.7±3.36 years, and the mean age of the control group was 25.9±3.44 years. No significant relationship was found between PRP disease and genotype and allele distribution of KCNJ8/ABCC9 genes.
Conclusion: This study presented the first findings about KCNJ8/ABCC9 gene variations in the Turkish population and may lead to future studies. Studies involving a higher number of cases and more mutations will be able to show whether there is a relationship between KATP channels and PRP and contribute to the elucidation of PRP pathogenesis in terms of genetic factors.
Anahtar Kelimeler
Raynaud’s Phenomenon KATP Channel Proteins KCNJ8/ABCC9 Genes S422L/V734I (rs72554071/rs61688134) Variants.
Destekleyen Kurum
Mersin University Scientific Research Projects Unit
Proje Numarası
2016-1-TP2-1417
Teşekkür
This study was supported by Mersin University Scientific Research Projects Unit within the scope of the project numbered 2016-1-TP2-1417.
Kaynakça
- Karabacak K, Genç G, Kaya E, Kadan M, Doğancı S. Retrospective evaluation of clinical experiences with Raynaud’ s phenomenon in young age group. Damar Cerrahisi Dergisi. 2012;21:110-4.
- Casanegra AI, Shepherd RF. Raynaud phenomenon and other vasospastic disorders. Cardiol Clin. 2021;39:583–99.
- Cansu ÜD, Korkmaz C. Raynaud fenomenli hastalara yaklaşım. Türkiye Klinikleri J Immunol Rheumatol-Special Topics. 2009;2:15-7.
- Kadan M, Karabacak K, Kaya E. Vazospastik damar hastalıkları. Damar Cerrahi Dergisi. 2013;22:225-37.
- Herrick LA. Pathogenesis of Raynaud’s phenomenon. Rheumatology (Oxford). 2005;44:587-96.
- Noma A. ATP-regulated K+ channels in cardiac muscle. Nature. 1983;305:147–8.
- Zhao G, Greiser M, Lederer WJ. The surprising complexity of Katp channel biology and of genetic diseases. J Clin Invest. 2020;130:1112-5.
- Pipatpolkai T, Usher S, Stansfeld PJ, Ashcroft FM. New insights into KATP channel gene mutations and neonatal diabetes mellitus. Nat Rev Endocrinol. 2020;16:278–393.
- Chutkow WA, Pu J, Wheeler MT, Wada T, Makielski JC, Burant CF et al. Episodic coronary artery vasospasm and hypertension develop in the absence of SUR2 K(ATP) channels. J Clin Invest. 2002;110:203–8.
- The National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/ (accessed Feb 2022).
- Ermiş E. Erken repolarizasyon bulunan kişilerde ani ölüm ve aritmi belirteci testlerin değerlendirilmesi ve KCNJ8-S422L gen mutasyonu ilişkisi (Uzmanlık tezi). İstanbul, İstanbul Bilim Üniversitesi, 2012.
- Smith JK, Chadburn JA, Adomaviciene A, Minoretti P, Vignali L, Emanuele E et al. Coronary spasm and acute myocardial infarction due to a mutation(V734I) in the nucleotide binding domain 1 of ABCC9. Int J Cardiol. 2013;168:3506–13.
- Ye S, Dhillon S, Ke X, Collins AR, Day IN. An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res. 2001;29:E88-8.
- Medrano RF, de Oliveira CA. Guidelines for the tetra-primer ARMS-PCR technique development. Mol Biotechnol. 2014;56:599-608.
- Seino S, Iwanaga T, Nagashima K, Miki T. Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice. Diabetes. 2000;49:311–8.
- Shemirani AH, Szomjak E, Balogh E, Andras C, Kovacs D, Acs J et al. Polymorphism of clotting factors in Hungarian patients with Raynaud’s phenomenon. Blood Coagul Fibrinolysis. 2011;22:56-9.
- Takáts AT, Shemirani AH, Zsóri KS, András C, Csiki Z. Prothrombotic polymorphisms in patients with Raynaud’s phenomenon and migraine. Acta Physiol Hung. 2012;99:430-5.
- Gaudy-Marqueste C, Roll P, Esteves-VieiraV, Weiller JP, Grob JJ, Cau P et al. LBR mutation and nuclear envelope defects in a patient affected with Reynolds Syndrome. J Med Genet. 2010;47:361-370.
- Fujıta E, Komıne M, Tsuda H, Adachı A, Murata S, Kamata Y et al. Case of H syndrome with massive skin involvement, retroperitoneal fibrosis and Raynaud’s phenomenon with anovel mutation in the SLC29A3 Gene. J Dermatol. 2015;42:1–3.
- Ermiş E, Yolcu M, Demirelli S, İpek E, Çiftçi C, Hançer S. Investigation of arrhytmia markers and KCNJ8-S422L gene mutation in a population with early repolarization pattern on ECG. J Am Coll Cardiol. 2013;17:73-80.
- Fedele F, Mancone M, Chilian MW, Severino P, Canali E, Logan S et al. Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease. Basic Res Cardiol. 2013;108:387.
- Veeramah RK, Karafet MT, Wolf D, Samson AR, Hammer FM. The KCNJ8-S422L variant previously associated with J-wave syndromes is found at an increased frequency in Ashkenazi Jews. Eur J Hum Genet. 2014;22:94-8.
- Minoretti P, Falcone C, Aldeghi A, Olivieri V, Mori F, Emanuele E et al. A novel Val734Ile variant in the ABCC9 gene associated with myocardial infarction. Clin Chim Acta. 2006;124–8.
- Smith KJ, Chadburn AJ, Adomaviciene A, Minoretti P, Vignali L, Emanuele E et al. Coronary spasm and acute myocardial infarction due to a mutation (V734I) in the nucleotide binding domain 1 of ABCC9. Int J Cardiol. 2013;168:3506-13
Primer Raynaud fenomeni olgularında ATP-bağımlı potasyum kanal proteinlerini kodlayan genlerde rastlanan varyasyonların belirlenmesi
Öz
Amaç: Primer Raynaud fenomeni (PRF), el ve ayak parmaklarının soğuk veya stresle tekrarlayan vazospastik tepkisi ile karakterize vasküler bir hastalıktır. ATP-bağımlı potasyum (KATP) kanalları vaskülatürlerde yaygın olarak dağılır ve vasküler tonusun düzenlenmesinde önemli bir rol oynarlar. KATP kanallarının ana vasküler izoformu Kir6.1/SUR2'den (KCNJ8/ABCC9) oluşmaktadır. PRF ile ilgili KATP gen varyasyonlarının vazospazm ile ilişkili olup olmadığının belirlenmesi önemli olacaktır. Kalıtsal vasküler bozuklukların patogenezinde yer alan mekanizmaları açıklayan çalışmaların, patojenitenin erken evrelerinin araştırılması ve PRF ile ilişkili diğer hastalıkların teşhisi için en iyi fırsatı sunduğuna inanılmaktadır. Bu çalışmada, KATP kanalı kodlayan genlerde gözlenen genetik varyasyonlar ile PRP ile ilişkili vazospazm arasındaki olası ilişkiyi araştırmayı amaçladık.
Gereç ve Yöntem: Çalışmamızda; PRF'li olgularda KCNJ8/ABCC9 genlerindeki (S422L/V734I veya rs72554071/rs61688134) varyasyon arasındaki ilişki incelenmiştir. Çalışmaya PRF tanısı konan 50 kişi (hasta grubu) ve 50 sağlıklı kişi (kontrol grubu) dahil edilmiştir. Varyasyonlar Tetra-Primer Amplifikasyona Dirençli Mutasyon Sistemi-Polimeraz Zincir Reaksiyon (T-ARMS PCR) yöntemi kullanılarak belirlenmiştir.
Bulgular: Çalışmaya dahil edilen hasta ve kontrol grubundaki bireylerin 21’i erkek ve 29’u kadındı. Hastaların yaş ortalaması 25.7±3.36, kontrol grubunun yaş ortalaması 25.9±3.44 yıldı. KCNJ8/ABCC9 genlerinin genotip ve alel dağılımı ile PRF hastalığı arasında anlamlı bir ilişki bulunamamıştır.
Sonuç: Bu çalışma Türk popülasyonunda KCNJ8/ABCC9 gen varyasyonları ile ilgili ilk bulguları sunmuş olup, ileride yapılacak çalışmalara öncülük edebilecektir. Daha fazla vaka ve daha fazla mutasyon içeren çalışmaların KATP kanalları ile PRF arasında bir ilişki olup olmadığını gösterebilecek ve genetik faktörler açısından PRF'nin patogenezinin aydınlatılmasına katkı sağlayacaktır.
Anahtar Kelimeler
Raynaud Fenomeni KATP Kanal Proteinleri KCNJ8/ABCC9 Genleri S422L/V734I (rs72554071/rs61688134) Varyantları.
Proje Numarası
2016-1-TP2-1417
Kaynakça
- Karabacak K, Genç G, Kaya E, Kadan M, Doğancı S. Retrospective evaluation of clinical experiences with Raynaud’ s phenomenon in young age group. Damar Cerrahisi Dergisi. 2012;21:110-4.
- Casanegra AI, Shepherd RF. Raynaud phenomenon and other vasospastic disorders. Cardiol Clin. 2021;39:583–99.
- Cansu ÜD, Korkmaz C. Raynaud fenomenli hastalara yaklaşım. Türkiye Klinikleri J Immunol Rheumatol-Special Topics. 2009;2:15-7.
- Kadan M, Karabacak K, Kaya E. Vazospastik damar hastalıkları. Damar Cerrahi Dergisi. 2013;22:225-37.
- Herrick LA. Pathogenesis of Raynaud’s phenomenon. Rheumatology (Oxford). 2005;44:587-96.
- Noma A. ATP-regulated K+ channels in cardiac muscle. Nature. 1983;305:147–8.
- Zhao G, Greiser M, Lederer WJ. The surprising complexity of Katp channel biology and of genetic diseases. J Clin Invest. 2020;130:1112-5.
- Pipatpolkai T, Usher S, Stansfeld PJ, Ashcroft FM. New insights into KATP channel gene mutations and neonatal diabetes mellitus. Nat Rev Endocrinol. 2020;16:278–393.
- Chutkow WA, Pu J, Wheeler MT, Wada T, Makielski JC, Burant CF et al. Episodic coronary artery vasospasm and hypertension develop in the absence of SUR2 K(ATP) channels. J Clin Invest. 2002;110:203–8.
- The National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/ (accessed Feb 2022).
- Ermiş E. Erken repolarizasyon bulunan kişilerde ani ölüm ve aritmi belirteci testlerin değerlendirilmesi ve KCNJ8-S422L gen mutasyonu ilişkisi (Uzmanlık tezi). İstanbul, İstanbul Bilim Üniversitesi, 2012.
- Smith JK, Chadburn JA, Adomaviciene A, Minoretti P, Vignali L, Emanuele E et al. Coronary spasm and acute myocardial infarction due to a mutation(V734I) in the nucleotide binding domain 1 of ABCC9. Int J Cardiol. 2013;168:3506–13.
- Ye S, Dhillon S, Ke X, Collins AR, Day IN. An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res. 2001;29:E88-8.
- Medrano RF, de Oliveira CA. Guidelines for the tetra-primer ARMS-PCR technique development. Mol Biotechnol. 2014;56:599-608.
- Seino S, Iwanaga T, Nagashima K, Miki T. Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice. Diabetes. 2000;49:311–8.
- Shemirani AH, Szomjak E, Balogh E, Andras C, Kovacs D, Acs J et al. Polymorphism of clotting factors in Hungarian patients with Raynaud’s phenomenon. Blood Coagul Fibrinolysis. 2011;22:56-9.
- Takáts AT, Shemirani AH, Zsóri KS, András C, Csiki Z. Prothrombotic polymorphisms in patients with Raynaud’s phenomenon and migraine. Acta Physiol Hung. 2012;99:430-5.
- Gaudy-Marqueste C, Roll P, Esteves-VieiraV, Weiller JP, Grob JJ, Cau P et al. LBR mutation and nuclear envelope defects in a patient affected with Reynolds Syndrome. J Med Genet. 2010;47:361-370.
- Fujıta E, Komıne M, Tsuda H, Adachı A, Murata S, Kamata Y et al. Case of H syndrome with massive skin involvement, retroperitoneal fibrosis and Raynaud’s phenomenon with anovel mutation in the SLC29A3 Gene. J Dermatol. 2015;42:1–3.
- Ermiş E, Yolcu M, Demirelli S, İpek E, Çiftçi C, Hançer S. Investigation of arrhytmia markers and KCNJ8-S422L gene mutation in a population with early repolarization pattern on ECG. J Am Coll Cardiol. 2013;17:73-80.
- Fedele F, Mancone M, Chilian MW, Severino P, Canali E, Logan S et al. Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease. Basic Res Cardiol. 2013;108:387.
- Veeramah RK, Karafet MT, Wolf D, Samson AR, Hammer FM. The KCNJ8-S422L variant previously associated with J-wave syndromes is found at an increased frequency in Ashkenazi Jews. Eur J Hum Genet. 2014;22:94-8.
- Minoretti P, Falcone C, Aldeghi A, Olivieri V, Mori F, Emanuele E et al. A novel Val734Ile variant in the ABCC9 gene associated with myocardial infarction. Clin Chim Acta. 2006;124–8.
- Smith KJ, Chadburn AJ, Adomaviciene A, Minoretti P, Vignali L, Emanuele E et al. Coronary spasm and acute myocardial infarction due to a mutation (V734I) in the nucleotide binding domain 1 of ABCC9. Int J Cardiol. 2013;168:3506-13
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Klinik Tıp Bilimleri |
| Bölüm | Araştırma |
| Yazarlar | |
| Proje Numarası | 2016-1-TP2-1417 |
| Yayımlanma Tarihi | 31 Mart 2023 |
| Kabul Tarihi | 3 Ocak 2023 |
| Yayımlandığı Sayı | Yıl 2023 Cilt: 48 Sayı: 1 |
