Pulmonary arterial hypertension (PAH) is a progressive disease with a complex pathogenesis. The polymorphism of the gene of multidrug resistance-1 (MDR1) has been associated with many diseases including PAH.
Objective. In this study we aimed to investigate the relevance of the MDR1 polymorphism to pediatric PAH clinical course.
Methods. A total of 40 pediatric patients with PAH (secondary to congenital heart defects or idiopathic) and 40 control subjects were enrolled. Patients with PAH were divided into 2 groups, according to their evolution: 28 patients who remained clinically stable at 12-months (non-worsening group) and 12 patients who presented clinical worsening at 12-months (worsening group). Genomic DNA was genotyped for MDR1 gene polymorphisms as follows: C1236T, G2677T and C3435T.
Results. There were no significant differences between PAH children groups (clinical worsening and non-worsening) nor between PAH children and controls in terms of frequency distribution of the three studied genotypes or alleles.
Conclusions. The MDR1 polymorphism could not be correlated with the clinical evolution of pediatric PAH patients in our study.
1. Bazan IS, Fares WH. Pulmonary hypertension: diagnosis and therapeutic challenges. Ther Clin Risk Manag. 2015 Aug 17;11:1221-33.
2. Crosswhite P, Sun Z. Nitric Oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J Hipertens. 2010; 28(2):201-12. DOI: 10.1097/HJH.0b013e328332bcdb
3. Ghasemzadeh N, Patel RS, Eapen DJ, Veledar E, Kassem HA, Manocha P, et al. Oxidative stress is associated with increased pulmonary artery systolic pressure in humans. Hypertension. 2014 Jun;63(6):1270-5. DOI: 10.1161/HYPERTENSIONAHA.113.02360
4. Sanders KA, Hoidal JR. The NOX on pulmonary hypertension. Circ Res. 2007; 101:224-6. DOI: 10.1161/CIRCRESAHA.107.158246
5. Fulton DJR, Li X, Bordan Zs, Haigh S, Bentley A, Chen F, et al. Reactive Oxygen and Nitrogen Species in the Development of Pulmonary Hypertension. Antioxidants (Basel). 2017; 6(3):54. DOI: 10.3390/antiox6030054
7. Humbert M, Lau EMT, Montani D, Jais X, Sitbon O, Simonneau G. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2014; 130:2189-208. DOI: 10.1161/CIRCULATIONAHA.114.006974
8. Fares WH, Trow TK. Targeted approaches to the treatment of pulmonary hypertension. Ther Adv Respir Dis. 2012; 6:147-59. DOI: 10.1177/1753465812441849
9. Austin ED, Loyd JE. The genetics of pulmonary arterial hypertension. Circ Res. 2014; 115(1):189-202. DOI: 10.1161/CIRCRESAHA.115.303404
10. Muntean I, Togănel R, Benedek T. Genetics of congenital heart disease: past and present. Biochem Genet. 2017; 55(2):105-23. DOI: 10.1007/s10528-016-9780-7
11. Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jaïs X, et al. Clinical outcomes of pulmonary arterial hyper-tension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med. 2010; 181(8):851-61. DOI: 10.1164/rccm.200908-1284OC
12. Girerd B, Weatherald J, Montani D, Humbert M. Heritable pulmonary hypertension: from bench to bedside. Eur Respir Rev. 2017;26(145):170037. DOI: 10.1183/16000617.0037-2017
13. Pânzaru M, Rusu C, Voloşciuc M, Braha E, Butnariu L, Gramescu M, et al. Benefits of cytogenetic testing in diagnosis of plurimalformative syndromes with congenital heart defects. Rev Romana Med Lab. 2012;20(3):265-72.
14. Togănel R, Muntean I, Duicu C, Făgărăşan A, Gozar L, Bănescu C. The role of eNOS and AGT gene polymorphisms in secondary pulmonary arterial hypertension in Romanian children with congenital heart disease. Rev Romana Med Lab. 2013; 21(3):267-74. DOI: 10.2478/rrlm-2013-0031
15. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmöller J, Johne A et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000; 97(7):3473-8. DOI: 10.1073/pnas.97.7.3473
16. van der Deen M, de Vries EG, Timens W, Scheper RJ, Timmer-Bosscha H, Postma DS. ATP-binding cassette (ABC) transporters in normal and pathological lung. Respir Res. 2005; 6:59. DOI: 10.1186/1465-9921-6-59
17. Manduz Ş, Katrancıoğlu N, Karahan O, Yılmaz MB, Özdemir Ö, Berkan Ö. Associations between common 3435 C>T variants of the multi-drug resistance [MDR-1 (ABCB1)] gene and abdominal aortic aneurysm: a pilot study. Turkish Journal of Thoracic and Cardiovascular Surgery. 2011; 19(2):177-81. DOI: 10.5606/tgkdc.dergisi.2011.008
18. Batetta B, Dessì S, Putzolu M, Sanna F, Spano O, Mulas MF et al. MDR1 gene expression in normal and atherosclerotic human arteries (1). J Vasc Res. 1999; 36:261-71. DOI: 10.1159/000025654
19. Dombrowski SM, Desai SY, Marroni M, Cucullo L, Goodrich K, Bingaman W, et al. Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia. 2001; 42:1501-6. DOI: 10.1046/j.1528-1157.2001.12301.x
20. Bebek N, Çine N, Öner GÖ, Eşkazan E, Özbek U. Genotype and Allele frequencies of MDR-1 C3435T polymorphism in Turkish population. J Neurol Sci. 2005; 22(37):261-6.
21. Ji-Ye Y, Qiong H, Youyun Y, Jian-Ting Z, Mei-Zuo Z, Hong-Hao Z, et al. Characterization and analyses of multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in Chinese population. Pharmacogenet Genomics. 2009; 19(3):206–16. DOI: 10.1097/FPC.0b013e328323f680
22. Tang K, Ngoi SM, Gwee PC, Chua JM, Lee EJ, Chong SS et al. Distinct haplotype profiles and strong linkage disequilibriumat the MDR1 multidrug transporter gene locus in three ethnic Asian populations. Pharmacogenetics. 2002; 12:437–50. DOI: 10.1097/00008571-200208000-00004
23. Wang LH, Song YB, Zheng WL, Jiang L, Wen-Li. The association between polymorphisms in the MDR1 gene and risk of cancer: a systematic review and pooled analysis of 52 case–control studies. Cancer Cell Int. 2013; 13:46. DOI: 10.1186/1475-2867-13-46
24. Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37(1):67-119 DOI: 10.1093/eurheartj/ehv317
25. American Thoracic Society. American Thoracic Society statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002; 166:111-7. DOI: 10.1164/ajrccm.166.1.at1102
26. Dong L, Luo R, Tong Y, Cai X, Mao M, Yu D. Lack of association between ABCB1 gene polymorphisms and pharmacoresistant epilepsy: an analysis in a western Chinese pediatric population. Brain Res. 2011; 1391:114-24. DOI: 10.1016/j.brainres.2011.03.028
27. Todoran Butila A, Sin A, Racoş Szabo E, Micheu C, Moldovan VG, Voidazan S et al. ABCB1 gene polymorphisms is not associated with drug-resistant epilepsy in Romanian children. Rev Romana Med Lab. 2015; 23(4):469-82. DOI: 10.1515/rrlm-2015-0037
28. Wolking S, Schaeffeler E, Lerche H, Schwab M, Nies AT. Impact of genetic polymorphisms of ABCB1 (MDR1, G-Glycoprotein) on drug disposition and potential clinical implications: update of the literature. Clin Pharmacokinet. 2015; 54(7):709-35. DOI: 10.1007/s40262-015-0267-1
29. Wartenberg M, Ling FC, Schallenberg M, Bäumer AT, Petrat K, Hescheler J et al. Down-regulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by reactive oxygen species. J Biol Chem. 2001; 276(20):17420-8. DOI: 10.1074/jbc.M100141200
30. Dorfmüller P, Perros F, Balabanian K, Hum-bert M. Inflammation in pulmonary arterial hypertension. Eur Respir J. 2003; 22:358–63. DOI: 10.1183/09031936.03.00038903
31. Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994; 144:275–85.
32. Sakamaki F, Kyotani S, Nagaya N, Nagato Sato N, Oya H, Satoh T, et al. Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hyper-tension were improved by continuous prostacyclin therapy. Circulation. 2000; 102:2720-5. DOI: 10.1161/01.CIR.102.22.2720
33. Sapmaz A, Ozen Karatayli SC, Dağli U, Kiliç ZM, Törüner M, Celik Y et al. Effects of polymorphism in G2677T/A triallelic region of MDR1 gene in Turkish patients with inflammatory bowel disease. Turk J Gastroenterol. 2008; 19:168-73.
34. Kedmi M, Maayan S, Cohen SB, Hauzi M, Rund D. MDR1 and CYP3A4 polymorphisms are associated with HIV seropositivity in Israeli patients but do not influence the course of HIV disease. AIDS Patient Care STDS. 2007; 21:653-8. DOI: 10.1089/apc.2006.0148
35. Elghannam DM, Ibrahim L, Ebrahim MA, Azmy E, Hakem H. Association of MDR1 gene polymorphism (G2677T) with imatinib response in Egyptian chronic myeloid leukemia patients. Hematology. 2014;19:123–8. DOI: 10.1179/1607845413Y.0000000102
36. Ma L, Liu H, Ruan L, Yang X, Yang H, Feng Y. Multi-drug resistance gene 1 C123T polymorphism and susceptibility to leukemia: a meta-analysis. Biomed Rep. 2015; 3(1):83-7. DOI: 10.3892/br.2014.387
37. Sabin O, Bocșan IC, Trifa A, Major ZZ, Heghes SC, Brusturean Bota E, et al. Correlation between ABCB1 gene polymorphisms, antiepileptic drug concentrations and treatment response. Rev Romana Med Lab. 2018 (ahead of print). DOI:10.2478/rrlm-2018-0012
38. Yamamoto-Furusho JK, Villeda-Ramirez MA, Fonseca-Camarillo G, Sanchez-Munoz F, Dominiquez-Lopez A, Barreto-Zuniga R, et al. High gene expression of MDR1 (ABCB1) is associated with medical treatment response and long-term remission in patients with ulcerative colitis. Inflam Bowel Dis. 2010; 16:541-2. DOI: 10.1002/ibd.21016
39. Milojkovic M, Milacic N, Radovic J, Ljubisavljevic S. MDR1 gene polymorphisms and p-glycoprotein expression in respiratory diseases. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015; 159(3):341-6. DOI: 10.5507/bp.2014.032
40. Dogan OT, Katrancioglu N, Karahan O, Sanli GC, Zorlu A, Manduz S. Frequency of the MDR-1 C>T gene polymorphism in patients with COPD. Clinics (Sao Paulo). 2010; 65:1115-7.
41. Martinelli M, Scapoli L, Pacilli AMG, Carbonara P, Girardi A, Mattei G, et al. Human Multidrug Resistance 1 gene polymorphisms and idiopathic pulmonary fibrosis. J Res Med Sci. 2015; 20(1):93-6.
42. Takatsuki S, Ivy DD. Current Challenges in Pediatric Pulmonary Hypertension. Semin Respir Crit Care Med. 2013; 34(5):627-44. DOI: 10.1055/s-0033-1356461