Investigation of the SNPs of IRF6 gene in non-syndromic cleft lip and/or palate (NSCLP) in a Turkish population

Yıl 2022, Cilt: 2 Sayı: 1, 14 - 19, 03.04.2022

Zeynep Yeğin , Ömer Uslukaya , Fatih Taşkesen , İbrahim Yıldırım

https://doi.org/10.29228/HMJ.9

Cited By: 1

Öz

Objective Non-syndromic cleft lip and/or palate (NSCLP) is a complex malformation with both genetic and environmental effects and interferon regulatory factor 6 (IRF6) is the most focused gene to unravel the genetic etiology of the disease since its important role in the formation and maintenance of the oral periderm to ensure appropriate palatal adhesion has been demonstrated. The aim of this study was to investigate the association between two SNPs (rs2235371 and rs2013162) of IRF6 gene and NSCLP in Turkish population.
Materials and Methods Genotyping of both SNPs were performed with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method in 38 NSCLP patients, their mothers and the same number of healthy control individuals.
Results Our results did not indicate significant differences in neither genotypic nor allelic distributions between children and controls. The same situation was observed when the mothers of children were also compared with the controls.
Conclusion Considering both contradictive results in different populations worldwide and our relatively small sample size that may be a limitation for this study, we strongly encourage the replication studies with larger sample sizes to draw a precise conclusion about the role of IRF6 gene variants for susceptibility to NSCLP.

Anahtar Kelimeler

cleft lip, cleft palate, interferon regulatory factor 6 (IRF6) gene

Investigation of the SNPs of IRF6 gene in non-syndromic cleft lip and/or palate (NSCLP) in a Turkish population

Öz

Amaç Non-sendromik dudak ve/veya damak yarığı (NSDDY) hem genetik hem de çevresel etkilere sahip kompleks bir malformasyondur ve uygun palatal adezyonu sağlamak için oral periderm oluşumu ve devamlılığındaki önemli rolünden dolayı IRF6 hastalığın genetik etiyolojisini çözmek için üzerinde en çok yoğunlaşılmış gendir. Bu çalışmanın amacı, Türk popülasyonunda IRF6 genindeki iki SNP (rs2235371 ve rs2013162) ile NSDDY arasındaki ilişkiyi araştırmaktır.
Gereç ve Yöntemle Her iki SNP’nin genotiplemesi, Polimeraz Zincir Reaksiyonu-Restriksiyon Fragment Uzunluk Polimorfizmi yöntemi ile 38 NSDDY hastasında, annelerinde ve aynı sayıda kontrol grubu bireylerde yapıldı. Bulgular: Sonuçlarımız, çocuklar ve kontroller arasında ne genotipik ne de allelik dağılımlarda önemli farklılıklar belirtmedi. Aynı durum çocukların anneleri ile kontroller karşılaştırıldığında da gözlendi.
Bulgular Çalışmaya toplam 154 hasta dahil edildi. Alt gastrointestinal sistem ve özofagus varis kanaması olan hastalar çalışma dışı bırakıldı. Üst gastrointestinal sistem kanaması ile başvuran hastaların 28%’i kadın, 72%’si erkekti. Hastaların yaş ortalaması 61.23±15.37 yıl saptandı. Forrest endoskopik sınıflamasına göre erkeklerde 5 hasta (4.50%) derece Ia, 15 hasta (13.51%) derece Ib, 13 hasta (11.71%) derece IIa, 9 hasta (8.11%) derece IIb, 69 hasta (62.16%) kadınlarda evre III, 3 hastada (6.98%) evre Ia, 8 hastada (18.60%) evre Ib, 4 hastada (9.30%) evre IIb ve 28 hastada (65.12%) evre III saptandı. Bu hastaların ortalama hastanede kalış süreleri 8.20±4.42 gündü. 7 hastada (4.54%) 30 günlük mortalite saptandı.
Sonuç Hem dünya çapındaki farklı popülasyonlardaki çelişkili sonuçlar hem de bu çalışma için bir sınırlama olabilecek nispeten küçük örneklem büyüklüğümüz göz önüne alındığında, NSDDY’ye yatkınlık oluşturmada IRF6 gen varyantlarının rolü hakkında kesin bir sonuç çıkarabilmek için daha büyük örneklem boyutlarına sahip replikasyon çalışmalarını güçlü bir şekilde desteklemekteyiz.

Anahtar Kelimeler

cleft lip, cleft palate, interferon regulatory factor 6 (IRF6) gene

Kaynakça

• Shi J, Song T, Jiao X, Qin C, Zhou J. Single-nucleotide polymorphisms (SNPs) of the IRF6 and TFAP2A in non-syndromic cleft lip with or without cleft palate (NSCLP) in a northern Chinese population. Biochem Biophys Res Commun 2011;410(4):732-6.
• Charzewska A, Obersztyn E, Hoffman-Zacharska D, Lenart J, Poznański J, Bal J. Novel Mutations in the IRF6 Gene on the Background of Known Polymorphisms in Polish Patients With Orofacial Clefting. Cleft Palate Craniofac J 2015;52(5):e161-7.
• Wang M, Pan Y, Zhang Z, Wang L. Three polymorphisms in IRF6 and 8q24 are associated with nonsyndromic cleft lip with or without cleft palate: evidence from 20 studies. Am J Med Genet A 2012;158A(12):3080-6.
• Gritli-Linde A. p63 and IRF6: brothers in arms against cleft palate. J Clin Invest 2010;120(5):1386-9.
• Moretti F, Marinari B, Lo Iacono N, Botti E, Giunta A, Spallone G, Garaffo G, Vernersson-Lindahl E, Merlo G, Mills Aa, Ballarò C, Alemà S, Chimenti S, Guerrini L, Costanzo A. A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias. J Clin Invest 2010;120(5):1570-7.
• Thomason HA, Zhou H, Kouwenhoven EN, Dotto GP, Restivo G, Nguyen BC, Little H, Dixon MJ, Van Bokhoven H, Dixon J. Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice. J Clin Invest 2010;120(5):1561-9.
• Ke CY, Xiao WL, Chen CM, Lo LJ, Wong FH. IRF6 is the mediator of TGFβ3 during regulation of the epithelial mesenchymal transition and palatal fusion. Sci Rep 2015; 5: 12791.
• Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu YE, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med 2004;351(8):769-80.
• Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16(3):1215.
• Pan Y, Ma J, Zhang W, Du Y, Niu Y, Wang M, Zhang Z, Wang L. IRF6 polymorphisms are associated with nonsyndromic orofacial clefts in a Chinese Han population. Am J Med Genet A 2010;152A(10):2505-11.
• Huang Y, Wu J, Ma J, Beaty TH, Sull JW, Zhu L, Lu D, Wang Y, Meng T, Shi B. Association between IRF6 SNPs and Oral Celfts in West China. J Dent Res 2009;88(8):715-718.
• Scapoli L, Palmieri A, Martinelli M, Pezzetti F, Carinci P, Tognon M, Carinci F. Strong evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and nonsyndromic cleft lip with or without cleft palate, in an Italian population. Am J Hum Genet 2005;76(1):180-3.
• Jugessur A, Rahimov F, Lie RT, Wilcox AJ, Gjessing HK, Nilsen RM, Nguyen TT, Murray JC. Genetic variants in IRF6 and the risk of facial clefts: single-marker and haplotype-based analyses in a population-based case-control study of facial clefts in Norway. Genet Epidemiol 2008;32(5):413-24.
• Hering R and Grundmann K. The IRF6 p.274V polymorphism is not a risk factor for isolated cleft lip. Genet Med 2005;7(3):209; author reply 209-10.
• Paranaíba LM, Bufalino A, Martelli-Júnior H, De Barros LM, Graner E, Coletta RD. Lack of association between IRF6 polymorphisms (rs2235371 and rs642961) and non-syndromic cleft lip and/or palate in a Brazilian population. Oral Dis 2010;16(2):193-7.
• Letra A, Fakhouri W, Fonseca RF, Menezes R, Kempa I, Prasad JL, Mchenry TG, Lidral AC, Moreno L, Murray JC, Daack-Hirsch S, Marazita ML, Castilla EE, Lace B, Orioli IM, Granjeiro JM, Schutte BC, Vieira AR. Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate. PLoS One 2012;7(9):e45441.
• Larrabee YC, Birkeland AC, Kent DT, Flores C, Su GH, Lee JH, Haddad J JR. Association of common variants, not rare mutations, in IRF6 with nonsyndromic clefts in a Honduran population. Laryngoscope 2011;121(8):1756-9.
• Birnbaum S, Ludwig KU, Reutter H, Herms S, De Assis NA, Diaz-Lacava A, Barth S, Lauster C, Schmidt G, Scheer M, Saffar M, Martini M, Reich RH, Schiefke F, Hemprich A, Pötzsch S, Pötzsch B, Wienker TF, Hoffmann P, Knapp M, Kramer FJ, Nöthen MM, Mangold E. IRF6 gene variants in Central European patients with non-syndromic cleft lip with or without cleft palate. Eur J Oral Sci 2009;117(6):766-9.
• Salahshourifar I, Sulaiman WA, Zilfalil BA, Halim AS. Contribution of variants in and near the IRF6 gene to the risk of nonsyndromic cleft lip with or without cleft palate in a Malay population. Am J Med Genet A 2011;155A(9):2302-7.
• Song T, Wu D, Wang Y, Li H, Yin N, Zhao Z. SNPs and interaction analyses of IRF6, MSX1 and PAX9 genes in patients with nonsyndromic cleft lip with or without palate. Mol Med Rep 2013;8(4):1228-34.
• Lu Y, Liu Q, Xu W, Li Z, Jiang M, Li X, Zhao N, Liu W, Sui Y, Ma C, Feng W, Han W, Li J. TGFA and IRF6 contribute to the risk of nonsyndromic cleft lip with or without cleft palate in northeast China.PLoS One. 2013;8(8):e70754. Print 2013. Erratum in: PLoS One 2014;9(12):e116257
• Xu W, Han WT, Lu YP, Feng WH, Dai M. Association of single-nucleotide polymorphisms, rs2235371 and rs2013162, in the IRF6 gene with non-syndromic cleft palate in northeast China. Genet Mol Res 2016;15(3).
• Zhou Q, Li M, Zhu W, Guo J, Wang Y, Li Y, Li S. Association between interferon regulatory factor 6 gene polymorphisms and nonsyndromic cleft lip with or without cleft palate in a chinese population. Cleft Palate Craniofac J 2013;50(5):570-6.