No Association of Polymorphisms in the Genes Encoding Interleukin-6 and Interleukin-6 Receptor Subunit Alpha with the Risk of Keloids in Polish Patients
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Keloid Patients and Control Subjects
4.2. Genetic Analyses
4.3. Statistical Analyses
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Pastuszak-Gabinowska, M.; Peregud-Pogorzelski, J.; Łuksza, K.; Sznelewski, P.; Brodkiewicz, A. Some aspects of molecular bases of keloid formation. Ann. Acad. Med. Stetin. 2011, 57, 10–17. [Google Scholar] [PubMed]
- Breasted, J.H. The Edwin Smith Surgical Papyrus, Volume 1: Hieroglyphic Transliteration, Translation, and Commentary; Oriental Institute Publications 3; The University of Chicago Press: Chicago, IL, USA, 1930; pp. 403–406. [Google Scholar]
- Sand, M.; Sand, D.; Brors, D.; Altmeyer, P.; Mann, B.; Bechara, F.G. Cutaneous lesions of the external ear. Head Face Med. 2008, 4, 2. [Google Scholar] [CrossRef] [PubMed]
- Retz, N. Traite des Maladies de la Peau et de Celles de l’Esprit; Mequignon: Paris, France, 1790; Volume 155. [Google Scholar]
- Alibert, J.L.M. Note sur la keloide. J. Univ. Sci. Med. 1816, 2, 207–216. [Google Scholar]
- Ojeh, N.; Bharatha, A.; Gaur, U.; Forde, A.L. Keloids: Current and emerging therapies. Scars Burn. Heal. 2020, 6, 2059513120940499. [Google Scholar] [CrossRef] [PubMed]
- Shih, B.; Bayat, A. Genetics of keloid scarring. Arch. Dermatol. Res. 2010, 302, 319–339. [Google Scholar] [CrossRef]
- Baisch, A.; Riedel, F. Hyperplastic scars and keloids: Part I: Basics and prevention. HNO 2006, 54, 893–905. [Google Scholar] [CrossRef]
- Sakaue, S.; Kanai, M.; Tanigawa, Y.; Karjalainen, J.; Kurki, M.; Koshiba, S.; Narita, A.; Konuma, T.; Yamamoto, K.; Akiyama, M.; et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat. Genet. 2021, 53, 1415–1424. [Google Scholar] [CrossRef]
- Ishigaki, K.; Akiyama, M.; Kanai, M.; Takahashi, A.; Kawakami, E.; Sugishita, H.; Sakaue, S.; Matoba, N.; Low, S.K.; Okada, Y.; et al. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases. Nat. Genet. 2020, 52, 669–679. [Google Scholar] [CrossRef] [PubMed]
- Nakashima, M.; Chung, S.; Takahashi, A.; Kamatani, N.; Kawaguchi, T.; Tsunoda, T.; Hosono, N.; Kubo, M.; Nakamura, Y.; Zembutsu, H. A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population. Nat. Genet. 2010, 42, 768–771. [Google Scholar] [CrossRef]
- Teng, G.; Liu, C.; Chen, M.; Ma, K.; Liang, L.; Yan, T. Differential susceptible loci expression in keloid and hypertrophic scars in the Chinese Han population. Ann. Plast. Surg. 2015, 74, 26–29. [Google Scholar] [CrossRef]
- Tosa, M.; Watanabe, A.; Ghazizadeh, M. IL-6 Polymorphism and Susceptibility to Keloid Formation in a Japanese Population. J. Investig. Dermatol. 2016, 136, 1069–1072. [Google Scholar] [CrossRef] [PubMed]
- Zhu, X.J.; Li, W.Z.; Li, H.; Fu, C.Q.; Liu, J. Association of interleukin-6 gene polymorphisms and circulating levels with keloid scars in a Chinese Han population. Genet. Mol. Res. 2017, 16, 1–7. [Google Scholar] [CrossRef] [PubMed]
- Zhu, F.; Wu, B.; Li, P.; Wang, J.; Tang, H.; Liu, Y.; Zuo, X.; Cheng, H.; Ding, Y.; Wang, W.; et al. Association study confirmed susceptibility loci with keloid in the Chinese Han population. PLoS ONE. 2013, 8, e62377. [Google Scholar] [CrossRef] [PubMed]
- Zhao, Y.; Liu, S.L.; Xie, J.; Ding, M.Q.; Lu, M.Z.; Zhang, L.F.; Yao, X.H.; Hu, B.; Lu, W.S.; Zheng, X.D. NEDD4 single nucleotide polymorphism rs2271289 is associated with keloids in Chinese Han population. Am. J. Transl. Res. 2016, 8, 544–555. [Google Scholar] [PubMed]
- Abdu Allah, A.M.K.; Mohammed, K.I.; Farag, A.G.A.; Hagag, M.M.; Essam, M.; Tayel, N.R. Interleukin-6 serum level and gene polymorphism in keloid patients. Cell. Mol. Biol. 2019, 65, 43–48. [Google Scholar] [CrossRef] [PubMed]
- Velez Edwards, D.R.; Tsosie, K.S.; Williams, S.M.; Edwards, T.L.; Russell, S.B. Admixture mapping identifies a locus at 15q21.2-22.3 associated with keloid formation in African Americans. Hum. Genet. 2014, 133, 1513–1523. [Google Scholar] [CrossRef] [PubMed]
- Wu, Y.; Wang, B.; Li, Y.H.; Xu, X.G.; Luo, Y.J.; Chen, J.Z.; Wei, H.C.; Gao, X.H.; Chen, H.D. Meta-analysis demonstrates association between Arg72Pro polymorphism in the P53 gene and susceptibility to keloids in the Chinese population. Genet. Mol. Res. 2012, 11, 1701–1711. [Google Scholar] [CrossRef] [PubMed]
- Dmytrzak, A.; Boroń, A.; Łoniewska, B.; Lewandowska, K.; Gorący, I.; Kaczmarczyk, M.; Ciechanowicz, A. Two Functional TP53 Genetic Variants and Predisposition to Keloid Scarring in Caucasians. Dermatol. Res. Pract. 2019, 2019, 6179063. [Google Scholar] [CrossRef] [PubMed]
- Dmytrzak, A.; Boroń, A.; Łoniewska, B.; Clark, J.S.C.; Kaczmarczyk, M.; Ciechanowicz, A. Replication study of four keloid-associated polymorphisms in patients of European descent—A single centre study. Intractable Rare Dis. Res. 2020, 9, 40–42. [Google Scholar] [CrossRef]
- Emami, A.; Halim, A.S.; Salahshourifar, I.; Yussof, S.J.; Khoo, T.L.; Kannan, T.P. Association of TGFβ1 and SMAD4 variants in the etiology of keloid scar in the Malay population. Arch. Dermatol. Res. 2012, 304, 541–547. [Google Scholar] [CrossRef]
- Pope, F.M.; Martin, G.R.; McKusick, V.A. Inheritance of Ehlers-Danlos type IV syndrome. J. Med. Genet. 1977, 14, 200–204. [Google Scholar] [CrossRef] [PubMed]
- Siraganian, P.A.; Rubinstein, J.H.; Miller, R.W. Keloids and neoplasms in the Rubinstein-Taybi syndrome. Med. Pediatr. Oncol. 1989, 17, 485–491. [Google Scholar] [CrossRef] [PubMed]
- Ghazizadeh, M.; Tosa, M.; Shimizu, H.; Hyakusoku, H.; Kawanami, O. Functional implications of the IL-6 signaling pathway in keloid pathogenesis. J. Investig. Dermatol. 2007, 127, 98–105. [Google Scholar] [CrossRef] [PubMed]
- Tosa, M.; Ghazizadeh, M.; Shimizu, H.; Hirai, T.; Hyakusoku, H.; Kawanami, O. Global gene expression analysis of keloid fibroblasts in response to electron beam irradiation reveals the involvement of interleukin-6 pathway. J. Investig. Dermatol. 2005, 124, 704–713. [Google Scholar] [CrossRef] [PubMed]
- Garbers, C.; Monhasery, N.; Aparicio-Siegmund, S.; Lokau, J.; Baran, P.; Nowell, M.A.; Jones, S.A.; Rose-John, S.; Scheller, J. The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases. Biochim. Biophys. Acta 2014, 1842, 1485–1494. [Google Scholar] [CrossRef] [PubMed]
- Rivera-Chavez, F.A.; Peters-Hybki, D.L.; Barber, R.C.; O’Keefe, G.E. Interleukin-6 promoter haplotypes and interleukin-6 cytokine responses. Shock 2003, 20, 218–223. [Google Scholar] [CrossRef]
- Nash, D.; Hughes, M.G.; Butcher, L.; Aicheler, R.; Smith, P.; Cullen, T.; Webb, R. IL-6 signaling in acute exercise and chronic training: Potential consequences for health and athletic performance. Scand. J. Med. Sci. Sports 2023, 33, 4–19. [Google Scholar] [CrossRef] [PubMed]
- Lokau, J.; Agthe, M.; Garbers, C. Generation of soluble Interleukin-11 and Interleukin-6 receptors: A crucial function for proteases during inflammation. Mediators Inflamm. 2016, 2016, 1785021. [Google Scholar] [CrossRef]
- Hirano, T.; Yasukawa, K.; Harada, H.; Taga, T.; Watanabe, Y.; Matsuda, T.; Kashiwamura, S.; Nakajima, K.; Koyama, K.; Iwamatsu, A. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 1986, 324, 73–76. [Google Scholar] [CrossRef]
- Luo, Y.; Zheng, S.G. Hall of Fame among Pro-inflammatory Cytokines: Interleukin-6 Gene and Its Transcriptional Regulation Mechanisms. Front. Immunol. 2016, 7, 604. [Google Scholar] [CrossRef]
- Su, H.; Lei, C.T.; Zhang, C. Interleukin-6 Signaling Pathway and Its Role in Kidney Disease: An Update. Front. Immunol. 2017, 8, 405. [Google Scholar] [CrossRef] [PubMed]
- Aliyu, M.; Zohora, F.T.; Anka, A.U.; Ali, K.; Maleknia, S.; Saffarioun, M.; Azizi, G. Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach. Int. Immunopharmacol. 2022, 111, 109130. [Google Scholar] [CrossRef]
- Swaroop, A.K.; Negi, P.; Kar, A.; Mariappan, E.; Natarajan, J.; Namboori, P.K.K.; Selvaraj, J. Navigating IL-6: From molecular mechanisms to therapeutic breakthroughs. Cytokine Growth Factor. Rev. 2024, 76, 48–76. [Google Scholar] [CrossRef] [PubMed]
- Arking, D.E.; Krebsova, A.; Macek, M., Sr.; Macek, M., Jr.; Arking, A.; Mian, I.S.; Fried, L.; Hamosh, A.; Dey, S.; McIntosh, I.; et al. Association of human aging with a functional variant of klotho. Proc. Natl. Acad. Sci. USA 2002, 99, 856–861. [Google Scholar] [CrossRef]
- Cybulski, C.; Górski, B.; Huzarski, T.; Byrski, T.; Gronwald, J.; Debniak, T.; Wokolorczyk, D.; Jakubowska, A.; Kowalska, E.; Oszurek, O.; et al. CHEK2-positive breast cancers in young Polish women. Clin. Cancer Res. 2006, 12, 4832–4835. [Google Scholar] [CrossRef] [PubMed]
- Freiberger, T.; Vyskocilová, M.; Kolárová, L.; Kuklínek, P.; Krystůfková, O.; Lahodná, M.; Hanzlíková, J.; Litzman, J. Exon 1 polymorphism of the B2BKR gene does not influence the clinical status of patients with hereditary angioedema. Hum. Immunol. 2002, 63, 492–494. [Google Scholar] [CrossRef]
- Larsen, T.B.; Lassen, J.F.; Brandslund, I.; Byriel, L.; Petersen, G.B.; Nørgaard-Pedersen, B. The Arg506Gln mutation (FV Leiden) among a cohort of 4188 unselected Danish newborns. Thromb. Res. 1998, 89, 211–215. [Google Scholar] [CrossRef]
- Han, T.; Wang, X.; Cui, Y.; Ye, H.; Tong, X.; Piao, M. Relationship between angiotensin-converting enzyme gene insertion or deletion polymorphism and insulin sensitivity in healthy newborns. Pediatrics 2007, 119, 1089–1094. [Google Scholar] [CrossRef]
- Ploski, R.; Wozniak, M.; Pawlowski, R.; Monies, D.M.; Branicki, W.; Kupiec, T.; Kloosterman, A.; Dobosz, T.; Bosch, E.; Nowak, M.; et al. Homogeneity and distinctiveness of Polish paternal lineages revealed by Y chromosome microsatellite haplotype analysis. Hum. Genet. 2002, 110, 592–600. [Google Scholar] [CrossRef]
- Kayser, M.; Lao, O.; Anslinger, K.; Augustin, C.; Bargel, G.; Edelmann, J.; Elias, S.; Heinrich, M.; Henke, J.; Henke, L.; et al. Significant genetic differentiation between Poland and Germany follows present-day political borders, as revealed by Y-chromosome analysis. Hum. Genet. 2005, 117, 428–443. [Google Scholar] [CrossRef]
- Debniak, T.; Scott, R.J.; Huzarski, T.; Byrski, T.; Rozmiarek, A.; Debniak, B.; Załuga, E.; Maleszka, R.; Kładny, J.; Górski, B.; et al. CDKN2A common variants and their association with melanoma risk: A population-based study. Cancer Res. 2005, 65, 835–839. [Google Scholar] [CrossRef] [PubMed]
- Adler, G.; Łoniewska, B.; Parczewski, M.; Kordek, A.; Ciechanowicz, A. Frequency of common CYP3A5 gene variants in healthy Polish newborn infants. Pharmacol. Rep. 2009, 61, 947–951. [Google Scholar] [CrossRef] [PubMed]
- Maculewicz, E.; Antkowiak, B.; Antkowiak, O.; Mastalerz, A.; Białek, A.; Cywińska, A.; Borecka, A.; Humińska-Lisowska, K.; Garbacz, A.; Lorenz, K.; et al. IL-6 Polymorphisms Are Not Related to Obesity Parameters in Physically Active Young Men. Genes 2021, 12, 1498. [Google Scholar] [CrossRef] [PubMed]
- Moreno Velásquez, I.; Golabkesh, Z.; Källberg, H.; Leander, K.; de Faire, U.; Gigante, B. Circulating levels of interleukin 6 soluble receptor and its natural antagonist, sgp130, and the risk of myocardial infarction. Atherosclerosis 2015, 240, 477–481. [Google Scholar] [CrossRef]
- Müllberg, J.; Oberthür, W.; Lottspeich, F.; Mehl, E.; Dittrich, E.; Graeve, L.; Heinrich, P.C.; Rose-John, S. The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site. J. Immunol. 1994, 152, 4958–4968. [Google Scholar] [CrossRef] [PubMed]
- Peters, M.; Jacobs, S.; Ehlers, M.; Vollmer, P.; Müllberg, J.; Wolf, E.; Brem, G.; Meyer zum Büschenfelde, K.H.; Rose-John, S. The function of the soluble interleukin 6 (IL-6) receptor in vivo: Sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6. J. Exp. Med. 1996, 183, 1399–1406. [Google Scholar] [CrossRef] [PubMed]
- Galicia, J.C.; Tai, H.; Komatsu, Y.; Shimada, Y.; Akazawa, K.; Yoshie, H. Polymorphisms in the IL-6 receptor (IL-6R) gene: Strong evidence that serum levels of soluble IL-6R are genetically influenced. Genes Immun. 2004, 5, 513–516. [Google Scholar] [CrossRef]
- Esparza-Gordillo, J.; Schaarschmidt, H.; Liang, L.; Cookson, W.; Bauerfeind, A.; Lee-Kirsch, M.A.; Nemat, K.; Henderson, J.; Paternoster, L.; Harper, J.I.; et al. A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis. J. Allergy Clin. Immunol. 2013, 132, 371–377. [Google Scholar] [CrossRef] [PubMed]
- Szpakowicz, A.; Pepinski, W.; Waszkiewicz, E.; Skawronska, M.; Niemcunowicz-Janica, A.; Musial, W.J.; Kaminski, K.A. The rs2228145 polymorphism in the interleukin-6 receptor and its association with long-term prognosis after myocardial infarction in a pilot study. Arch. Med. Sci. 2017, 13, 93–99. [Google Scholar] [CrossRef]
- Kapelski, P.; Skibinska, M.; Maciukiewicz, M.; Pawlak, J.; Permoda-Osip, A.; Twarowska-Hauser, J. Family-based association study of interleukin 6 (IL6) and its receptor (IL6R) functional polymorphisms in schizophrenia in the Polish population. J. Neuroimmunol. 2015, 285, 62–67. [Google Scholar] [CrossRef]
- Kapelski, P.; Skibinska, M.; Maciukiewicz, M.; Wilkosc, M.; Frydecka, D.; Groszewska, A.; Narozna, B.; Dmitrzak-Weglarz, M.; Czerski, P.; Pawlak, J.; et al. Association study of functional polymorphisms in interleukins and interleukin receptors genes: IL1A, IL1B, IL1RN, IL6, IL6R, IL10, IL10RA and TGFB1 in schizophrenia in Polish population. Schizophr. Res. 2015, 169, 1–9. [Google Scholar] [CrossRef] [PubMed]
- Sokolik, R.; Iwaszko, M.; Świerkot, J.; Wysoczańska, B.; Korman, L.; Wiland, P.; Bogunia-Kubik, K. Relationship between Interleukin-6 -174G/C Genetic Variant and Efficacy of Methotrexate Treatment in Psoriatic Arthritis Patients. Pharmgenom. Pers. Med. 2021, 14, 157–166. [Google Scholar] [CrossRef] [PubMed]
- Lulińska-Kuklik, E.; Maculewicz, E.; Moska, W.; Ficek, K.; Kaczmarczyk, M.; Michałowska-Sawczyn, M.; Humińska-Lisowska, K.; Buryta, M.; Chycki, J.; Cięszczyk, P.; et al. Are IL1B, IL6 and IL6R Gene Variants Associated with Anterior Cruciate Ligament Rupture Susceptibility? J. Sports Sci. Med. 2019, 18, 137–145. [Google Scholar] [PubMed]
- Drozdzik, M.; Szlarb, N.; Kurzawski, M. Interleukin-6 level and gene polymorphism in spontaneous miscarriage. Tissue Antigens 2013, 82, 171–176. [Google Scholar] [CrossRef] [PubMed]
Polymorphism (Chromosomal Location a) | Allele b | Distribution of Alleles, n (%) | p | Distribution of Genotypes, n (%) | p | pA | pR | pD | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
(1/2) | Keloid Patients | Control Group | Keloid Patients (n = 86) | Control Group (n = 100) | ||||||||||
1/2 | 1/2 | 1;1 | 1;2 | 2;2 | 1;1 | 1;2 | 2;2 | |||||||
rs1800797 (7:22726602) | G/A | 102/70 (59.3/40.7) | 123/77 (61.5/38.5) | 0.665 | 32 (37.2) | 38 (44.2) | 16 (18.6) | 39 (39.0) | 45 (45.0) | 16 (16.0) | 0.893 | 0.865 | 0.794 | 0.963 |
rs1800796 (7:22726627) | G/C | 154/18 (89.5/10.5) | 188/12 (94.0/6.0) | 0.115 | 70 (81.4) | 14 (16.3) | 2 (2.3) | 88 (88.0) | 12 (12.0) | 0 (0.0) | 0.206 | - c | - c | 0.212 |
rs1800795 (7:22727026) | G/C | 105/67 (61.0/39.0) | 125/75 (62.5/37.5) | 0.773 | 33 (38.4) | 39 (45.3) | 14 (16.3) | 41 (41.0) | 43 (43.0) | 16 (16.0) | 0.933 | 0.946 | 0.824 | 0.942 |
rs2228145 (1:154454494) | A/C | 105/67 (61.0/39.0) | 127/73 (63.5/36.5) | 0.626 | 31 (36.0) | 43 (50.0) | 12 (14.0) | 40 (40.0) | 47 (47.0) | 13 (13.0) | 0.858 | 0.334 | 0.977 | 0.181 |
Haplotype | Whole Group *, n (%) | Keloid Patients, n (%) | Control Group n (%) | pA | pR | pD |
---|---|---|---|---|---|---|
H1 (G-G-G) | 197 (53.0) H1 | 87 (50.6) | 110 (55.0) | Reference haplotype | ||
H2 (A-G-C) | 133 (35.8) H2 | 59 (34.0) | 74 (37.0) | 0.927 | 0.806 | 0.974 |
H3 (G-C-G) | 24 (6.4) H3 | 12 (6.9) | 12 (6.0) | 0.235 | - | 0.287 |
H4 (A-G-G) | 9 (2.4) H4 | 6 (3.6) | 3 (1.5) | 0.287 | 0.484 | 0.269 |
H5 (A-C-C) # | 5 (1.3) | 5 (3.1) | 0 (0.0) | |||
H6 (G-G-C) # | 3 (0.8) | 2 (1.4) | 1 (0.5) | |||
H7 (G-C-C) # | 1 (0.3) | 1 (0.4) | 0 (0.0) | |||
H8 (A-C-G) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |||
H2+H4+H7 | 9 (2.4) | 8 (4.9) | 1 (0.5) | 0.205 | - | 0.222 |
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Dmytrzak, A.; Lewandowska, K.; Boroń, A.; Łoniewska, B.; Grzesch, N.; Brodkiewicz, A.; Clark, J.S.C.; Ciechanowicz, A.; Kostrzewa-Nowak, D. No Association of Polymorphisms in the Genes Encoding Interleukin-6 and Interleukin-6 Receptor Subunit Alpha with the Risk of Keloids in Polish Patients. Int. J. Mol. Sci. 2024, 25, 5284. https://doi.org/10.3390/ijms25105284
Dmytrzak A, Lewandowska K, Boroń A, Łoniewska B, Grzesch N, Brodkiewicz A, Clark JSC, Ciechanowicz A, Kostrzewa-Nowak D. No Association of Polymorphisms in the Genes Encoding Interleukin-6 and Interleukin-6 Receptor Subunit Alpha with the Risk of Keloids in Polish Patients. International Journal of Molecular Sciences. 2024; 25(10):5284. https://doi.org/10.3390/ijms25105284
Chicago/Turabian StyleDmytrzak, Andrzej, Klaudyna Lewandowska, Agnieszka Boroń, Beata Łoniewska, Natalie Grzesch, Andrzej Brodkiewicz, Jeremy S. C. Clark, Andrzej Ciechanowicz, and Dorota Kostrzewa-Nowak. 2024. "No Association of Polymorphisms in the Genes Encoding Interleukin-6 and Interleukin-6 Receptor Subunit Alpha with the Risk of Keloids in Polish Patients" International Journal of Molecular Sciences 25, no. 10: 5284. https://doi.org/10.3390/ijms25105284