Association of CD40 gene polymorphisms rs1883832 and rs4810485 with familial mediterranean fever in pediatric patients

Binici, Mahir; Yücel, İlyas; Tekeş, Selahattin; Oral, Diclehan; Balkan, Mahmut; Katar, Selahattin

doi:10.2478/rrlm-2025-0010

Abstract

Background

Familial Mediterranean fever (FMF) is a recessively inherited autoinflammatory disease characterized by a combination of multiple clinical symptoms potentially associated with numerous genetic and non-genetic risk factors. The CD40 gene, which plays an essential role in inflammatory responses and immune system regulation, contains single-nucleotide polymorphisms (SNPs) that have been linked to various diseases. This research aimed to examine potential associations between CD40 SNPs and FMF in pediatric patients.

Methods

Data regarding common MEFV gene mutations in the patient cohort were analyzed using pyrosequencing techniques. For both patient and control groups, CD40 gene SNPs were genotyped using real-time PCR with rs1883832 and rs4810485 Taq-Man genotyping probes.

Results

The analysis of the CD40 gene's rs1883832 SNP revealed the following distribution in the patient group: CC genotype at 43.0%, CT genotype at 56.0%, and TT genotype at 1.0%. In comparison, the control group showed CC genotype in 47.0% and CT genotype in 53.0% of cases. For the rs4810485 SNP of the CD40 gene, the patient group exhibited GG genotype in 43.0%, GT genotype in 43.0%, and TT genotype in 14.0% of cases. The control group showed distributions of 47.0% for GG genotype, 45.0% for GT genotype, and 8.0% for TT genotype.

Conclusions

The study found no statistically significant correlations between FMF disease and either the rs1883832 or rs4810485 SNPs of the CD40 gene.

References

Dundar M, Fahrioglu U, Yildiz SH, Bakir-Gungor B, Temel SG, Akin H, et al. Clinical and molecular evaluation of MEFV gene variants in the Turkish population: A study by the National Genetics Consortium. Funct Integr Genom. 2022;22:291-315. DOI: 10.1007/s10142-021-00819-3
Search in Google Scholar Back to article
Alghamdi M. Familial Mediterranean fever, review of the literature. Clin Rheumatol. 2017;36:1707-1713 DOI: 10.1007/s10067-017-3715-5
Search in Google Scholar Back to article
Soriano A, Manna R. Familial Mediterranean fever: New phenotypes. Autoimmun Rev. 2012;12:31-37 DOI: 10.1016/j.autrev.2012.07.019
Search in Google Scholar Back to article
Chaaban A, Salman Z, Karam L, Kobeissy PH, Ibrahim JN. Updates on the role of epigenetics in familial mediterranean fever (FMF). Orphanet Journal of Rare Diseases. 2024;19(1):90 DOI: 10.1186/s13023-024-03098-w
Search in Google Scholar Back to article
De Torre-Minguela C, Mesa del Castillo P, Pelegrín P. The NLRP3 and pyrin inflammasomes: implications in the pathophysiology of autoinflammatory diseases. Front Immunol. 2017;8:43 DOI: 10.3389/fimmu.2017.00043
Search in Google Scholar Back to article
Lancieri M, Bustaffa M, Palmeri S, Prigione I, Penco F, Papa R, et al. An update on familial Mediterranean fever. Int J Molec Sciences. 2023;24(11):9584 DOI: 10.3390/ijms24119584
Search in Google Scholar Back to article
Veyssiere M, Aghamiri SS, Cervantes AH, Henry T, Soumelis V. A mathematical model of Familial Medi-terranean Fever predicts mechanisms controlling inflammation. Clin Immunol. 2023;257:109839 DOI: 10.1016/j.clim.2023.109839
Search in Google Scholar Back to article
Yigit S, Tural S, Tekcan A, Tasliyurt T, Inanir A, Uzunkaya S, et al. The role of IL-4 gene 70 bp VNTR and ACE gene I/D variants in Familial Mediterranean fever. Cytokine. 2014;67:1-6 DOI: 10.1016/j.cyto.2014.01.007
Search in Google Scholar Back to article
Wagner AH, Klersy A, Sultan CS, Hecker M. Potential role of soluble CD40 receptor in chronic inflammatory diseases. Biochem Pharmacol. 2023;217:115858 DOI: 10.1016/j.bcp.2023.115858
Search in Google Scholar Back to article
Chatzigeorgiou A, Lyberi M, Chatzilymperis G, Nezos A, Kamper E. CD40/CD40L signaling and its implication in health and disease. Biofactors. 2009;35:474-483 DOI: 10.1002/biof.62
Search in Google Scholar Back to article
Bonizzi G, Karin M. The two NF-kappa B activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004;25:280-288 DOI: 10.1016/j.it.2004.03.008
Search in Google Scholar Back to article
Deng ZH, Sun MH, Li YS, Luo W, Zhang FJ, Tian J, et al. Single nucleotide polymorphisms in the CD40 gene associate with the disease susceptibility and severity in knee osteoarthritis in the Chinese Han population: A case-control study. BMC Musculoskelet Disord. 2017;18:115 DOI: 10.1186/s12891-017-1466-8
Search in Google Scholar Back to article
Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40:1879-1885. DOI: 10.1002/art.1780401023
Search in Google Scholar Back to article
Nursal AF, Kaya S, Sezer O, Karakus N, Yigit S. MTHFR gene C677T and A1298C variants are associated with FMF risk in a Turkish cohort. J Clin Lab Anal. 2018;32:e22259 DOI: 10.1002/jcla.22259
Search in Google Scholar Back to article
Tufan A, Babaoglu MO, Akdogan A, Yasar U, Calguneri M, Kalyoncu U et al. Association of drug transporter gene ABCB1 (MDR1) 3435C to T polymorphism with colchicine response in familial Mediterranean fever. J rheumatol. 2007;34(7):1540-1544.
Search in Google Scholar Back to article
Keskin O, Yilmaz E, Kutlay S, Bakkaloglu A, Topaloglu R, Arici M et al. Is the CD14 C159T polymorphism effective in the development of secondary amyloidosis in Familial Mediterranean fever?. Rheumatol Int. 2007;27:691-694. DOI: 10.1007/s00296-006-0286-1
Search in Google Scholar Back to article
Celebi Kobak A, Kobak S, Kabasakal Y, Akarca US. Tumor necrosis factor-alpha gene promoter polymorphism in patients with familial Mediterranean fever. Clin rheumatol. 2007;26:908-910. DOI: 10.1007/s10067-006-0430-z
Search in Google Scholar Back to article
Balci-Peynircioglu B, Taskiran ZE, Türel B, Arici M, Bakkaloglu A, Ozen S et al. The analysis of interleukin-1 receptor antagonist and interleukin-1beta gene polymorphisms in Turkish FMF patients: do they predispose to secondary amyloidosis. Clin Exp Rheumatol. 2008;26(4 Suppl 50):S99-S102.
Search in Google Scholar Back to article
Bezalel Y, Gershoni-Baruch R, Dagan E, Lidar M, Livneh A. The 3435T polymorphism in the ABCB1 gene and colchicine unresponsiveness in familial Mediterranean fever. Clin Experimental Rheumatol. 2009;27(2):S103.
Search in Google Scholar Back to article
Erken E, Gunesacar R, Ozer HT. Investigation of C5a receptor gene 450 C/T polymorphism in Turkish patients with familial Mediterranean fever. Molecular biology reports. 2010;37:273-276. DOI: 10.1007/s11033-009-9677-1
Search in Google Scholar Back to article
Ozen F, Silan C, Uludag A, Candan F, Silan F, Ozdemir S et al. Association between ABCB1 (MDR1) gene 3435 C> T polymorphism and colchicine unresponsiveness of FMF patients. Renal failure.2011;33(9):899-903. DOI: 10.3109/0886022X.2011.605980
Search in Google Scholar Back to article
Rüstemoglu A, Gumus-Akay G, Yigit S, Tasliyurt T. Analysis of common MDR1 (ABCB1) gene C1236T and C3435T polymorphisms in Turkish patients with familial Mediterranean fever. Genet Mol Res. 2011;10(4):3411-20. DOI: 10.4238/2011.December.14.7
Search in Google Scholar Back to article
Bonyadi M, Bahrami S, Jahanafrooz Z, Dastgiri S. Tumor necrosis factor-α gene polymorphisms in FMF and their association with amyloidosis. Clinical and Applied Thrombosis/Hemostasis. 2012;18(6):633-637. DOI: 10.1177/1076029611432743
Search in Google Scholar Back to article
Dundar M, Kiraz A, Balta B, Emirogullari EF, Zararsiz G, Yurci A et al. The role of TNF-α and PAI-1 gene polymorphisms in familial Mediterranean fever. Modern Rheumatol. 2013;23:140-145. DOI: 10.3109/s10165-012-0687-9
Search in Google Scholar Back to article
Gunesacar R, Erken E, Dinkci S. Analysis of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) Promoter− 318C/T and+ 49A/G Gene Polymorphisms in Turkish Patients with Familial Mediterranean Fever. Cell biochem biophys. 2013;65:181-186. DOI: 10.1007/s12013-012-9416-4
Search in Google Scholar Back to article
Dogruer D, Tug E, Bes C, Soy M. Lack of an effect of CYP3A4 and MDR1 gene polymorphisms on colchicine pharmacogenetics in the treatment of Familial Mediterranean fever. Genet Mol Res. 2013;12(3):3521-8. DOI: 10.4238/2013.January.24.2
Search in Google Scholar Back to article
Migita K, Agematsu K, Masumoto J, Ida H, Honda S, Jiuchi Y et al. The contribution of SAA1 polymorphisms to Familial Mediterranean fever susceptibility in the Japanese population. PLoS One. 2013;8(2):e55227. DOI: 10.1371/journal.pone.0055227
Search in Google Scholar Back to article
Öktem F, Anıl H, Sütcü R, Kuybulu AE. Genetic polymorphisms of paraoxonase1 192 and glutathione peroxidase1 197 enzymes in familial Mediterranean fever. Genet Mol Res. 2014;13(2):3292-300. DOI: 10.4238/2014.April.29.7
Search in Google Scholar Back to article
El Hawary R, Elanwary S, Meshaal S. Mediterranean fever gene mutations: correlation with cytotoxic T-lymphocyte-associated antigen 4 gene polymorphism. Microbiol immunol. 2015;59(3):160-165. DOI: 10.1111/1348-0421.12229
Search in Google Scholar Back to article
Ibrahim JN, Chouery E, Lecron JC, Mégarbané A, & Medlej-Hashim M. Study of the association of IL-1β and IL-1RA gene polymorphisms with occurrence and severity of Familial Mediterranean fever. Eur J Med Genetics. 2015;58(12):668-673. DOI: 10.1016/j.ejmg.2015.11.007
Search in Google Scholar Back to article
Wilson M, Abou-Elalla AA, Zakaria MT, Marzouk H, Fayed HL, Hanna MOF. Serum amyloid A Type 1 gene polymorphism in Egyptian children with familial Mediterranean fever. Pathobiology. 2016;83(6):295-300. DOI: 10.1159/000444933
Search in Google Scholar Back to article
Ozer S, Yilmaz R, Sonmezgoz E, Unuvar S, Ates O. Is the IL-6 -174G/C Gene Polymorphism Related to the Disease Severity Score in Turkish Children with Familial Mediterranean Fever?. Biochem Genet. 2016;54:886-893. DOI: 10.1007/s10528-016-9764-7
Search in Google Scholar Back to article
Nursal AF, Tekcan A, Kaya SU, Sezer O, Yigit S. Interleukin-1Ra rs2234663 and interleukin-4 rs79071878 polymorphisms in familial Mediterranean fever. Gene. 2016;582(2):173-177. DOI: 10.1016/j.gene.2016.02.008
Search in Google Scholar Back to article
Küçükşahin O, Şeker Z, Şahin A, Kinikli G, Tuncali T, Turgay M et al. Lack of the Association of the PTPN22 C1858T Gene Polymorphism With Susceptibility to Familial Mediterranean Fever. Archives of rheumatology. 2016;31(2):107. DOI: 10.5606/ArchRheumatol.2016.5788
Search in Google Scholar Back to article
Ozel EG, Duran GG, Celik MM, Duran N, Gunesacar R. Fas and Fas ligand gene polymorphisms in Turkish patients with Familial Mediterranean Fever. Gene. 2017;623:29-32. DOI: 10.1016/j.gene.2017.04.037
Search in Google Scholar Back to article
Erken E, Kudaş Ö, Dinkçi S, Kuyucu Y, Taşlıyurt T, Erken E. Mannose binding lectin (mbl) gene polymorphisms and their relations with clinical features in patients with familial mediterranean fever (fmf). Journal of Istanbul Faculty of Medicine. 2017;80(4):125-130. DOI: 10.18017/iuitfd.348847
Search in Google Scholar Back to article
Marzouk H, Farag Y, El-Hanafi HM, Ibrahim E. Serum IL 4 and its gene polymorphism (rs79071878) in Egyptian children with familial Mediterranean fever. Clin Rheumatol. 2018;37:3397-3403. DOI: 10.1007/s10067-018-4214-z
Search in Google Scholar Back to article
Yigit S, Nursal AF, Keskin A, Kaya S, Kuruca N, Sezer O. Association of MIF-173G/C, IL-4 VNTR, and IL-1RA VNTR variants with FMF-related amyloidosis in a Turkish cohort. J Investigative Med. 2024;72(1):17-25. DOI: 10.1177/10815589231207789
Search in Google Scholar Back to article
Krishnappa P, Kong HM, Mohamad IB, Voon K, Somanath SD. CD40 polymorphism in cervical carcinoma in a subset of Malaysian population. J Obstet Gynaecol Res. 2017;43:923-928 DOI: 10.1111/jog.13277
Search in Google Scholar Back to article
Zhang B, Wu T, Song C, Chen M, Li H, Guo R. Association of CD40--1C/T polymorphism with cerebral infarction susceptibility and its effect on sCD40L in Chinese population. Int Immunopharmacol. 2013;16:461-465 DOI: 10.1016/j.intimp.2013.04.028
Search in Google Scholar Back to article
Liu ZL, Hu J, Xiao XF, Peng Y, Zhao SP, Xiao XZ, et al. The CD40 rs1883832 polymorphism affects sepsis susceptibility and sCD40L levels. BioMed Res. Int. 2018;2018:7497314 DOI: 10.1155/2018/7497314
Search in Google Scholar Back to article
Wang D, Chen J, Zhang H, Yang L, Mou Y. Role of different CD40 polymorphisms in Graves’ disease and Hashimoto’s thyroiditis. Immunol Invest. 2017;46:544-551 DOI: 10.1080/08820139.2017.1319382
Search in Google Scholar Back to article
Hamta A, Safaei PG. Evaluating the relationship between polymorphisms in the CD40 gene with the prevalence of breast cancer: A case-control study. Med J Tabriz Uni Med Sciences. 2023;45(4) DOI: 10.34172/mj.2023.34
Search in Google Scholar Back to article
Tian S, Wang Y, Wan J, Yang M, Fu Z. Co-stimulators CD40-CD40L, a potential immune-therapy target for atherosclerosis: A review. Medicine. 2024;103(14):e37718 DOI: 10.1097/MD.0000000000037718
Search in Google Scholar Back to article
Vermersch P, Wagner D, Mars L T, Noelle R, Giovannoni G. Inhibiting CD40 Ligand in Multiple Sclerosis: A Review of Emerging Therapeutic Potential. Current Treatment Options in Neurology. 2025;27(1):7 DOI: 10.1007/s11940-024-00818-2
Search in Google Scholar Back to article
Ahmed HA, Abdelkreem E, Hamed EO, Abo Elmahassen NM, Younis MAA. Frequency of CD40-1C> T polymorphism (rs1883832) and association with response to treatment in children with primary immune thrombocytopenia. Pediatric Blood & Cancer. 2024;71(12):e31356 DOI: 10.1002/pbc.31356
Search in Google Scholar Back to article
Gümüş A, Sönmez D, Demirkol Ş, Tolgahan Hakan M, Verim A, Süoğlu Y, et al. Impact of CD40 (rs1883832) and CD40L (rs1126535) gene variants on laryngeal cancer susceptibility and their association with serum biomarker levels of sCD40 and sCD40L. PloS one. 2014;19(12):e0312576 DOI: 10.1371/journal.pone.0312576
Search in Google Scholar Back to article
Joshi P, Mohr F, Rumig C, Kliemank E, Krenning G, Kopf S, et al. Impact of the-1T> C single-nucleotide polymorphism of the CD40 gene on the development of endothelial dysfunction in a pro-diabetic microenvironment. Atherosclerosis. 2024;394:117386 DOI: 10.1016/j.atherosclerosis.2023.117386
Search in Google Scholar Back to article
Inal EE, Rüstemoğlu A, Inanır A, Ekinci D, Gül Ü, Yiğit S, et al. Associations of rs4810485 and rs1883832 polymorphisms of CD40 gene with susceptibility and clinical findings of Behçet’s disease. Rheumatol Int. 2015;35:837-843 DOI: 10.1007/s00296-014-3171-3
Search in Google Scholar Back to article
Abd El Dayem OY, Aboukhalil REA, Abd Elhady M, Masoud M, Abou-Elalla AA. Impact of CD40 gene variants [(rs1883832) and (rs4810485)] on the risk of immune thrombocytopenic purpura in Egyptian paediatric patients: a case-control study. Egyptian J Haematol. 2024;49(1):10-21 DOI: 10.4103/ejh.ejh_77_23
Search in Google Scholar Back to article
Shi Z, Zhang Q, Chen H, Miao X, Liu J, Lian Z, et al. Association of CD40 gene polymorphisms with susceptibility to neuromyelitis optica spectrum disorders. Molec Neurobiol. 2017;54:5236-5242 DOI: 10.1007/s12035-016-0070-5
Search in Google Scholar Back to article
Dolen Y, Yilmaz G, Esendagli G, Guler N, Guc D. CD40 -1C >T single nucleotide polymorphism and CD40 expression on breast tumors. Cytokine 2010;50:243-244 DOI: 10.1016/j.cyto.2010.03.010
Search in Google Scholar Back to article
Kuo HC, Chao MC, Hsu YW, Lin YC, Huang YH, Yu HR, et al. CD40 Gene polymorphisms associated with susceptibility and coronary artery lesions of Kawasaki disease in the Taiwanese population. Sci World J. 2012;2012: 520865 DOI: 10.1100/2012/520865
Search in Google Scholar Back to article
Budlewski T, Sarnik J, Galita G, Dragan G, Brzezińska O, Popławska M, et al. SNP in PTPN22, PADI4, and STAT4 but Not TRAF1 and CD40 Increase the Risk of Rheumatoid Arthritis in Polish Population. Int J Molec Sci. 2023;24(8):7586 DOI: 10.3390/ijms24087586
Search in Google Scholar Back to article
Zhu M, Li X, Feng Y, Jia T, Li S, Gong L, et al. Impact of CD40 gene polymorphisms on the risk of cervical squamous cell carcinoma: a case-control study. BMC cancer. 2023; 23(1):845 DOI: 10.1186/s12885-023-11367-3
Search in Google Scholar Back to article
Shuang C, Dalin L, Weiguang Y, Zhenkun F, Fengyan X, Da P, et al. Association of CD40 gene polymorphisms with sporadic breast cancer in Chinese Han women of Northeast China. PloS one. 2011;6(8):e23762. DOI: 10.1371/journal.pone.0023762
Search in Google Scholar Back to article