Nazan ERAS, Etem AKBAŞ, Olgu HALİLOĞLU, Oznur BUCAK, Derya KARPUZ, Sibel BALCI, Badel ARSLAN

Mersin ilinde yaşayan çocuklarda MASP-2 Geni Asp105Gly polimorfizmi ile romatizmal kalp hastalığı arasındaki ilişkinin değerlendirilmesi

Amaç: Mannoz bağlayıcı lektinler ile ilişkili serin proteaz (MASP) lektin yolu ile kompleman aktivasyonunda rol oynayan bir proteazdır. MASP-2'nin fonksiyonel aktivasyonunun enfeksiyon hastalıklarının gelişim sürecine katkıda bulunduğu düşünülmektedir. MASP-2 geninin 3. ekzonundaki adenin ile guaninin yer değiştirmesi, 105. pozisyonda aspartik asidin glisin amino asid (Asp105Gly) ile değişimine neden olur. Bu aminoasit değişikliği lektin yolunun aktivasyonunu durdurabilir ve ortaya çıkan MASP-2 eksikliği, enfeksiyon ve otoimmün hastalıklara yatkınlığı artırabilir. Çalışmamızda MASP2 geni Asp105Gly mutasyonunun insidansını ve romatizmal kalp hastalığı ile ilişkisini araştırmayı hedefledik. Yöntem: Çalışmamız yaş ortalaması 12.48±2.59 olan 82 romatizmal kalp hastası ve yaş ortalaması 11.99±2.66 olan 108 sağlıklı çocuk içerdi. Bireylerin genotipleri polimeraz zincir reaksiyonu–restriksiyon parça uzunluk polimorfizmi yöntemiyle belirlendi. Elde edilen veriler Kruskal Wallis testi ile değerlendirildi. Bulgular: Romatizmal kalp hastaları ve kontrol grubunda G allelinin sıklığı sırasıyla %15.9 ve %20.4 idi (p=0.35). AA, AG ve GG genotiplerinin frekansları vakalarda sırasıyla %70.7, %26.8 ve %2.5 iken, kontrol grubunda sırasıyla %62, %35.2 ve %2.8 idi. GG genotipinin frekansı mitral yetersizlikli hastalarda %5.3, aort yetersizliği olanlarda %0 ve çoklu kapak tutulumu olanlarda %2.1 olarak saptandı (p=0.506, OR:2.636, %95GA:0.151–45.914). Sonuç: Bu çalışma ile Mersin ilinde MASP-2 Asp105Gly mutasyonunun genotip frekansları belirlenmiştir. Ayrıca MASP2 Asp105Gly mutasyonu ile romatizmal kalp hastalığı arasında ilişki olmadığı saptanmıştır.

Anahtar Kelimeler:

ARA, çocuk, MASP, PCR, romatizmal kalp hastalığı

Evaluation of the relationship between MASP-2 Gene Asp105Gly polymorphism and rheumatic heart disease in children living in Mersin province

Aim: MBL-associated serine protease (MASP) is a protease that plays a role in complement activation via the lectin pathway. Functional activation of MASP-2 is thought to contribute to the development process of infectious diseases. Substitution of adenine to guanine in exon 3 of the MASP2 gene causes the exchange of aspartic acid with glycine amino acid at position 105 (Asp105Gly). This amino acid change can cause abrogate the activation of the lectin pathway, and the resulting MASP-2 deficiency could increase susceptibility to infections and autoimmune diseases. In our study, we aimed to investigate the incidence of the MASP2 Asp105Gly mutation and its relationship with rheumatic heart disease. Method: Our study included 82 patients with rheumatic heart disease (mean age 12.48±2.59 years) and 108 healthy children (mean age 11.99±2.66 years). Genotypes of individuals were determined by the polymerase chain reaction-restriction fragment length polymorphism method. The data were evaluated with the Kruskal Wallis test. Results: The frequency of the G allele was 15.9% and 20.4% in patients with rheumatic heart disease and control groups, respectively (p=0.35). The frequencies of genotypes AA, AG, and GG in the cases were 70.7%, 26.8%, and 2.5%, respectively, while in the control group they were 62%, 35.2%, and 2.8%, respectively. The frequency of the GG genotype was 5.3% in patients with mitral regurgitation, 0% in patients with aortic regurgitation, and 2.1% in patients with multiple valve involvement (p=0.506; OR:2.636; %95CI:0.151–45.914). Conclusion: In this study, genotype frequencies of MASP2 Asp105Gly mutation were determined in Mersin Province. In addition, no relation was found between MASP2 Asp105Gly mutation and RHD.

Keywords:

ARA, child, MASP, PCR, rheumatic heart disease,

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Düzgün N, Duman T, Haydardedeoğlu FE, Tutkak H. The lack of genetic association of the Toll-like receptor 2 (TLR2) Arg753Gln and Arg677Trp polymorphisms with rheumatic heart disease. Clin Rheumatol. 2007; 26(6): 915-919. doi: 10.1007/s10067-006-0432-x.
Chou HT, Tsai CH, Chen WC, Tsai FJ. Lack of association of genetic polymorphisms in the interleukin-1beta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 genes with risk of rheumatic heart disease in Taiwan Chinese. Int Heart J. 2005; 46(3): 397-406. doi: 10.1536/ihj.46.397.
Arvind B, Ramakrishnan S. Rheumatic Fever and Rheumatic Heart Disease in Children. Indian J Pediatr. 2020; 87(4): 305-311. doi: 10.1007/s12098-019-03128-7.
Sika-Paotonu D, Beaton A, Raghu A, Steer A, Carapetis J. Acute rheumatic fever and rheumatic heart disease. İçinde: Ferretti JJ, Stevens DL, Fischetti VA, eds. Streptococcus pyogenes: Basic Biology to Clinical Manifestations. Oklahoma City: University of Oklahoma Health Sciences Center; 2016.
Fu J, Wang J, Luo Y, et al. Association between MASP-2 gene polymorphism and risk of infection diseases: A meta-analysis. Microb Pathog. 2016; 100: 221-228. doi: 10.1016/j.micpath.2016.10.004.
Turner MW. The role of mannose-binding lectin in health and disease. Mol Immunol. 2003; 40(7):423-429. doi: 10.1016/s0161-5890(03)00155-x.
Stengaard-Pedersen K, Thiel S, Gadjeva M, et al. Inherited deficiency of mannan-binding lectin-associated serine protease 2. N Engl J Med. 2003; 349(6): 554-560. doi: 10.1056/NEJMoa022836.
Matsushita M, Fujita T. Ficolins and the lectin complement pathway. Immunol Rev 2001; 180(1):78-85. doi: 10.1034/j.1600-065x.2001.1800107.x.
Stover CM, Schwaeble WJ, Lynch NJ, Thiel S, Speicher MR. Assignment of the gene encoding mannan-binding lectin-associated serine protease 2 (MASP2) to human chromosome 1p36.3-->p36.2 by in situ hybridization and somatic cell hybrid analysis. Cytogenet Cell Genet. 1999;84(3-4):148-149. doi: 10.1159/000015243.
Stover C, Endo Y, Takahashi M, et al. The human gene for mannan-binding lectin-associated serine protease-2 (MASP-2), the effector component of the lectin route of complement activation, is part of a tightly linked gene cluster on chromosome 1p36.2-3. Genes Immun. 2001; 2(3):119-127. doi: 10.1038/sj.gene.6363745.
Yongqing T, Drentin N, Duncan RC, Wijeyewickrema LC, Pike RN. Mannose-binding lectin serine proteases and associated proteins of the lectin pathway of complement: Two genes, five proteins and many functions? Biochim Biophys Acta. 2012; 1824(1):253-262. doi: 10.1016/j.bbapap.2011.05.021.
Stover C, Barrett S, Lynch NJ, et al. Functional MASP2 single nucleotide polymorphism plays no role in psoriasis. Br J Dermatol. 2005; 152(6):1313-1315. doi: 10.1111/j.1365-2133.2005.06547.x.
Kjaer TR, Le le TM, Pedersen JS, et al. Structural insights into the initiating complex of the lectin pathway of complement activation. Structure. 2015; 23(2): 342-351. doi: 10.1016/j.str.2014.10.024.
Beltrame MH, Catarino SJ, Goeldner I, et al. The lectin pathway of complement and rheumatic heart disease. Front Pediatr. 2015;2: 148. doi: 10.3389/fped.2014.00148.
Sørensen R, Thiel S, Jensenius JC. Mannan-binding-lectin-associated serine proteases, characteristics and disease associations. Springer Semin Immunopathol. 2005; 27(3): 299-319. doi: 10.1007/s00281-005-0006-z.
Thiel S, Steffensen R, Christensen IJ, et al. Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms. Genes Immun. 2007; 8(2):154-163. doi: 10.1038/sj.gene.6364373.
García-Laorden MI, Hernández-Brito E, Muñoz-Almagro C, et al. Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway. J Clin Immunol. 2020; 40(1):203-210. doi: 10.1007/s10875-019-00714-4.
Boldt AB, Grisbach C, Steffensen R, et al. Multiplex sequence-specific polymerase chain reaction reveals new MASP2 haplotypes associated with MASP-2 and MAp19 serum levels. Hum Immunol. 2011; 72(9):753-760. doi: 10.1016/j.humimm.2011.05.015.
Ramasawmy R, Spina GS, Fae KC, et al. Association of mannose-binding lectin gene polymorphism but not of mannose-binding serine protease 2 with chronic severe aortic regurgitation of rheumatic etiology. Clin Vaccine Immunol. 2008; 15(6): 932-936. doi: 10.1128/CVI.00324-07.
Schafranski MD, Pereira Ferrari L, Scherner D, Torres R, de Messias-Reason IJ. Functional MASP2 gene polymorphism in patients with history of rheumatic fever. Hum Immunol. 2008;69(1):41-44. doi: 10.1016/j.humimm.2007.11.003.
Catarino SJ, Boldt AB, Beltrame MH, Nisihara RM, Schafranski MD, de Messias-Reason IJ. Association of MASP2 polymorphisms and protein levels with rheumatic fever and rheumatic heart disease. Hum Immunol. 2014;75(12):1197-1202. doi: 10.1016/j.humimm.2014.10.003.
Gewitz MH, Baltimore RS, Tani LY, et al. American Heart Association Committee on rheumatic fever, endocarditis, and kawasaki disease of the council on cardiovascular disease in the young. revision of the jones criteria for the diagnosis of acute rheumatic fever in the era of doppler echocardiography: A scientific statement from the American Heart Association. Circulation. 2015; 131(20): 1806-1818. doi: 10.1161/CIR.0000000000000205.
Ghaheri M, Kahrizi D, Yari K, Babaie A, Suthar RS, Kazemi E. A comparative evaluation of four DNA extraction protocols from whole blood sample. Cell Mol Biol (Noisy-le-grand). 2016; 62(3):120-124.
The Human Genomics Community. https://varsome.com/17 Haziran 2022’de erişildi.
Richards S, Aziz N, Bale S et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5): 405-24.
Collard C, Vakeva A, Morrissey MA, et al. Complement activation after oxidative stress. Role of the lectin complement pathway. Am J Pathol. 2000;156:1549-1556. doi: 10.1016/S0002-9440(10)65026-2.
Garred P, Madsen HO, Marquart H, et al. Two edged role of mannose binding lectin in rheumatoid arthritis: A cross sectional study. J Rheumatol. 2000; 27(1):26-34.
Hansen TK. Mannose-binding lectin (MBL) and vascular complications in diabetes. Horm Metab Res. 2005;37(S1):95-98. doi: 10.1055/s-2005-861372.
McMullen ME, Hart ML, Walsh MC, Buras J, Takahashi K, Stahl GL. Mannose-binding lectin binds IgM to activate the lectin complement pathway in vitro and in vivo. Immunobiology. 2006;211(10):759-766. doi: 10.1016/j.imbio.2006.06.011.
Özden A, Emir F. Genetik polimorfizm ve polimorfizm çalışmalar. Güncel Gastroenteroloji. 2006; 10(1): 24-28.
Segat L, Fabris A, Padovan L, et al. MBL2 and MASP2 gene polymorphisms in patients with hepatocellular carcinoma. J Viral Hepat. 2008; 15(5):387-391. doi: 10.1111/j.1365-2893.2007.00965.x.