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AİLESEL AKDENİZ ATEŞİ (AAA) HASTALARINDA MANNOZ BAĞLAYICI LEKTİN (MBL) GEN POLİMORFİZMLERİ VE KLİNİK ÖZELLİKLERLE İLİŞKİSİ

Year 2017, Volume: 80 Issue: 4, 125 - 130, 20.12.2017
https://doi.org/10.18017/iuitfd.348847

Abstract



Amaç: Kompleman aktivasyonunun lektin
yolağında rol oynayan ve doğal immün sistemin bir parçası olan mannoz bağlayıcı
lektin (MBL), çeşitli patojenlerin mannan gruplarının uyarısı ile aktive olur.
MBL genindeki bazı polimorfizmler (örn. kodon 52, kodon 54 polimorfizmleri)
MBL’nin serum düzeylerinde değişikliklere yol açarak, infeksiyon hastalıklarına
yatkınlığa neden olabildiği gibi, bazı otoimmün ve inflamatuvar hastalıkların
patogenezine de katkıda bulunabilir. Bu çalışmada, ailesel Akdeniz ateşi (AAA)
hastalarında MBL geni kodon 52 ve kodon 54 polimorfizmlerinin sıklığını ve
başta sekonder amiloidoz olmak üzere, hastalığın klinik özellikleri ile olası
ilişkilerini araştırmayı amaçladık.

Gereç ve Yöntem: Yüzelli-yedi AAA
hastasında ve hastalarla akrabalık ilişkisi olmayan benzer demografik
dağılımdaki 150 sağlıklı kontrolde MBL genindeki R52C C>T ve G54D G>A
polimorfizmleri sekanslama yöntemi ile araştırıldı. AAA hastalarının MEFV geni
analizleri, klinik özellikleri ve ataksız dönemdeki serum CRP düzeyleri
kaydedildi. Genetik sonuçlar ile klinik ve laboratuvar bulgular arasındaki
olası ilişkiler incelendi.

Bulgular: MBL geni R52C C>T polimorfizmi
hastaların %12,7’sinde, kontrol grubunun %10,6’sında saptandı. G54D G>A
polimorfizmi hastaların %26,8’sinde, kontrollerin %26,7’sinde saptandı.
Polimorfizm sıklığı açısından, iki grup arasında anlamlı fark bulunamadı
(p=0,79 ve 0,98). İncelenen MBL geni polimorfizmleri ile hastaların çeşitli
klinik özellikleri (ör. amiloidoz, ateş, kolşisin yanıtı, MEFV mutasyonları)
arasında anlamlı ilişki bulunamadı. AAA hastalarının ortalama CRP değeri
4,90±6,72 mg/dL olup, ataksız dönemde serum CRP düzeyi normalden yüksek
(>0,8 mg/dL) olan hastalarda MBL kodon 52 polimorfizmi sıklığı %25,2, kodon
54 polimorfizmi sıklığı %14,8 oranında bulundu. AAA hastalarında yüksek CRP
düzeyine göre kodon 52 ve kodon 54 polimorfizmi sıklıkları farklı bulunmadı
(p=0,399). AAA hastalarında M694V mutasyonu ile amiloidoz arasında (p=0,002) ve
M694I mutasyonu ile kolşisin direnci arasında (p=0,016) anlamlı ilişki
saptandı.







Sonuç: AAA hastaların ataksız dönemdeki CRP
düzeyleri ve taşıdıkları klinik özellikler ile MBL polimorfizmleri arasında
anlamlı ilişki bulunamaması, AAA hastalarının proinflamatuvar durumda olduğunu
ve MBL aracılı mekanizmaların bu süreçlere katkısının olmadığını
düşündürmektedir. Olgularımızda M694I ile kolşisin direnci arasında anlamlı
ilişki saptanmış olması dikkate değer bir bulgudur. Yine olgularımızda M694V
ile amiloidoz arasında anlamlı ilişki bulunması önceki literatür bulguları ile
uyumludur ve M694V’nin hastalık şiddeti ve prognozu için önemli olduğu görüşünü
desteklemektedir.

References

  • 1- Erken E. Mannoz Bağlayıcı Lektin Eksikliği ve Klinik Bulgular. Arşiv Kaynak Tarama Dergisi. Archives Medical Review Journal. 2013; 22(4):565-574.
  • 2- Degn SE, Thiel S, Jensenius JC. New perspectives on mannan-binding lectin-mediated complement activation. Immunobiology. 2007; 212:301-311.
  • 3- Worthley DL, Bardy PG, Mullighan CG. Mannose binding lectin biology and clinical implications. Intern Med J. 2005; 35:548-555.
  • 4- Heitzeneder S, Seidel M, Förster-Waldl E, Heitger A: Mannan binding lectin deficiency - Good news, bad news, doesn’t matter? Clin Immunol 2012; 143(1):22-38.
  • 5- Erken E, Erken E: Ailesel Akdeniz Ateşinin Patogenezi, Türkiye Klinikleri J Rheumatol-Special Topics 2017; 10(1):8-12.
  • 6- Booty MG, Chae JJ, Masters SL et al: Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum, 2009; 60:1851-1861.
  • 7- Marek-Yagel D, Berkun Y, Padeh S et al: Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009; 60(6):1862-1866.
  • 8- Garred P. Mannose-binding lectin genetics: From A to Z. Biochem Soc Trans 2008; 36:1461-1466.
  • 9- Garred P, Larsen F, Seyfarth J, Fujita R, Madsen HO. Mannose-binding lectin and its genetic variants. Genes Immun. 2006; 7:85-94.
  • 10- Larsen F, Madsen HO, Sim RB, Koch C, Garred P. Disease associated mutations in human mannose-binding lectin compromise oligomerization and activity of the final protein. J Biol Chem. 2004; 279:21302-21311.
  • 11- Lee YH, Witte T, Momot T, Schmidt RE, Kaufman KM, Harley JB, Sestak AL. The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: two case-control studies and a meta-analysis. Arthritis Rheum. 2005; 52:3966-3974.
  • 12- Graudal NA, Madsen HO, Tarp U, Svejgaard A, Jurik G, Graudal HK, Garred P (2000) The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis. Arthritis Rheum. 2000; 43:515-521.
  • 13- Im CH, Kim J, Lee YJ, Lee EY, Lee EB, Park KS, Song YW. Mannose-binding lectin 2 gene haplotype analysis in Korean patients with ankylosing spondylitis. Rheumatol Int. 2012; 32:2251-2255.
  • 14- Mkrtchyan GM, Boyajyan AS, Ayvazyan AA, Beglaryan AA: Classical pathway complement activity in Familial Mediterranean fever. Clinical Biochemistry. 2006; 39(7):688-691.
  • 15- Ayesh SK, Azar Y, Babior BM, Matzner Y. Inactivation of interleukin-8 by the C5a-inactivating protease from serosal fluid. Blood. 1993; 81(6):1424-1427.
  • 16- Berkun Y, Eisenstein EM: Diagnostic criteria of familial Mediterranean fever. Autoimmun Rev, 2014; 13(4–5): 388–390. 17- Onen F: Familial Mediterranean fever. Rheumatol Int. 2006; 26: 489–496.
  • 18- Erken E, Torun D, Sezgin N, Micozkadioglu H, Zumrutdal A, Ozelsancak R, Yildiz I. The Effect of Serum Mannose-Binding Lectin Levels on DialysisRelated Peritonitis and Catheter-Related Bacteremia. Turk Neph Dial Transpl. 2015; 24 (2):189-194.
  • 19- Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. Mannose binding lectin: a biomarker of systemic lupus erythematosus disease activity. Arthritis Res Ther. 2012; 15:14(5):R218. doi: 10.1186/ar4057.
  • 20- Monticielo OA, Mucenic T, Xavier RM, Brenol JC, Chies JA. The role of mannose-binding lectin in systemic lupus erythematosus. Clin Rheumatol. 2008; 27:413-419.
  • 21- Maury CP, Aittoniemi J, Tiitinen S, Laiho K, Kaarela K, Hurme M. Variant mannose-binding lectin 2 genotype is a risk factor for reactive systemic amyloidosis in rheumatoid arthritis. Blackwell Publishing Ltd Journal of Internal Medicine. 2007; 262:466-469.
  • 22-Wang DQH, Bonfrate L, de Bari O, Wang TY, Portincasa P. Familial Mediterranean fever: From pathogenesis to treatment. J Genet Syndr Gene Ther. 2014; 5:248. Doi: 10.4172/2157-7412. 1000248
  • 23- Pandiarajan Vignesh, Amit Rawat, Madhubala Sharma, Surjit Singh: Complement in autoimmune diseases Clinica Chimica Acta 465 (2017) 123–130.
  • 24- Matzner Y, Brzezinski A (1984) C5a inhibitor deficiency in peritoneal fluids from patients with familial Mediterranean fever. N Engl J Med 311:287-290.

MANNOSE BINDING LECTIN (MBL) GENE POLYMORPHISMS AND THEIR RELATIONS WITH CLINICAL FEATURES IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER (FMF)

Year 2017, Volume: 80 Issue: 4, 125 - 130, 20.12.2017
https://doi.org/10.18017/iuitfd.348847

Abstract



Objective: Mannose-binding lectin (MBL),
which takes part in the lectin pathway of the complement system as a component
of innate immunity, is activated by the stimulation of various bacterial
lectins. It is known that some of the MBL gene polymorphisms (eg, codon 52,
codon 54) that may lead to alterations in MBL serum levels are responsible for
the susceptibility to infectious diseases and contribute to the pathogenesis of
various autoimmune and inflammatory diseases. In this study, we planned to
investigate the frequencies of codon 52 and codon 54 polymorphisms of the MBL
gene in FMF patients and their association with the clinical features of the
disease.

Materials and Methods: MBL gene
polymorphisms of the R52C C>T and G54D G>A were investigated by
sequencing in 157 FMF patients and 150 unrelated healthy controls. MEFV gene
mutations in FMF patients were investigated by sequencing method. The clinical
characteristics of the patients and the C-reactive protein (CRP) values in
attack-free phase were recorded. Statistical analysis of the findings was
performed with the SPSS version 18.0.

Results: The MBL gene R52C C>T
polymorphism was detected in 12.7% of the patients and 10.6% of the controls.
G54D G>A polymorphism was detected in 26.7% of the  patients and 26.6% of  the controls. There was no significant
difference between the two groups (p=0.794). No significant correlations
between MBL gene polymorphisms and various clinical characteristics of patients
(amyloidosis, fever, colchicine response) were found. Mean CRP level of the FMF
patients was 4.90±6.72 mg/dL. In FMF patients with elevated serum CRP levels
(>0.8 mg/L), codon 54 MBL polymorphism frequency was 14.8%, codon 52
polymorphism frequency was 25.2%.  Codon
52 and codon 54 polymorphism frequencies were not different between the groups
according to CRP level (p>0.05). In FMF patients, significant correlations
were found between M694V and amyloidosis (p=0.002) as well as between M694I and
colchicine resistance (p=0.016).







Conclusion: The absence of a relationship
between MBL polymorphisms and high CRP levels in attack-free phase of FMF
patients suggests that the proinflammatory state in some FMF patients is not
related to MBL mediated mechanisms. In our cases, the significant relationship
between M694I and colchicine resistance is remarkable. Our finding of the
significant relationship between M694V and amyloidosis is consistent with previous
literature and demonstrating the importance of M694V in disease severity and
prognosis.

References

  • 1- Erken E. Mannoz Bağlayıcı Lektin Eksikliği ve Klinik Bulgular. Arşiv Kaynak Tarama Dergisi. Archives Medical Review Journal. 2013; 22(4):565-574.
  • 2- Degn SE, Thiel S, Jensenius JC. New perspectives on mannan-binding lectin-mediated complement activation. Immunobiology. 2007; 212:301-311.
  • 3- Worthley DL, Bardy PG, Mullighan CG. Mannose binding lectin biology and clinical implications. Intern Med J. 2005; 35:548-555.
  • 4- Heitzeneder S, Seidel M, Förster-Waldl E, Heitger A: Mannan binding lectin deficiency - Good news, bad news, doesn’t matter? Clin Immunol 2012; 143(1):22-38.
  • 5- Erken E, Erken E: Ailesel Akdeniz Ateşinin Patogenezi, Türkiye Klinikleri J Rheumatol-Special Topics 2017; 10(1):8-12.
  • 6- Booty MG, Chae JJ, Masters SL et al: Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum, 2009; 60:1851-1861.
  • 7- Marek-Yagel D, Berkun Y, Padeh S et al: Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009; 60(6):1862-1866.
  • 8- Garred P. Mannose-binding lectin genetics: From A to Z. Biochem Soc Trans 2008; 36:1461-1466.
  • 9- Garred P, Larsen F, Seyfarth J, Fujita R, Madsen HO. Mannose-binding lectin and its genetic variants. Genes Immun. 2006; 7:85-94.
  • 10- Larsen F, Madsen HO, Sim RB, Koch C, Garred P. Disease associated mutations in human mannose-binding lectin compromise oligomerization and activity of the final protein. J Biol Chem. 2004; 279:21302-21311.
  • 11- Lee YH, Witte T, Momot T, Schmidt RE, Kaufman KM, Harley JB, Sestak AL. The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: two case-control studies and a meta-analysis. Arthritis Rheum. 2005; 52:3966-3974.
  • 12- Graudal NA, Madsen HO, Tarp U, Svejgaard A, Jurik G, Graudal HK, Garred P (2000) The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis. Arthritis Rheum. 2000; 43:515-521.
  • 13- Im CH, Kim J, Lee YJ, Lee EY, Lee EB, Park KS, Song YW. Mannose-binding lectin 2 gene haplotype analysis in Korean patients with ankylosing spondylitis. Rheumatol Int. 2012; 32:2251-2255.
  • 14- Mkrtchyan GM, Boyajyan AS, Ayvazyan AA, Beglaryan AA: Classical pathway complement activity in Familial Mediterranean fever. Clinical Biochemistry. 2006; 39(7):688-691.
  • 15- Ayesh SK, Azar Y, Babior BM, Matzner Y. Inactivation of interleukin-8 by the C5a-inactivating protease from serosal fluid. Blood. 1993; 81(6):1424-1427.
  • 16- Berkun Y, Eisenstein EM: Diagnostic criteria of familial Mediterranean fever. Autoimmun Rev, 2014; 13(4–5): 388–390. 17- Onen F: Familial Mediterranean fever. Rheumatol Int. 2006; 26: 489–496.
  • 18- Erken E, Torun D, Sezgin N, Micozkadioglu H, Zumrutdal A, Ozelsancak R, Yildiz I. The Effect of Serum Mannose-Binding Lectin Levels on DialysisRelated Peritonitis and Catheter-Related Bacteremia. Turk Neph Dial Transpl. 2015; 24 (2):189-194.
  • 19- Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. Mannose binding lectin: a biomarker of systemic lupus erythematosus disease activity. Arthritis Res Ther. 2012; 15:14(5):R218. doi: 10.1186/ar4057.
  • 20- Monticielo OA, Mucenic T, Xavier RM, Brenol JC, Chies JA. The role of mannose-binding lectin in systemic lupus erythematosus. Clin Rheumatol. 2008; 27:413-419.
  • 21- Maury CP, Aittoniemi J, Tiitinen S, Laiho K, Kaarela K, Hurme M. Variant mannose-binding lectin 2 genotype is a risk factor for reactive systemic amyloidosis in rheumatoid arthritis. Blackwell Publishing Ltd Journal of Internal Medicine. 2007; 262:466-469.
  • 22-Wang DQH, Bonfrate L, de Bari O, Wang TY, Portincasa P. Familial Mediterranean fever: From pathogenesis to treatment. J Genet Syndr Gene Ther. 2014; 5:248. Doi: 10.4172/2157-7412. 1000248
  • 23- Pandiarajan Vignesh, Amit Rawat, Madhubala Sharma, Surjit Singh: Complement in autoimmune diseases Clinica Chimica Acta 465 (2017) 123–130.
  • 24- Matzner Y, Brzezinski A (1984) C5a inhibitor deficiency in peritoneal fluids from patients with familial Mediterranean fever. N Engl J Med 311:287-290.
There are 23 citations in total.

Details

Subjects Health Care Administration
Journal Section Clinical Research
Authors

Ertuğrul Erken

Özlem Kudaş

Suzan Dinkçi This is me

Yunus Kuyucu This is me

Türker Taşlıyurt

Eren Erken This is me

Publication Date December 20, 2017
Submission Date November 2, 2017
Published in Issue Year 2017 Volume: 80 Issue: 4

Cite

APA Erken, E., Kudaş, Ö., Dinkçi, S., Kuyucu, Y., et al. (2017). 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, 80(4), 125-130. https://doi.org/10.18017/iuitfd.348847
AMA 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). İst Tıp Fak Derg. December 2017;80(4):125-130. doi:10.18017/iuitfd.348847
Chicago Erken, Ertuğrul, Özlem Kudaş, Suzan Dinkçi, Yunus Kuyucu, Türker Taşlıyurt, and Eren Erken. “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 80, no. 4 (December 2017): 125-30. https://doi.org/10.18017/iuitfd.348847.
EndNote Erken E, Kudaş Ö, Dinkçi S, Kuyucu Y, Taşlıyurt T, Erken E (December 1, 2017) 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 80 4 125–130.
IEEE E. Erken, Ö. Kudaş, S. Dinkçi, Y. Kuyucu, T. Taşlıyurt, and E. Erken, “MANNOSE BINDING LECTIN (MBL) GENE POLYMORPHISMS AND THEIR RELATIONS WITH CLINICAL FEATURES IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER (FMF)”, İst Tıp Fak Derg, vol. 80, no. 4, pp. 125–130, 2017, doi: 10.18017/iuitfd.348847.
ISNAD Erken, Ertuğrul et al. “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 80/4 (December 2017), 125-130. https://doi.org/10.18017/iuitfd.348847.
JAMA 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). İst Tıp Fak Derg. 2017;80:125–130.
MLA Erken, Ertuğrul et al. “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, vol. 80, no. 4, 2017, pp. 125-30, doi:10.18017/iuitfd.348847.
Vancouver 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). İst Tıp Fak Derg. 2017;80(4):125-30.

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