.: ORİJİNAL ARAŞTIRMA
Effect of CTLA-4 and TNF-α Gene Polymorphisms on Inhibitor Development in a Turkish Cohort of Severe Hemophilia A Cases with Intron 22 Inversion Mutation: An Analytical Study
İntron 22 Mutasyon Taşıyıcısı Ağır Hemofili A Hastalarında CTLA-4 ve TNF-α Gen Polimorfizmlerinin İnhibitör Gelişimi Üzerine Etkisi: Analitik Bir Araştırma
Turkiye Klinikleri J Med Sci. 2022;42(3):159-63
doi: 10.5336/medsci.2021-86664
Makale Dili: EN
Tam Metin
ABSTRACT
Objective: The development of neutralizing antibodies against infused factor VIII called inhibitor is the most challenging treatment complication in hemophilia A (HA) patients. Associated factors for inhibitor development are classified into 2 groups (genetics and non-genetics). Genetic factors other than mutation type of F8 gene include family history, ethnical origin, human leucocyte antigen haplotype, and a number of polymorphisms in genes which play role in immune system. In this study, we aimed to analyze the association between 3 variants in 2 genes [c.-318C>T; rs5742909 and c.49A>G; rs231775 in CTLA-4 and c.-308G>A; rs1800629 in tumor necrosis factor alpha (TNF-α)] and inhibitor development in a cohort of severe HA patients with intron 22 inversion (inv22) mutation. Material and Methods: The study included in 94 severe HA patients with inv22. Two groups were established according to the inhibitor status: inhibitor positive and inhibitor negative. We investigated 2 single nucleotide polymorphisms in CTLA-4 (c.- 318C>T; rs5742909 and c.49A>G; rs231775) and one in TNF-α (c.-308G>A; rs1800629) using Sanger sequencing in both groups. Results: In this study, no significant relationship between CTLA-4 polymorphisms and inhibitor development was observed in severe HA patients with inv22 mutation. However, the A allele for c.-308G>A variant in TNF-α was found to be associated with the increased risk for inhibitor development in those patients. Conclusion: In Turkish severe HA patients with inv22 mutation, c.-318C>T and c.49A>G variants in CTLA-4 gene are not associated with the inhibitor development, whereas c.-308G>A variant in TNF-α, the A allele is related to the risk of inhibitor development.
Keywords: Hemophilia; inhibitor; CTLA-4; TNF-α; intron 22 inversion
Objective: The development of neutralizing antibodies against infused factor VIII called inhibitor is the most challenging treatment complication in hemophilia A (HA) patients. Associated factors for inhibitor development are classified into 2 groups (genetics and non-genetics). Genetic factors other than mutation type of F8 gene include family history, ethnical origin, human leucocyte antigen haplotype, and a number of polymorphisms in genes which play role in immune system. In this study, we aimed to analyze the association between 3 variants in 2 genes [c.-318C>T; rs5742909 and c.49A>G; rs231775 in CTLA-4 and c.-308G>A; rs1800629 in tumor necrosis factor alpha (TNF-α)] and inhibitor development in a cohort of severe HA patients with intron 22 inversion (inv22) mutation. Material and Methods: The study included in 94 severe HA patients with inv22. Two groups were established according to the inhibitor status: inhibitor positive and inhibitor negative. We investigated 2 single nucleotide polymorphisms in CTLA-4 (c.- 318C>T; rs5742909 and c.49A>G; rs231775) and one in TNF-α (c.-308G>A; rs1800629) using Sanger sequencing in both groups. Results: In this study, no significant relationship between CTLA-4 polymorphisms and inhibitor development was observed in severe HA patients with inv22 mutation. However, the A allele for c.-308G>A variant in TNF-α was found to be associated with the increased risk for inhibitor development in those patients. Conclusion: In Turkish severe HA patients with inv22 mutation, c.-318C>T and c.49A>G variants in CTLA-4 gene are not associated with the inhibitor development, whereas c.-308G>A variant in TNF-α, the A allele is related to the risk of inhibitor development.
Keywords: Hemophilia; inhibitor; CTLA-4; TNF-α; intron 22 inversion
ÖZET
Amaç: Hemofili A (HA) hastalarında faktör VIII'e karşı inhibitör adı verilen nötralizan antikorların gelişmesi en önemli tedavi komplikasyonudur. İnhibitör gelişimi ile ilişkili faktörler 2 gruba (genetik ve genetik olmayan) ayrılır. F8 geni mutasyon tipi dışındaki genetik faktörler arasında aile öyküsü, etnik köken, insan lökosit antijen haplotipi ve immün sistemde rol oynayan genlerdeki birtakım polimorfizmler bulunur. Bu çalışmada, intron 22 inversiyon (inv22) mutasyonu taşıyan ağır HA hastalarından oluşan bir kohortta CTLA-4 (c.-318C> T; rs5742909 ve c.49A>G; rs231775) ve tümör nekrozis faktör alfa (TNF-α) (c.-308G>A; rs1800629) gen polimorfizimleri ile inhibitör gelişimi arasındaki ilişkinin araştırılması amaçlanmıştır. Gereç ve Yöntemler: Çalışmaya, inv22 mutasyonu taşıyan 94 ağır HA hastası dâhil edildi. Hastalar, inhibitör varlığına göre 2 gruba ayrıldı: İnhibitör pozitif ve inhibitör negatif. Her iki grupta da Sanger dizi analizi yöntemi kullanılarak CTLA-4 geninde c.-318C>T; rs5742909 ve c.49A>G; rs231775 ve TNF-α geninde de c.-308G>A; rs1800629 polimorfizimleri araştırıldı. Bulgular: Bu çalışmada, inv22 mutasyonu taşıyan ağır HA hastalarında CTLA-4 polimorfizmleri ile inhibitör gelişimi arasında anlamlı bir ilişki saptanmamıştır. Bununla birlikte, TNF-α genindeki c.-308G>A varyantının A allelinin, bu hastalarda inhibitör gelişimi için artmış risk ile ilişkili olduğu bulunmuştur. Sonuç: İnv22 mutasyonu taşıyan ağır HA hastalarında, CTLA-4 genindeki c.-318C>T ve c.49A>G varyantları inhibitör gelişimi ile ilişkili değildir, oysa TNF-α genindeki c.-308G>A varyantı, A alleli, inhibitör gelişme riski ile ilgilidir.
Anahtar Kelimeler: Hemofili; inhibitör; CTLA-4; TNF-α; intron 22 inversiyon
Amaç: Hemofili A (HA) hastalarında faktör VIII'e karşı inhibitör adı verilen nötralizan antikorların gelişmesi en önemli tedavi komplikasyonudur. İnhibitör gelişimi ile ilişkili faktörler 2 gruba (genetik ve genetik olmayan) ayrılır. F8 geni mutasyon tipi dışındaki genetik faktörler arasında aile öyküsü, etnik köken, insan lökosit antijen haplotipi ve immün sistemde rol oynayan genlerdeki birtakım polimorfizmler bulunur. Bu çalışmada, intron 22 inversiyon (inv22) mutasyonu taşıyan ağır HA hastalarından oluşan bir kohortta CTLA-4 (c.-318C> T; rs5742909 ve c.49A>G; rs231775) ve tümör nekrozis faktör alfa (TNF-α) (c.-308G>A; rs1800629) gen polimorfizimleri ile inhibitör gelişimi arasındaki ilişkinin araştırılması amaçlanmıştır. Gereç ve Yöntemler: Çalışmaya, inv22 mutasyonu taşıyan 94 ağır HA hastası dâhil edildi. Hastalar, inhibitör varlığına göre 2 gruba ayrıldı: İnhibitör pozitif ve inhibitör negatif. Her iki grupta da Sanger dizi analizi yöntemi kullanılarak CTLA-4 geninde c.-318C>T; rs5742909 ve c.49A>G; rs231775 ve TNF-α geninde de c.-308G>A; rs1800629 polimorfizimleri araştırıldı. Bulgular: Bu çalışmada, inv22 mutasyonu taşıyan ağır HA hastalarında CTLA-4 polimorfizmleri ile inhibitör gelişimi arasında anlamlı bir ilişki saptanmamıştır. Bununla birlikte, TNF-α genindeki c.-308G>A varyantının A allelinin, bu hastalarda inhibitör gelişimi için artmış risk ile ilişkili olduğu bulunmuştur. Sonuç: İnv22 mutasyonu taşıyan ağır HA hastalarında, CTLA-4 genindeki c.-318C>T ve c.49A>G varyantları inhibitör gelişimi ile ilişkili değildir, oysa TNF-α genindeki c.-308G>A varyantı, A alleli, inhibitör gelişme riski ile ilgilidir.
Anahtar Kelimeler: Hemofili; inhibitör; CTLA-4; TNF-α; intron 22 inversiyon
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