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

Öz:

Objective: The development of neutralizing antibodies against in- fused factor VIII called inhibitor is the most challenging treatment complication in hemophilia A (HA) p atients. Associated factors for inhibitor development are classified into 2 groups (genetics and non-genetics). Genetic factors other than mu- tation type of F8 gene include family history, ethnical origin, human leucocyte anti- gen 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 sig- nificant 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 as- sociated with the inhibitor development, whereas c.-308G>A variant in TNF-α, the A allele is related to the risk of inhibitor development.

Anahtar Kelime:

İntron 22 Mutasyon Taşıyıcısı Ağır Hemofili A Hastalarında CTLA-4 ve TNF-α Gen Polimorfizmlerinin İnhibitör Gelişimi Üzerine Etkisi: Analitik Bir Araştırma

Öz:

Amaç: Hemofili A (HA) hastalarında faktör VIII’e karşı inhibitör adı ve- rilen nötralizan antikorların gelişmesi en önemli tedavi komplikasyonudur. İnhi- bitör gelişimi ile ili şkili faktörler 2 gruba (genetik ve genetik olmayan) ayr ılır. F8 geni mutasyon tipi d ışındaki genetik faktörler aras ında aile öyküsü, etnik köken, insan lökosit antijen haplotipi ve immün sistemde rol oynayan genlerdeki birtakım polimorfizmler bulunur. Bu çalışmada, intron 22 inversiyon (inv22) mu- tasyonu 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 geli şimi arasındaki ilişkinin araştırılması amaçlanmıştır. Gereç ve Yöntemler: Çalışmaya, inv22 mutasyonu taşıyan 94 ağır HA hastası dâhil edildi. Hastalar, inhibitör varl ığına göre 2 gruba ayrıldı: İnhibitör pozitif ve inhibitör negatif. Her iki grupta da San- ger 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 polimorfizim- leri araştırıldı. Bulgular: Bu çalışmada, inv22 mutasyonu ta şıyan ağır HA has- talarında CTLA-4 polimorfizmleri ile inhibitör gelişimi arasında anlamlı bir ilişki saptanmamıştır. Bununla birlikte, TNF-α genindeki c.-308G>A varyantının A al- lelinin, bu hastalarda inhibitör gelişimi için artmış risk ile ilişkili olduğu bulun- muştur. Sonuç: İnv22 mutasyonu ta şıyan a ğır HA hastalar ında, CTLA-4 genindeki c.-318C>T ve c.49A>G varyantları inhibitör gelişimi ile ilişkili değil- dir, oysa TNF-α genindeki c.-308G>A varyantı, A alleli, inhibitör gelişme riski ile ilgilidir.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

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APA	Mehdiyeva H, isik e, köse m, Akgun B, Durmuş Özen B, ALPAY A, Kavakli K, sezgin evim m, ozbek n, Onay H, Ozkinay F, ATIK T (2022). 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. , 159 - 163. 10.5336/medsci.2021-86664
Chicago	Mehdiyeva Humay,isik esra,köse melis,Akgun Bilcag,Durmuş Özen Başak,ALPAY ARAZ,Kavakli Kaan,sezgin evim melike,ozbek namik yasar,Onay Huseyin,Ozkinay Ferda,ATIK TAHIR 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. (2022): 159 - 163. 10.5336/medsci.2021-86664
MLA	Mehdiyeva Humay,isik esra,köse melis,Akgun Bilcag,Durmuş Özen Başak,ALPAY ARAZ,Kavakli Kaan,sezgin evim melike,ozbek namik yasar,Onay Huseyin,Ozkinay Ferda,ATIK TAHIR 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. , 2022, ss.159 - 163. 10.5336/medsci.2021-86664
AMA	Mehdiyeva H,isik e,köse m,Akgun B,Durmuş Özen B,ALPAY A,Kavakli K,sezgin evim m,ozbek n,Onay H,Ozkinay F,ATIK T 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. . 2022; 159 - 163. 10.5336/medsci.2021-86664
Vancouver	Mehdiyeva H,isik e,köse m,Akgun B,Durmuş Özen B,ALPAY A,Kavakli K,sezgin evim m,ozbek n,Onay H,Ozkinay F,ATIK T 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. . 2022; 159 - 163. 10.5336/medsci.2021-86664
IEEE	Mehdiyeva H,isik e,köse m,Akgun B,Durmuş Özen B,ALPAY A,Kavakli K,sezgin evim m,ozbek n,Onay H,Ozkinay F,ATIK T "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." , ss.159 - 163, 2022. 10.5336/medsci.2021-86664
ISNAD	Mehdiyeva, Humay vd. "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". (2022), 159-163. https://doi.org/10.5336/medsci.2021-86664

APA	Mehdiyeva H, isik e, köse m, Akgun B, Durmuş Özen B, ALPAY A, Kavakli K, sezgin evim m, ozbek n, Onay H, Ozkinay F, ATIK T (2022). 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. Türkiye Klinikleri Tıp Bilimleri Dergisi, 42(3), 159 - 163. 10.5336/medsci.2021-86664
Chicago	Mehdiyeva Humay,isik esra,köse melis,Akgun Bilcag,Durmuş Özen Başak,ALPAY ARAZ,Kavakli Kaan,sezgin evim melike,ozbek namik yasar,Onay Huseyin,Ozkinay Ferda,ATIK TAHIR 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. Türkiye Klinikleri Tıp Bilimleri Dergisi 42, no.3 (2022): 159 - 163. 10.5336/medsci.2021-86664
MLA	Mehdiyeva Humay,isik esra,köse melis,Akgun Bilcag,Durmuş Özen Başak,ALPAY ARAZ,Kavakli Kaan,sezgin evim melike,ozbek namik yasar,Onay Huseyin,Ozkinay Ferda,ATIK TAHIR 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. Türkiye Klinikleri Tıp Bilimleri Dergisi, vol.42, no.3, 2022, ss.159 - 163. 10.5336/medsci.2021-86664
AMA	Mehdiyeva H,isik e,köse m,Akgun B,Durmuş Özen B,ALPAY A,Kavakli K,sezgin evim m,ozbek n,Onay H,Ozkinay F,ATIK T 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. Türkiye Klinikleri Tıp Bilimleri Dergisi. 2022; 42(3): 159 - 163. 10.5336/medsci.2021-86664
Vancouver	Mehdiyeva H,isik e,köse m,Akgun B,Durmuş Özen B,ALPAY A,Kavakli K,sezgin evim m,ozbek n,Onay H,Ozkinay F,ATIK T 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. Türkiye Klinikleri Tıp Bilimleri Dergisi. 2022; 42(3): 159 - 163. 10.5336/medsci.2021-86664
IEEE	Mehdiyeva H,isik e,köse m,Akgun B,Durmuş Özen B,ALPAY A,Kavakli K,sezgin evim m,ozbek n,Onay H,Ozkinay F,ATIK T "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." Türkiye Klinikleri Tıp Bilimleri Dergisi, 42, ss.159 - 163, 2022. 10.5336/medsci.2021-86664
ISNAD	Mehdiyeva, Humay vd. "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". Türkiye Klinikleri Tıp Bilimleri Dergisi 42/3 (2022), 159-163. https://doi.org/10.5336/medsci.2021-86664