Aslı KARACAN, Güven TOKSOY, Birsen KARAMAN, Oya UYGUNER1, Seher BAŞARAN, Evrim KÖMÜRCÜ BAYRAK

TÜRK POPÜLASYONUNDA IRF7, TBK1, IFNAR1, IFNAR2 VE TLR3 GEN VARYANTLARININ POPÜLASYONLAR ARASI KARŞILAŞTIRMALARI VE ENFEKSİYON HASTALIKLARINDAKİ ÖNEMİ

Amaç: Halen devam etmekte olan pandemi sürecinde yapılan araştırmalarda, IRF7, TBK1, IFNAR1, IFNAR2 ve TLR3 immünite genlerinin SARS-CoV-2 enfeksiyona yatkınlıkta önemli rol oynadıkları belirlenmiştir. Ancak, Türk popülasyonunda bu genlerdeki varyantlar ile ilgili detaylı bilgi bulunmamaktadır. Bu çalışmada, enfeksiyonlara yatkınlık oluşturan bu genlerdeki toplumumuza özgü varyantların belirlenmesi ve diğer popülasyonlarla karşılaştırılması amaçlandı.Gereç ve Yöntem: IRF7, TBK1, IFNAR1, IFNAR2 ve TLR3 genlerindeki ekzonik ve komşu intronik bölgelerdeki gen varyantları, 139 anonim bireye ait kurum içi tüm ekzom dizileme verilerinde analiz edildi. Varyantların allel sıklıkları, diğer popülasyonların veri setleri ile karşılaştırıldı. Ek olarak, literatürdeki bu 5 aday gen ile ilişkili hastalıkları belirlemek için DisGeNET veri tabanı kullanıldı.Bulgular: Toplumumuzdaki immünite gen varyantları belirlenerek allel sıklıkları diğer popülasyonlar ile karşılaştırıldı. Buna göre IRF7 geninde 28, TBK1’de 16, IFNAR1’de 18, IFNAR2’de 19, TLR3’de 9 varyant tespit edildi. Bu varyantlardan dokuzunun daha önce bildirilmemiş yeni varyant oldukları belirlendi. DisGe- NET veri tabanına göre, bu genlerin çoğunlukla kanser ve enfek- siyon hastalıklarında özellikle viral enfeksiyonlarla ilgili oldukları gösterildi. Sonuç: Toplumuza özgü immünite gen varyantlarının belirlen- mesi ve popülasyonlar arasında allel sıklıklarının değişkenlik göstermesi, özellikle SARS-CoV-2 enfeksiyonuna immün yanıtta farklılıklara sebep olabileceğini düşündürmektedir. Bu çalışma- da, enfeksiyon hastalıklarının klinik bulguları ile immünite gen varyantları arasındaki ilişkiyi araştıracak çalışmalar için önbilgiler elde edilmiştir.

Anahtar Kelimeler:

Enfeksiyon hastalıkları, popülasyon, immünite genleri, varyant

INTER-POPULATION COMPARISONS AND THE IMPORTANCE IN INFECTIOUS DISEASES OF THE IRF7, TBK1, IFNAR1, IFNAR2 AND TLR3 GENE VARIANTS IN TURKISH INDIVIDUALS

Objective: In the research conducted during the pandemic period, it has been determined that IRF7, TBK1, IFNAR1, IFNAR2, and TLR3 immunity genes play an important role in the predisposition to SARS-CoV-2 infection. However, there is no information about variants of these genes in the Turkish population. The aim of this study was to determine the variants specific to the our study’s population in these genes that predispose to infections and to compare them with other populations.Materials and Methods: The variants in the exonic and flanking intronic regions of these five genes were analysed in in-house whole-exome sequencing data of 139 unrelated non-anonymous individuals. The allele frequencies of variants were compared with other population datasets. The DysGeNet database was used to determine human diseases associated with these genes.Results: In our population, gene variants were detected including 28 in IRF7, 16 in TBK1, 18 in IFNAR1, 19 in IFNAR2, and 9 in TLR3. The allele frequencies of variants were compared with other populations. Of these variants, 9 were determined to be novel, previously unreported variants. It was shown that these genes are mainly involved in cancer and infectious diseases, especially viral infections according to the DisGeNET database. Conclusion: The determination of immunity gene variants specific to our population and the variability of allele frequencies among populations suggest that it may cause differences in immune response, especially to SARS-CoV-2 infection. In this study, preliminary information was obtained for studies that will investigate the relationship between the clinical manifestations of infectious diseases and immunity gene variants.

Keywords:

Infectious diseases, population, immunity genes, variant,

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1. Channappanavar R, Zhao J, Perlman S. T cell-mediated immune response to respiratory coronaviruses. Immunol Res 2014;59(1-3):118-28. [CrossRef] google scholar
2. Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J 2019;16(1):69. [CrossRef] google scholar
3. Fung TS, Liu DX. Human Coronavirus: Host-Pathogen Interaction. Annu Rev Microbiol 2019;73:529-57. [CrossRef] google scholar
4. Sohrabi C, Alsafi Z, O’Neill N, Khan M, Kerwan A, Al-Jabir A, et al. World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). Int J Surg 2020;76:71-6. [CrossRef] google scholar
5. Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, Duan G. Virology, Epidemiology, Pathogenesis, and Control of COVID-19. Viruses 2020;12(4):372. [CrossRef] google scholar
6. Emami A, Javanmardi F, Pirbonyeh N, Akbari A. Prevalence of Underlying Diseases in Hospitalized Patients with COVID-19: a Systematic Review and Meta- Analysis. Arch Acad Emerg Med 2020;8(1):e35. [CrossRef] google scholar
7. Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 2020;370(6515):eabd4570. [CrossRef] google scholar
8. Zhang Q. Human genetics of life-threatening influenza pneumonitis. Hum Genet 2020;139(6-7):941-8. [CrossRef] google scholar
9. Ciancanelli MJ, Huang SX, Luthra P, Garner H, Itan Y, Volpi S, et al. Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science 2015;348(6233):448-53. [CrossRef] google scholar
10. Herman M, Ciancanelli M, Ou YH, Lorenzo L, Klaudel-Dreszler M, Pauwels E, et al. Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J Exp Med 2012;209(9):1567-82. [CrossRef] google scholar
11. Hernandez N, Bucciol G, Moens L, Le Pen J, Shahrooei M, Goudouris E, et al. Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines. J Exp Med 2019;216(9):2057-70. [CrossRef] google scholar
12. Duncan CJ, Mohamad SM, Young DF, Skelton AJ, Leahy TR, Munday DC, et al. Human IFNAR2 deficiency: Lessons for antiviral immunity. Sci Transl Med 2015;7(307):307ra154. [CrossRef] google scholar
13. Lim HK, Huang SXL, Chen J, Kerner G, Gilliaux O, Bastard P, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med 2019;216(9):2038-56. [CrossRef] google scholar
14. Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science 2007;317(5844):1522-7. [CrossRef] google scholar
15. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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. [CrossRef] google scholar
16. Kömürcü-Bayrak E, Toksoy G, Uyguner O, Karaman B, Başaran S. Inter-Populations Comparative Analysis of the ACE2, TMPRSS2, CTSB and CTSL Gene Variants Identified in Turkish Individuals. In: Cakmakoğlu B, Ekmekci SS, Kucuksezer UC, Yılmaz V, Deniz G, COVID-19: Molecular and Clinical Approach. Istanbul University Publication No: 5268, 2020;67-76. google scholar
17. Pinero J, Saüch J, Sanz F, Furlong LI. The DisGeNET cytoscape app: Exploring and visualizing disease genomics data. Comput Struct Biotechnol J 2021;11(19):2960-7. [CrossRef] google scholar
18. Ricci D, Etna MP, Rizzo F, Sandini S, Severa M, Coccia EM. Innate Immune Response to SARS-CoV-2 Infection: From Cells to Soluble Mediators. Int J Mol Sci 2021;22(13):7017. [CrossRef] google scholar
19. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 2020;370(6515):eabd4585. [CrossRef] google scholar
20. Pairo-Castineira E, Clohisey S, Klaric L, Bretherick AD, Rawlik K, Pasko D, et al. Genetic mechanisms of critical illness in COVID-19. Nature 2021;591(7848):92-8. [CrossRef] google scholar
21. Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, Korf BR. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genetics in Medicine 2017;19(2):249-55. [CrossRef] google scholar