Immunogenetic Echoes of Demographic Change: A Quarter-Century Temporal Analysis of HLA Evolution at a Single Turkish Centre

Year 2025, Volume: 8 Issue: 3 , 176 - 235 , 28.10.2025

Emel Yantır , Ertuğrul Çolak

https://doi.org/10.26650/JARHS2025-1755402

https://izlik.org/JA69XE32CJ

Abstract

Objective: The distribution of human leukocyte antigen (HLA) allele frequencies is markedly heterogeneous among different populations, largely shaped by unique evolutionary pressures and demographic histories. This study aimed to analyse 25 years of HLA data from Central Western Anatolia to determine how low (2001– 2011) and high (2011–2025) migration periods affected the regional HLA gene pool.

Material and Methods: In this retrospective study, HLA-A, -B, - C, -DRB1, -DQB1, and -DPB1 data from 6550 healthy donors were analysed. Allele frequency differences were evaluated by Fisher’s exact test, and population genetics analyses, including Hardy– Weinberg equilibrium (HWE), were performed using the PyPop software.

Results: The frequencies of 18 alleles changed significantly (p<0.05). In the post-2011 period, the frequency of alleles with Middle Eastern/Asian origins (e.g., B*52, DRB1*03) increased, whereas the frequency of European-associated alleles (e.g., B*44, DQB1*05) decreased. The East Asian allele B*46 appeared for the first time, while two low-frequency alleles (DPB1*01, DPB1*19) were no longer detected. The cohort from the high-migration period showed a significant deviation from HWE, and the observed excess of homozygotes indicated a Wahlund effect resulting from population stratification.

Conclusion: The HLA gene pool has evolved, and this evolution is likely driven by the combined effects of not only gene flow from migration but also the resulting population substructure, ongoing natural selection, and genetic drift. Our findings underscore the need for transplant registries to be periodically updated to reflect current population immunogenetics and for public health initiatives to consider emerging HLA-associated disease risks.

Keywords

Human leukocyte antigen (HLA) , immunogenetic , migration , evolution , Wahlund effect , Türkiye

Demografik Değişimin İmmunogenetik Yankıları: Türkiye’de Tek Merkezli HLA Evriminin Çeyrek Yüzyıllık Zamansal Analizi

https://izlik.org/JA69XE32CJ

Abstract

Amaç: İnsan lökosit antijen (HLA) frekansları küresel olarak farklılık gösterir. Türkiye'nin tarihi bir göç kavşağı olması ve 2011'den bu yana yaşadığı büyük demografik değişimler göz önüne alındığında, bu değişimlerin HLA üzerine olan etkileri incelenmemiştir. Bu çalışma, Orta Batı Anadolu'daki 25 yıllık HLA verilerini analiz ederek, düşük (2001–2011) ve yüksek (2011–2025) göç dönemlerinin bölgesel HLA gen havuzunu nasıl etkilediğini belirlemeyi amaçlamıştır.

Gereç ve Yöntemler: Bu geriye dönük çalışmada, 6550 sağlıklı donörden alınan HLA-A, -B, -C, -DRB1, -DQB1 ve -DPB1 verileri 2001– 2011 ve 2011–2025 olmak üzere iki döneme ayrılarak incelenmiştir. Alel frekans farklılıkları Fisher’in Exact testi ile değerlendirilmiş ve Hardy–Weinberg dengesi (HWE) dahil olmak üzere popülasyon genetiği analizleri yapılmıştır.

Bulgular: On sekiz alelin frekansı anlamlı düzeyde değişmiştir (p<0,05). 2011 sonrası dönemde, Orta Doğu/Asya kökenli alellerin (örn. B*52, DRB1*03) frekansı artarken, Avrupa ile ilişkili aleller (örn. B*44, DQB1*05) azalmıştır. Doğu Asya aleli B*46 ilk kez ortaya çıkarken, düşük frekanslı iki alel (DPB1*01, DPB1*19) saptanamaz düzeye düşmüştür. Yüksek göç dönemindeki kohort, HWE'den anlamlı sapma göstermiş ve gözlenen homozigot fazlalığı, popülasyon katmanlaşmasından kaynaklanan bir Wahlund etkisine işaret etmiştir.

Sonuç: Orta Batı Anadolu'daki HLA gen havuzu, 2011'den sonra önemli ölçüde evrimleşmiştir. Bu durum sadece göçle gelen gen akışının değil, aynı zamanda bu durumun yarattığı popülasyon alt yapılanmasının, süregelen doğal seçilimin ve genetik sürüklenmenin birleşik etkileriyle oluşmuş olabilir. Bulgularımız, transplantasyon kayıtlarının güncel popülasyon genetiğini yansıtacak şekilde periyodik olarak güncellenmesi ve halk sağlığı girişimlerinin ortaya çıkan HLA ile ilişkili hastalık risklerini dikkate alması gerektiğinin altını çizmektedir.

Keywords

İnsan lökosit antijeni (HLA) , immünogenetik , Wahlund etkisi , Türkiye , göç , evrim

References

• Shiina T, Hosomichi K, Inoko H, Kuiski JK. The HLA genomic ioci map: expression, interaction, diversity and disease. J Hum Genet 2009;54(1):15-39. google scholar
• Sanchez-Mazas A, Nunes JM, Di D, Dominguez EA, Gerbauit P, Faye NK, et ai. The most frequent HLA aiieies around the worid: A fundamentai synopsis. Best Pract Res Ciin Haematoi 2024;37(2):101559. google scholar
• Di D, Sanchez-Mazas A. HLA variation reveais genetic continuity rather than popuiation group structure in East Asia. Immunogenetics 2014;66(3):153-60. google scholar
• Arrieta-Boianos E, Hernândez-Zaragoza Dİ, Barquera R. An HLA map of the worid: A comparison of HLA frequencies in 200 woridwide popuiations reveais diverse patterns for ciass İ and ciass İİ. Front Genet 2023;14:866407. google scholar
• Uyar FA, Dorak MT, Saruhan-Direskeneii G. Human ieukocyte antigen-A, -B and -C aiieies and human ieukocyte antigen hapiotypes in Turkey: reiationship to other popuiations. Tissue Antigens 2004;64(2):180-7. google scholar
• Fernandez Vina MA, Hoiienbach JA, Lyke KE, Sztein MB, Maiers M, Kiitz W, et ai. Tracking human migrations by the anaiysis of the distribution of HLA aiieies, iineages and hapiotypes in ciosed and open popuiations. Phiios Trans R Soc Lond B Bioi Sci 2012;367(1590):820-9. google scholar
• Sanchez-Mazas A, Fernandez-Vina M, Middieton D, Hoiienbach JA, Buhier S, Di D, et ai. İmmunogenetics as a tooi in anthropoiogicai studies. İmmunoiogy 2011;133(2):143-64. google scholar
• Baydemir R, Özmen A. Topiumsai Hareketiiiikier ve Bir Meiez Kimiik Örneği Oiarak “Türkiyeii Suriyeiiier”. İnsan Hareketiiiiği Uiusiararası Derg 2025;5(1):1-28. google scholar
• Petersdorf EW, Maikki M, O’hUigin C, Carrington M, Gooiey T, Haagenson MD, et ai. High HLA-DP Expression and Graft-versus-Host Disease. New Eng J Med 2015;373(7):599-609. google scholar
• Littie A-M, Akbarzad-Yousefi A, Anand A, Diaz Buriinson N, Dunn PPJ, Evseeva İ, et ai. BSHİ guideiine: HLA matching and donor seiection for haematopoietic progenitor ceii transpiantation. İnt J İmmunogenetics 2021;48(2):75-109. google scholar
• Yantır E, Gündüz E, Çoiak E. HLA Aiieies, Genotype and Hapiotype Anaiyzes from Centrai Anatoiia Region of Turkey. Baikan Med J 2023;40(5):358-66. google scholar
• Nunes JM, Buhier S, Roessii D, Sanchez-Mazas A, coiiaboration tH-n. The HLA-net GENE[RATE] pipeiine for effective HLA data anaiysis and its appiication to 145 popuiation sampies from Europe and neighbouring areas. Tissue Antigens 2014;83(5):307-23. google scholar
• Lancaster AK, Single RM, Mack SJ, Sochat V, Mariani MP, Webster GD. PyPop: a mature open-source software pipeline for population genomics. Frontiers Immunol 2024;15. google scholar
• Lancaster AK, Nelson MP, Single R, Solberg O, Tsai Y, Meyer D, et al. PyPop: Python for Population Genomics (v1.2.1). Zenodo. Zenod. 2025;https://doi.org/10.5281/ zenodo.15300323 google scholar
• Baştürk B, Kantaroğlu B, Kavuzlu M, Sarıtürk Ç. The Most Common HLA Alleles and Anti-HLA Antibodies to Know for Virtual Cross-Match. Exp Clin Transplant 2016;14(Suppl 3):53-5. google scholar
• Kulpa DA, Collins KL. The emerging role of HLA-C in HIV-1 infection. Immunology 2011;134(2):116-22. google scholar
• Sanchez-Mazas A, Meyer D. The relevance of HLA sequencing in population genetics studies. J Immunol Res 2014;2014:971818. google scholar
• Pingel J, Solloch UV, Hofmann JA, Lange V, Ehninger G, Schmidt AH. High-resolution HLA haplotype frequencies of stem cell donors in Germany with foreign parentage: how can they be used to improve unrelated donor searches? Hum Immunol 2013;74(3):330-40. google scholar
• Arrieta-Bolanos E, Hernândez-Zaragoza Dİ, Barquera R. An HLA map of the world: A comparison of HLA frequencies in 200 worldwide populations reveals diverse patterns for class İ and class İİ. Frontiers Genetics 2023;14. google scholar
• İkhtiar AM, Jazairi B, Khansa İ, Othman A. HLA class İ alleles frequencies in the Syrian population. BMC Res Notes 2018;11(1):324. google scholar
• Eberhard HP, Schmidt AH, Mytilineos J, Fleischhauer K, Müller CR. Common and well-documented HLA alleles of German stem cell donors by haplotype frequency estimation. Hla 2018;92(4):206-14. google scholar
• Oğuz F, Karadeniz S. İmmünogenetik ve Biyoenformatik Uygulamalarının Tıp Bilişimine Entegrasyonu. İn Medıcal İnformatics. İstanbul: İstanbul University, 2021, p. 187-202. google scholar
• Wahlund s. Zusammensetzung von populatıonen und korrelatıonserscheınungen vom standpunkt der vererbungslehre aus betrachtet. Hereditas 1928;11(1):65-106. google scholar
• Creary LE, Sacchi N, Mazzocco M, Morris GP, Montero-Martin G, Chong W, et al. High-resolution HLA allele and haplotype frequencies in several unrelated populations determined by next generation sequencing: 17th İnternational HLA and İmmunogenetics Workshop joint report. Hum İmmunol 2021;82(7):505-22. google scholar
• Hajjej A, Almawi WY, Arnaiz-Villena A, Hattab L, Hmida S. The genetic heterogeneity of Arab populations as inferred from HLA genes. PLOS One 2018;13(3):e0192269. google scholar
• Arnaiz-Villena A, Karin M, Bendikuze N, Gomez-Casado E, Moscoso J, Silvera C, et al. HLA alleles and haplotypes in the Turkish population: relatedness to Kurds, Armenians and other Mediterraneans. Tissue Antigens 2001;57(4):308-17. google scholar
• Santos EJMd, McCabe A, Gonzalez-Galarza FF, Jones AR, Middleton D. Allele Frequencies Net Database: İmprovements for storage of individual genotypes and analysis of existing data. Human İmmunol 2016;77(3):238-48. google scholar
• Gonzâlez-Galarza FF, Takeshita LY, Santos EJ, Kempson F, Maia MH, da Silva AL, et al. Allele frequency net 2015 update: new features for HLA epitopes, KİR and disease and HLA adverse drug reaction associations. Nucleic Acids Res 2015;43(Database issue):D784-8. google scholar
• Velastegui E, Vera E, Vanden Berghe W, Munoz MS, Orellana-Manzano A. HLA-C: evolution, epigenetics, and pathological implications in the major histocompatibility complex. Frontiers Gen 2023;14. google scholar
• Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science 2002;296(5576):2225-9. google scholar
• Meyer D, VR CA, Bitarello BD, DY CB, Nunes K. A genomic perspective on HLA evolution. İmmunogenetics 2018;70(1):5-27. google scholar
• Saruhan-Direskeneli G, Uyar FA, Bakar Ş, Eraksoy M. Molecular analysis of HLA-DRB1, -DQA1 and -DQB1 polymorphism in Turkey. Tissue Antigens 2000;55(2):171-4. google scholar
• Balkan E, Yaşar E, Doğan H. The Dıagnosıs of Human Leukocyte Antıgen Class İ and Class İİ Allel ın Eastern Anatolıa Regıon. Van Med J 2019;26(2):162-6. google scholar
• Arnaiz-Villena A, Dimitroski K, Pacho A, Moscoso J, Gömez-Casado E, Silvera-Redondo C, et al. HLA genes in Macedonians and the sub-Saharan origin of the Greeks. Tissue Antigens 2001;57(2):118-27. google scholar
• Sanchez-Mazas A, Vidan-Jeras B, Nunes JM, Fischer G, Little AM, Bekmane U, et al. Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations. İnt J İmmunogenet 2012;39(6):459-72; quiz 73-6. google scholar
• Fleischhauer K, Shaw BE. HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities. Blood 2017;130(9):1089-96. google scholar
• Tiercy JM. How to select the best available related or unrelated donor of hematopoietic stem cells? Haematologica 2016;101(6):680-7. google scholar
• Trowsdale J, Knight JC. Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet 2013;14:301-23. google scholar
• Medhasi S, Chantratita N. Human Leukocyte Antigen (HLA) System: Genetics and Association with Bacterial and Viral İnfections. J İmmunol Res 2022;2022:9710376. google scholar
• Mignot E, Lin L, Rogers W, Honda Y, Qiu X, Lin X, et al. Complex HLA-DR and -DQ İnteractions Confer Risk of Narcolepsy-Cataplexy in Three Ethnic Groups. Am J Human Gen 2001;68(3):686-99. google scholar