Journal of Medical Virology Phylogenetic Analysis of HCV-4d in Turkey: The Curious Case of Kayseri Province Massimo Ciccozzi, 1 * Gianguglielmo Zehender, 2 Ceylan Polat, 3 Alessia Lai, 2 Tuba Kayman, 4 Chiara Sorrentino, 2 Erika Ebranati, 2 Eleonora Cella, 1 Alessandra Lo Presti, 1 and Hakan Abacioglu 3 1 Department of Infectious, Parasitic and Immunomediated Diseases, National Institute of Health, Rome, Italy 2 Department of Biomedical and Clinical Sciences “L. Sacco”, University of Milan, Milan, Italy 3 Department of Medical Microbiology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey 4 Department of Medical Microbiology, Kayseri Training and Research Hospital, Kayseri, Turkey In Turkey, genotype 1, especially type 1b virus, causes approximately 90% of these infections, while types 2, 3, and 4 exist, albeit in low prevalences and are due to relatively recent and limited introductions. Two recent reports from Kayseri, a relatively large city in Central Anato- lia, indicated unusually high prevalence for type 4 infections in the province reaching a 35% among patients admitted to hospitals for treat- ment of chronic hepatitis C. In this study, the origin, the demographic history, and the dynam- ic of the epidemic of unusual HCV genotype 4d in Turkey by using Bayesian coalescent-based method were investigated. A gene flow migra- tion approach was also used to describe the synchronous geographical dispersal and genetic diversification of this unusual genotype in Kay- seri province. The Turkish clade had a tMRCA of 44 years corresponding to the year 1967 and seems to have a different origin being complete- ly segregated from the European one. Gene flow migration analysis indicated that Kayseri province appeared to be the epicenter of HCV- 4d epidemic, exporting the infections. The de- mographic history of HCV-4d showed that the epidemic started in 1970s year then following a slow exponential growth until 1980s. The Turk- ish monophyletic clade suggests a segregate circulation of the epidemic in this region mostly due to unsafe parenteral medical procedures (with drug addiction playing a relatively negli- gible role). J. Med. Virol. # 2013 Wiley Periodicals, Inc. KEY WORDS: HCV 4d; phylogeny; Turkey INTRODUCTION In Turkey, it is estimated that around 0.75–1.5 million people are infected with HCV, corresponding to prevalence of 1–2% [Lavanchy, 2011]. Genotype 1, especially type 1b virus, causes approximately 90% of these infections, while types 2, 3, and 4 exist, albeit in low prevalences [Abacioglu et al., 1995] and are due to relatively recent and limited introductions from endemic areas [Smith et al., 1997]. The intro- duction of HCV type 1b to Turkey has been estimated to take place within the first decade of twentieth century through Greece [Ciccozzi et al., 2011]. Unsafe medical procedures, including blood transfusions and surgeries, were probably instrumental in the dissemi- nation of virus between 1940 and 1999 in Turkey [Karaca et al., 2006; Ciccozzi et al., 2011]. The spread of epidemics seems to have reached a plateau after 1999, suggesting a partial success of improved trans- fusion policies and safe medical procedures [Ciccozzi et al., 2011]. However, two recent reports from Kayseri, a rela- tively large city in Central Anatolia, indicated unusu- ally high for type 4 infections in the province reaching a 35% among patients admitted to hospitals for treatment of chronic hepatitis C [Gokahmetoglu et al., 2011; Kayman et al., 2012]. These are signifi- cantly higher than the average prevalence of 1.4% reported for type 4 HCV infections in Turkey [Kay- man et al., 2012]. It was shown recently that Kayseri type 4 isolates are closely related with subtype 4d sequences (submitted for publication). The same study also showed that patients infected with types 1b and 4d viruses had comparable age and sex distribution suggesting that these patients may have  Correspondence to: Massimo Ciccozzi, Department of Infec- tious, Parasitic and Immunomediated Diseases, National Insti- tute of Health, Viale Regina Elena 299, 00161 Rome, Italy. E-mail: massimo.ciccozzi@iss.it Accepted 5 September 2013 DOI 10.1002/jmv.23787 Published online in Wiley Online Library (wileyonlinelibrary.com).  C 2013 WILEY PERIODICALS, INC.