The changing epidemiology of ß-thalassemia in the Greek-Cypriot population.

The first epidemiological study for thalassemia in Cyprus was performed by Fawdry in 1946. The study determined that the frequency of ß-thalassemia (ß-thal) carriers was around 18.0% and that of α(0)-thal carriers (individuals with both cis α-globin genes inactive) at around 2.0%. In 1998, another study concluded that Cyprus had one of the highest frequencies of ß-thal carriers worldwide (17.2%). Based on Haldane's hypothesis that malaria might be the selective agent responsible for the maintenance of high levels of thalassemia and sickle cell disease in many populations around the world, it is expected that following the eradication of the disease in Cyprus in 1948, the carriers of ß-thal should decline with each generation. In order to determine whether this has been the case, we compiled frequency data for ß-thal carriers from three separate surveys performed as part of the Cyprus National Thalassaemia Screening Programme (NTSP). The surveys were carried out in 1986, 2003 and 2010 involving 9622, 6711 and 5228 subjects, respectively. The expected drop in the prevalence of ß-thal carriers for each successive generation following the eradication of malaria, i.e., in the absence of selection pressure, was calculated using the Hardy-Weinberg equation and the mathematical model of Hartl and Clark. The surveys provide supporting evidence for the decrease of the frequency of the ß-thal carriers in the Greek Cypriot population, with a drop of 1.89% in 24 years.

Hemoglobin variants in Cyprus.

Cyprus, located at the eastern end of the Mediterranean region, has been a place of eastern and western civilizations, and the presence of various hemoglobin (Hb) variants can be considered a testimony to past colonizations of the island. In this study, we report the structural Hb variants identified in the Cypriot population (Greek Cypriots, Maronites, Armenians, and Latinos) during the thalassemia screening of 248,000 subjects carried out at the Thalassaemia Centre, Nicosia, Cyprus, over a period of 26 years. A sample population of 65,668 people was used to determine the frequency and localization of several of the variants identified in Cyprus. The localization of some of the variants in regions where the presence of foreign people was most prevalent provides important clues to the origin of the variants. Twelve structural variants have been identified by DNA sequencing, nine concerning the beta-globin gene and three concerning the alpha-globin gene. The most common beta-globin variants identified were Hb S (0.2%), Hb D-Punjab (0.02%), and Hb Lepore-Washington-Boston (Hb Lepore-WB) (0.03%); the most common alpha-globin variant was Hb Setif (0.1%). The presence of some of these variants is likely to be directly linked to the history of Cyprus, as archeological monuments have been found throughout the island which signify the presence for many years of the Greeks, Syrians, Persians, Arabs, Byzantines, Franks, Venetians, and Turks.

Hb Agrinio [alpha29(B10)Le-->uPro (alpha2)] in combination with --(MED I). Results in a severe form of Hb H disease.

We report two cases of compound heterozygote patients for the --(MED I) and Hb Agrinio [alpha29(B10)Le-->uPro (alpha2)] anomalies in two unrelated Greek Cypriot families. The first patient had a serious form of Hb H disease and died at the age of 21 due to complications arising during an operation. The second patient showed a severe hematological picture and has been regularly transfused since an early age. This patient exhibits bone abnormalities as well as hepatosplenomegaly. The severity of these two incidences emphasizes the need for the inclusion of a screening test for the --(MED I)/alpha(Agrinio)alpha genotype among those already offered during prenatal diagnosis. Two homozygotes, as well as a number of simple, compound, and double heterozygotes for Hb Agrinio have been identified in Cyprus and their hematological indices are presented.

The molecular spectrum and distribution of haemoglobinopathies in Cyprus: a 20-year retrospective study.

Haemoglobinopathies are the most common monogenic diseases, posing a major public health challenge worldwide. Cyprus has one the highest prevalences of thalassaemia in the world and has been the first country to introduce a successful population-wide prevention programme, based on premarital screening. In this study, we report the most significant and comprehensive update on the status of haemoglobinopathies in Cyprus for at least two decades. First, we identified and analysed all known 592 ß-thalassaemia patients and 595 Hb H disease patients in Cyprus. Moreover, we report the molecular spectrum of α-, ß- and δ-globin gene mutations in the population and their geographic distribution, using a set of 13824 carriers genotyped from 1995 to 2015, and estimate relative allele frequencies in carriers of ß- and δ-globin gene mutations. Notably, several mutations are reported for the first time in the Cypriot population, whereas important differences are observed in the distribution of mutations across different districts of the island.

Delta-thalassemia in Cyprus.

To help clarify the hematological picture of patients who may be positive for beta- and delta-globin gene mutations, the following study was carried out. Our aim was to identify the delta-globin gene mutations found in the Greek Cypriot population, their frequencies and the Hb A2 values associated with them. Seventy-four samples were selected from a random sample of 5,030 individuals, and the database of the Molecular Genetics Thalassaemia Department containing diagnostic analyses data was also mined for relevant information. Four novel for Cyprus delta-globin gene mutations: -30 (T-->C), Hb A2-Wrens [delta98(FG5)Val-->Met, GTG-->ATG], IVS-I-2 (T-->C) and Hb A2-Yokoshima [delta25(B7)Gly-->Asp (GGT-->GAT)] were identified. Hb A2-Yialousa [delta27(B9)Ala-->Ser, GCC-->TCC], Hb A2-Yokoshima, Hb A2-Troodos [delta116(G18)Arg-->Cys, CGC-->TGC], Hb A2-Pelendri [delta141(H19)Leu-->Pro, CTG-->CCG], codon 4 [delta4(A1)Thr-->Ile], codon 59 (-A), Hb A2-Wrens, IVS-II-897 (A-->G), IVS-I-2, -55 (T-->C) and -30 bring the total to 11 delta-globin alleles found in the Greek Cypriot population. Hb A2-Yialousa is the most common mutation followed by codon 4, with frequencies of 60.7 and 17.8%, respectively.Hb A2 levels above 1.9% have been found to indicate a significantly reduced possibility for the presence of a delta-globin gene mutation in this population. For Hb A2 levels of 1.7 and 1.8% the possibility of a delta-globin gene mutation rises to 90.9% and reaches 100% for lower Hb A2 levels. The frequency of all the mutant delta-globin chromosomes in the sample is 0.0067 and the carrier frequency is 1.26%.