Epidemiology of haemoglobinopathies

Genetic epidemiology and public health
There are quite a few examples of genetic diseases that are more prevalent in one population then in another. Just to mention the common one: Cystic Fibrosis (CF), which is most prevalent in people of European heritage; Tay-Sachs disease (TSD) is frequent among Ashkenazi Jews; Hereditary Haemochromatosis (HFE), most common among people of Northern European Celtic descent and the most common of them all and subject of this review, the Haemoglobinopathies (HBP) better known in the two major forms as Sickle cell Disease (SCD) and Thalassaemia Major (TM). Not just by chance these genetic diseases are autosomal recessive, meaning that the conditions are not sex linked and that carriers are just healthy persons, with or without some minor symptoms. Recessive means also that when two carriers get children, the traits will be inherited according to the Mendelian law of inheritance and that at each and every pregnancy the statistical outcome will be 25% chance to have a severely affected child, 50% chance to have a healthy carrier just like the parents and 25% chance to have a child not carrier. In origin HBPs were restricted to populations living in the tropical and subtropical regions of the “Old World” infested for thousands of years by malaria and by malaria tropica in particular. This brings us to the question why these diseases are prevalent in specific populations.

Diseases, selection mechanisms, epidemiology and prevention
The key mechanism at the base of evolution is the selection of random gametic mutations passed to the progeny to be tested for their beneficial or adverse effect. If a new recessive mutation gives an advantage to the offspring (better genetic fitness to survive and reproduce) in a particular environment then it will be passed more frequently to the following generations and become prevalent in that particular population living in that particular environment. In spite of the adverse effects, recessive trait advantageous in the carriers will then become more and more common until equilibrium is reached between advantages and disadvantages at a stabilized level that will characterize the epidemiology of the severe disease in a particular population.

Due to the severity of recessive diseases that manifest in the children of healthy carrier couples, prevention and carrier detection are important public health issues. Morbidity prevention can be offered by newborn screening to reduce the severe symptoms in the born child and primary prevention can be made available to  couples at risk to prevent the birth of a severely affected child. Primary prevention can be prospective if offered before the first affected child is born or retrospective if made available after the birth of the first affected offspring.

Molecular basis
HBP carriers can be identified at any time with a simple, fast, and inexpensive Hb separation and measurement on high performance liquid chromatography (HPLC) or capillary electrophoresis (CE), the modern version of the classic Hb electrophoresis. With an incidence of over 350,000 affected newborn per annum, HBP are the most common autosomal recessive disease worldwide. The conditions are caused by mutations that impair or modify the expression of the globin genes causing respectively lack of globin synthesis ( thalassaemias) or structural defects (abnormal haemoglobins). But for some semi-dominant mutation, carriers are either slightly anaemic (thalassaemia) or asymptomatic (most abnormal haemoglobins) and thus healthy. Conversely, children of healthy carrier couples have 25% chance of being affected with the severe forms Thalassaemia Major (TM) and/or sickle cell disease (SCD). While thalassaemias can be caused by more than 450  mutations, almost 1200  mutationshave been reported changing the structure of the alpha-like and beta-like globin gene products that are needed to build up the  haemoglobin tetramers, the essential oxygen transport proteins during embryonic, fetal and postnatal life. Among this broad spectrum of mutations some are very frequent and population-specific. As mentioned above, specificity is explained by the random occurrence of a particular mutation and frequency by the advantage given against malaria in tropical or subtropical region of the old world by that particular mutation. Random HBP mutations might very well be archaic but positive selection have probably started with the beginning of agriculture around 10,000 years ago when man had to share his surrounding with the anopheles mosquitos. In these surroundings children carriers of the trait had better chances to survive malaria during infancy, to reproduce and to pass the trait to the next generation increasing the gene frequency. This mechanism has generated carrier frequencies of structural haemoglobin variants like HbS (the main cause of SCD) of around 40% in some regions of central Africa. Equally the HbE variant,  alpha thalassaemia and beta thalassaemia have reached respective frequencies of 40%, 50%, 8% in some highly endemic regions of Thailand, the Arabian Peninsula and the Mediterranean.

Prevention programmes
Due to the high incidence and the severity of the disease, pioneering Mediterranean countries have provided carrier screening and primary prevention mainly for TM, the most frequent form in the area. In countries like Italy, Greece, France, Cyprus, Israel and Palestine, , Turkey and Egypt,  the incidence of the disease have been reduced substantially and in some areas by more than 90%. The tools used are information, premarital/preconception screening or screening in early pregnancy identifying couples at risk in time for an informed reproductive choice. Ongoing screening programs are summarized in Table 1, adapted and updated from Cousens et al.

Table 1. ''Countries with longest experienced at the top. NBS= Newborn screening; * School and pregnancy screening interrupted in 1986 and 1995 respectively. # Mandatory before Church marriage only. & Mandatory before marriage. @ At secondary or high school level.''

Recent trends
Today, the historical epidemiology of these diseases has changed dramatically and healthy carriers are present all over the world, while more affected children are born in the non-endemic immigration areas of Northern Europe than in the endemic Mediterranean countries. The growing incidence in non-endemic areas is not only caused by the increasing number of immigrant carriers and endogamous marriages but by the fact that primary prevention, often available in the countries of origin, has not been properly introduced in the healthcare systems of most non-endemic immigration countries.