Tracing the molecular and historical background of inherited blood disorders in Oman – Fellows’ seminar by Shahina Daar

3 April 2023

“The inherited disorders of haemoglobin (haemoglobinopathies) are the commonest single-gene disorders in the world. They occur when a mutation arises in one or more of the globin genes that form haemoglobin and can affect the structure or quantity of haemoglobin. Using whole-genome data, it’s clear that these haemoglobinopathies have been present in human populations for thousands of years,” said Shahina Daar of the Department of Hematology at Sultan Qaboos University, Oman.  

STIAS Visiting Scholar Shahina Daar during her seminar on 28 March 2023

She explained that the most common examples of haemoglobinopathies are sickle cell disease where the gene mutation results in structurally abnormal haemoglobin, and the thalassemias (both alpha and beta) that result in a quantitative disorder of haemoglobin. “Worldwide about 250 million people carry the sickle cell gene and 300 000 are born with the disease annually. Most of these latter cases occur in Nigeria, the Democratic Republic of the Congo and India. An estimated 90 million people carry the beta thalassemia gene and 60 000 are born with the disease annually.”  

“But,” said Daar, “this is probably undercounting – as many children are not tested or do not survive.”  

“Both carrier forms (heterozygotes) of sickle cell and beta thalassemia have no discernible clinical symptoms – you can go your whole life without knowing you have it – whereas those who have inherited two copies of the mutant genes (homozygotes or compound heterozygotes) die early without adequate treatment.” 

In sickle cell disease, the red blood cells have an abnormal crescent shape, which blocks blood flow in small blood vessels, and do not last as long as normal red blood cells. Beta thalassemia causes reduced production of haemoglobin – the iron-containing protein in red blood cells that carries oxygen to cells throughout the body. Both eventually cause damage to organs and bones, and death – without treatment, homozygous beta thalassemia is fatal by about ages two to five. Curative therapies such as bone marrow transplantation are expensive and limited to those with a compatible donor and current management includes drug therapies and regular blood transfusions. 

Links to malaria 

Daar also pointed to the interesting relationship between these conditions and malaria.  

“The world distribution of haemoglobinopathies overlaps the geographic distribution of malaria,” she explained. “There is a complex relationship between haemoglobinopathies and malaria, and individuals who carry a single copy of a haemoglobinopathy gene, such as in sickle cell trait, may have a survival advantage in regions where malaria, in particular that caused by Plasmodium falciparum, is prevalent.”  

She pointed out that malaria is an ancient disease with evidence of its existence seen in Egyptian mummies dating from 3000 BC and in Mesopotamia and China from 2700 BC. It was widespread in the Mediterranean region by the Christian era. The prevalence is thought to have increased with more community living, settled agriculture and therefore standing water sources that encouraged mosquito breeding.  

Although there are four mosquito species that affect humans the most important is Plasmodium Falciparum which causes the largest number of deaths, many due to cerebral malaria. Once in the human red blood cells, the parasite goes through asexual reproduction and the parasite mass increases 32-fold in 48 hours. The parasite also stops damaged or infected blood cells from reaching the spleen where the infected red cells can be removed.  Plasmodium Falciparum, in particular, is able to produce an adhesive protein that it exports to the surface of the red blood cells making the cells sticky so that they clump together in rosettes stopping them from reaching the spleen and blocking capillaries causing problems in the lungs and brain.   

“Malaria is a very smart organism,” said Daar, “you never get over it.”  

But the presence of the genetic mutations in sickle cell in particular and beta thalassemia seem to assist in preventing the P. Falciparum malaria parasite from getting the adhesive proteins to the red cell surface and also interferes with the parasite’s asexual reproduction.  

“It doesn’t stop you from getting malaria but stops it from multiplying and also prevents it sticking to the blood vessels. So having the sickle cell or beta thalassemia trait seems to prevent you from dying from malaria. The sickle cell gene is highly protective (up to 90%), beta thalassemia less so. This means there is a survival advantage for carriers of sickle cell and beta thalassemia. But a lot of work is needed to understand it fully.” 


Turning specifically to her work in Oman, Daar explained: “The countries of the Arabian Peninsula, of which the Sultanate of Oman is one, have a high prevalence of alpha thalassemia (10-40%), sickle cell gene and beta thalassemia. However, despite being the commonest haemoglobin gene disorder in the region, the clinically debilitating form of alpha thalassemia is uncommon.”  

Sickle cell and beta thalassemia constitute the greatest clinical burden. “In Oman 6% of the population carry the sickle cell trait and 2.5% carry the beta thalassemia trait – so together that’s nearly 10% of the population.” 

Her work is aimed at understanding the molecular basis of the sickle cell and beta thalassemia genes, and how the genetics, combined with archaeological and historical data, can shed light on the origins of these two diseases in the Omani population. 

Sickle cell disease is caused by a single-point mutation in the haemoglobin beta gene found on chromosome 11. Haplotypes are a set of closely linked genetic markers and in sickle cell the presence of beta S-globin haplotypes allow identification of the geographic region from which patients originated. The haplotypes include Senegal, Benin, Bantu or Central African Republic, Cameroon and Arab-Indian. 

Identifying the haplotypes associated with sickle cell in the Omani population has shown that the Benin haplotype at 44% is much higher than the Bantu/Central Africa Republic and Arab Indian haplotypes both at 28%. 

It therefore seems likely that the mutation was introduced to Oman via the early African slave trade which was mostly with Central and West Africa. “Slavery was present in pre-Islamic times but probably increased due to an Islamic injunction against enslaving Muslims which led to the introduction of more slaves from outside specifically Africa. The Trans-Saharan Slave route from 650 – 1500 AD is estimated to have involved up to six million slaves.”   

In beta thalassemia the mutations which cause a reduction or absence of the beta-globin protein can occur in different parts of the gene. Six mutations have been found to be the commonest in the Omani population with the Indian mutation the most common. This is likely to be based on voluntary movements for trade with Asia, Mesopotamia, Iran, Iraq, the Red Sea, East Africa and the Far East.     

Oman has had strong trading links with what was known as the Harrapan civilisation in the Indus valley 4000 years ago. “In more recent history, people from the Baluchistan region, which was part of the Indus Valley, immigrated to Oman about 1400 years ago,” said Daar. “Baluchis were also active in Oman as mercenaries and soldiers from 1700 to 1970. In 1792 the Port of Gwadar was gifted to Oman and only returned in 1957.” 

“There are also strong ties between Oman and Zanzibar – with Zanzibar under Omani rule from 1698 to 1964.” 

“Testing in the thalassemia population in Oman showed that 90% of patients of Baluchi tribal background had Indian alleles while the non-Baluchi patients had a 50/50 split between Indian and other alleles making it probable that the gene flow from the Indian sub-continent occurred early enough to allow spread of the genes within the population.” 

“So it’s likely that sickle cell and beta thalassemia came to Oman by different routes,” said Daar. “Although both have been around for a very long time a confluence of factors encouraged their expansion in different regions.” 

In discussion, Daar emphasised the importance of this work and ongoing education activities to destigmatise carriers of these conditions. She also pointed out that as screening and management increase the lifespan of patients into their productive years, genetic testing and counselling becomes more important.   

“Genetic screening has its place. Some Arab countries do mandatory screening to identify couples at risk for passing on the mutation to their children.” 

She also addressed the political economies of such conditions. “Thalassemia is termed an orphan disease – there is not enough incentive for big pharma to make new drugs dealing with the disease. Sickle cell is also mostly seen in Africa. There is work being done on gene therapies but it’s exceptionally expensive and therefore will only help people in rich countries. Both are extremely expensive to treat. We fight for funding every year. We need cheaper gene therapy and treatment that is inexpensive and not toxic.”  


Michelle Galloway: Part-time media officer at STIAS
Photograph: Noloyiso Mtembu

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