Question rokitit Medical Sciences

The genetics of Haemoglobinopathies and G6PD deficiency. How do these diseases confer resistance to malaria species?

Sickle cell anaemia can confer protection from malaria. What other genetic factors can do this? Can other kinds of anaemia?

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Answer Internal Staff

Sickle cell disease is a group of inherited disorders associated with finding of predominantly haemoglobin S (HbS) or HbS along with other β-globin gene variants such as HbC. Normal human haemoglobin consists of two α-globin chains and two β-globin chains – HbS is the result of a mutation of a single nucleotide (single nucleotide polymorphism) of the β-globin gene. Sickle cell anaemia is a homozygous HbSS disease (possess two copies of HbS variant) and is the most severe of all sickle cell variants as the primary haemoglobin in their erythrocytes is sickle haemoglobin. Other variants of sickle disease are heterozygous disorders – individuals possess only one copy of the HbS variant plus one copy of another β-globin gene variant (such as HbC or Hb β-thalassemia). These individuals will produce a mixture of variant haemoglobins. Individuals who have one copy of the HbS variant and one copy of normal (HbAS) are carriers of the disease – this state is often referred to as the sickle cell trait. It is now widely accepted that there is a link between haemaglobinopathies (HbAS, HbSC, HbSβ- thalassemia) and protection against malaria (particularly Plasmodium falciparum). The geographic prevalence of the disorder correlates with the distribution of malaria. This link was first suspected >60 years ago and in the years that have followed, overwhelming evidence has been provided by multiple studies although the mechanism of protection is unclear. Some studies have hypothesised a lower prevalence of parasitaemia in individuals with HbAS trait due to an increased immunological and biochemical response that affects parasite metabolism and growth. In addition to haemoglobinopathies, another type of anaemia that provides protection against malaria is Glucose-6-phosphate Dehydrogenase (G6PD) deficiency - an X-chromosomally transmitted disease of erythrocytes. G6PD is an enzyme that catalyses a step in the pentose phosphate pathway leading to the production of NADPH- preventing the cell from oxidative stress. Cells with limited G6PD are therefore vulnerable to oxidative stress and as a result, undergo haemolysis. This vulnerability is the mechanism underlying its relative protection against P. falciparum as the parasites fail to thrive in the immature erythrocytes that are rapidly released to compensate for the haemolysis of normal erythrocytes.


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