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Discovery of genes linked to red blood cell biology gives insight into anaemia

Thu, 6 Dec 2012 11:46:32 EST

A genetic study published today reveals new insights into how red blood cells are made and how the body regulates the amount of oxygen-carrying haemoglobin they carry at any time. The findings lay the foundations for a better understanding of anaemia.

Anaemia is one of the most common disorders for which people visit their GP clinic. It is caused by a decrease in the number of red blood cells in the blood or a reduction in the amount of haemoglobin, the molecule carried by red blood cells that captures oxygen from the lungs for transport and delivery to tissues.

Each day, hundreds of millions of fresh red blood cells have to be formed by blood stem cells to replace the ones that come to the end of their life cycle. If the red blood cell lifespan is shortened for some reason, or if they are not replaced quickly enough, it can result in anaemia.

The international team of researchers used a combination of genetic analysis in people and subsequent research in fruit flies to identify genes linked to red blood cell biology and investigate their function.

They first looked at the genomes of more than 130 000 people to identify 75 genetic regions that seemed to influence the formation of red blood cells. The findings reveal new biological pathways and mechanisms involved in controlling the size and number of red blood cells and the levels of haemoglobin they contain. More than half of the gene regions identified have not been linked to red blood cells in people before, say the authors.

Using computational biology approaches, the team then looked at the 75 genetic regions more closely, along with more than 3000 genes responsible for protein production that lie close to these regions. They prioritised 121 genes that are likely to regulate a characteristic of red blood cells and investigated their function using existing data in public databases and new experiments in fruit flies.

The team searched through a database of findings from mouse experiments and found that 29 of the 121 candidate genes are linked to red blood cell formation in mice.

Professor Willem Ouwehand, lead author from the University of Cambridge and NHS Blood and Transplant, said: "These previous studies revealed that when the function of these genes was switched off, the mice frequently developed reduced numbers of red blood cells and anaemia. These observations made in mice make it highly likely that the remaining candidate genes, about which there is no knowledge yet, are also important regulators of red blood cell formation in people."

To investigate further, the team then reduced or 'silenced' the activity of the candidate genes in fruit flies. Although fruit flies do not have red blood cells, they share some of the gene functions leading to the formation of blood elements. These studies confirmed that sets of genes involved in controlling human red blood cell traits in people were also important for the formation of blood cells in flies.

"These results support the view that genetic association studies identify sets of genes that are conserved in evolution across a wide range of species," says Dr Nicole Soranzo, lead author from the Wellcome Trust Sanger Institute. "This is exciting because it means that we can obtain extensive new insights into the genetics and biological pathway of human health by studying model organisms.

"Although the underlying mechanisms for the majority of genes we've identified still need to be elucidated, our research is opening many doors for future studies on the generation of red blood cells for clinical use in the laboratory and may also provide insights which may lead to improvements in the treatment of patients with inherited anaemias."

The research is published online today in the journal 'Nature'.

Reference
P van der Harst et al. 75 genetic loci influencing the human red blood cell. Nature 2012 (epub ahead of print).


Source: WebWire



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