DDC Mutations Associated with Risk of Developing Severe Malaria, Review Study Shows

Mutations in the dopa decarboxylase (DDC) gene — the gene associated with aromatic L-amino acid decarboxylase (AADC) deficiency — are linked with an increased risk of severe malaria, according to a review study.

The study, “Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects,” was published in the journal BMC Medical Genomics.

AADC deficiency is a rare genetic disorder caused by mutations in the DDC gene, which result in a reduced activity of the AADC enzyme. AADC is necessary for the production of neurotransmitters — chemical messengers used by nerve cells to communicate with each other — such as dopamine and serotonin.

Apart from its presence in the nervous system, AADC has been detected in several peripheral organs, such as the liver and kidneys, but its function outside the brain remains largely unclear.

Increasing evidence points to an additional role of AADC in immunity and inflammation.

Mutations in the DDC gene were reported to be linked to resistance of mosquitoes to malaria parasites. And in invertebrates, AADC was shown to be involved in cell-based immunity and in the protection against parasitic disease, through the action of dopamine.

Several studies have highlighted that dopamine works not only as a neurotransmitter, but also as a regulator of the immune system. Dopamine was found to promote a balance between the central nervous system (brain and spinal cord) and the immune system. It was also found to be produced and released by immune cells themselves.

A review study has now reported an association between mutations in the DDC gene and different susceptibilities to malaria. Malaria is a life-threatening disease caused by Plasmodium falciparum parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes.

The researchers reviewed the results of genome wide association studies (GWAS) in malaria. These GWAS scanned complete sets of DNA, or genomes, of a large number of people to identify all the genetic changes associated with the development of malaria, and their different effects on the risk of developing the disease.

Two GWAS studies — one in the Gambian population, and the other in the Tanzanian population — showed an association between mutations in the DDC gene and the risk of developing severe malaria.

The results of the study in the Tanzanian population showed that this association was linked to the development of cerebral malaria, the most severe complication caused by the malaria parasite.

These findings highlight the potential role of the AADC enzyme — likely through its related neurotransmitters — in the immune system and in the protection against parasites, particularly in the brain.

Future studies are needed to clarify the underlying mechanisms between these associations, the researchers said.