Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common enzymatic disorders worldwide, affecting hundreds of millions of people, particularly in regions where malaria is or has been endemic. This genetic condition has a fascinating link with resistance to malaria, a disease caused by Plasmodium parasites transmitted by mosquitoes.

This article delves into how G6PD deficiency provides a protective advantage against malaria, the underlying biochemical mechanisms, and the implications for public health.

What Is G6PD Deficiency?

G6PD is a critical enzyme in the pentose phosphate pathway, responsible for producing NADPH, which helps protect red blood cells from oxidative damage. Deficiency in G6PD impairs this protective mechanism, making red blood cells more vulnerable to oxidative stress.

The deficiency is inherited in an X-linked recessive manner and is especially prevalent in Africa, the Mediterranean, the Middle East, and parts of Asia—areas historically burdened by malaria.

The Protective Link Between G6PD Deficiency and Malaria

Epidemiological studies have consistently observed that individuals with G6PD deficiency have a lower risk of severe malaria infection caused by Plasmodium species, particularly Plasmodium falciparum and Plasmodium vivax.

How Does G6PD Deficiency Confer Resistance?

• Increased Oxidative Stress in Red Blood Cells:
  G6PD-deficient red blood cells have reduced NADPH levels, leading to higher oxidative stress. This hostile environment is detrimental to the survival and replication of Plasmodium parasites inside the red blood cells.

• Selective Parasite Clearance:
  Oxidative damage may cause infected red blood cells to be preferentially removed by the spleen, reducing parasite load.

• Genetic Selection:
  The high prevalence of G6PD deficiency in malaria-endemic regions suggests positive selection, where the genetic mutation confers a survival advantage against malaria.

Supporting Evidence from Research

• Studies have shown reduced parasite densities in individuals with certain G6PD variants, such as the Mahidol variant in Southeast Asia.

• Protection is more pronounced in hemizygous males and homozygous females, with heterozygous females showing variable effects due to X-chromosome inactivation.

• Meta-analyses confirm a significant association between G6PD deficiency and decreased incidence or severity of malaria in African and Asian populations.

Other Infectious Agents and G6PD Deficiency

While G6PD deficiency impacts red blood cell metabolism and oxidative stress, its protective effect is specifically linked to Plasmodium parasites. There is no substantial evidence indicating resistance to fungal infections, Leishmania, or bacterial pathogens due to G6PD deficiency.

Clinical and Public Health Implications

• Malaria Treatment Caution:
  Certain antimalarial drugs like primaquine can induce hemolysis in G6PD-deficient individuals, necessitating screening before administration.

• Genetic Counseling:
  Awareness of G6PD deficiency prevalence aids in managing risks related to oxidative stress and malaria susceptibility.

• Therapeutic Research:
  Understanding the protective mechanisms may inspire new antimalarial strategies mimicking oxidative stress effects.

Summary Table

Conclusion

Glucose-6-phosphate dehydrogenase deficiency provides a natural protective effect against malaria caused by Plasmodium species. This resistance is primarily due to increased oxidative stress within red blood cells, creating an unfavorable environment for parasite survival. The evolutionary prevalence of G6PD deficiency in malaria-endemic regions underscores its significance as a genetic adaptation.

Correct answer: (1) Plasmodium