Can This Gene Protect Against A Cytokine Storm? (FCGR2A)

FCGR2A is a gene that encodes a protein on the surface of immune cells, called Fc-gamma receptor. Fc-gamma receptor binds antibodies (IgG) that are attached to microbes or infected cells and signals the immune system to destroy and remove them [R, R, R].

Fc-gamma receptors have a wide variety of roles, and control various immune processes such as [R, R]:

• Immune-cell production
• Cytokine production
• Phagocytosis by macrophages, which are a type of white blood cells. Phagocytosis is when immune cells engulf and “digest” microbes and infected cell debris.
• Degranulation of mast cells. Mast cells are rich in granules containing histamine which trigger inflammation.

Fc-gamma receptors get activated only when they bind multiple antibodies simultaneously — a single IgG does not activate them. This ensures that the immune system is triggered only when antibodies bind to bacteria or infected cells [R].

FCGR2A encodes a protein found on the surface of immune cells. This protein binds to antibodies attached to microbes and infected cells and signals the immune system to destroy them.

When it comes to respiratory infections, some people are barely affected, while others can develop serious symptoms and complications, such as a cytokine storm.

A cytokine storm is a dangerous inflammatory state that happens when the immune system overreacts to infection. During a cytokine storm, inflammatory signals go haywire, and the immune system ends up doing more damage than the infection itself [R].

Scientists discovered that Fc-gamma receptors are responsible for triggering cytokine release and may exacerbate cytokine storms [R]. 

For example, a study of 271 people found that those who had the ‘AA’ genotype for rs1801274, a SNP in the FCGR2A gene, had a heightened release of an inflammatory cytokine IFN-γ in response to antibodies (IgG) [R].

Similarly, in another study, people with the ‘AA’ genotype had a higher production of another inflammatory cytokine, IL-1beta, compared to people with the ‘AG’ and ‘GG’ genotypes [R].

A variant in the FCGR2A gene has been associated with a heightened release of inflammatory cytokines.

Scientists looked if the rs1801274 variant had an impact on infection severity, but the results are conflicting.

A Mexican study of 91 people looked into the link between influenza A (H1N1) severity and the rs1801274 SNP. They found that the ‘A’ allele was more common in those who developed severe pneumonia, compared to those who didn’t have serious symptoms [R].

However, two other studies failed to find any association between this SNP and disease severity in 436 Brazillian and 110 Greek people with influenza [R, R].

Similarly, a couple of studies, one of 97 Cuban and another of 700 Vietnamese people, suggest that people who carry the ‘A’ variant may develop more severe symptoms when infected with dengue [R, R]. 

However, another study of 473 Mexicans found no association between this SNP and dengue severity [R].

Some studies suggest there may be a link between a variant in the FCGR2A gene and the severity of infections such as influenza and dengue. However, other studies have found no association.

Researchers have discovered that the ‘A’ allele of rs1801724 results in stronger binding to some types of antibodies (IgG1 and IgG2), compared to the ‘G’ allele. In other words,  the ‘A’ allele is responsible for a stronger immune response [R, R, R, R].

For example, white blood cells from people who have the ‘AA’ genotype respond more aggressively (increased phagocytosis and degranulation) to microbes compared to white blood cells from those who have the ‘GG’ genotype [R, R].

Interestingly, scientists found that people who have the ‘G’ variant may be at a higher risk of:

• Lupus [R, R, R]
• Sepsis [R]
• Manifesting malaria [R]

People with the ‘A’ variant, on the other hand, may have a higher risk of inflammatory diseases, such as:

• Inflammatory bowel disease (IBD) [R, R, R]
• Rheumatoid arthritis (in Europeans but not East Asians) [R]
• Kawasaki disease [R, R, R, R]
• Childhood vasculitis (blood vessel inflammation) [R]

In the first case, scientists think that the lower immune activity associated with the  ‘G’ variant means that the immune system may be less effective at removing circulating debris (immune complexes) from the blood, which is a hallmark of diseases such as lupus [R, R].

In the second case, a more active immune response, conferred by the ‘A’ variant, may lead to excessive inflammation, seen in inflammatory diseases such as IBD, rheumatoid arthritis, and Kawasaki disease [R, R].

Research suggests that the ‘A’ allele of the rs1801724 FCGR2A gene variant is responsible for a stronger, more aggressive immune response to microbes.

SNP Summary and Table

FCGR2A rs1801274

• ‘A’ = major allele, associated with a stronger immune response, higher cytokine production, and possibly more severe reaction to viral infections
• ‘G’ = minor allele, associated with a weaker immune response and lower cytokine production

About 32% of people have the ‘AA’ genotype. The ‘A’ allele is more common in East Asians, where about 50% of people have the ‘AA’ genotype.