The Missing Link Between Immunity and Thyroid Disorders (FCRL3)

Synonyms: CD307c, FCRH3, IFGP3, IRTA3, SPAP2

FCRL3 (Fc receptor-like 3) gene encodes for a receptor with complex roles in the immune system. It can send both inhibitory and stimulatory signals to immune cells upon activation, enabling it to modulate the body’s response to infectious agents and other threats [R, R].

As its full name suggests, FCRL3 resembles Fc receptors on immunoglobulin (antibody) chains. Despite recent progress in understanding, scientists are still exploring its exact roles in immunity [R, R].

Both B-cells and T-cells express FCRL3 receptors, which mediate their communication and development. Unfortunately, like many other genes involved in immune response, FCRL3 has a dark side—certain variations may impair its function and correlate with autoimmunity [R, R]. 

FCRL3 encodes for a receptor that can both suppress and stimulate immune cells, but its exact role remains unknown. Specific variants in this gene have been associated with autoimmunity.

Back in 2005, a group of Japanese authors investigated the connection between the SNPs in FCRL3 and different autoimmune conditions. According to their results, the “G” allele at rs7528684 correlates with thyroid autoimmunity—particularly Graves’ disease [R].

The study provided valuable insights into the mechanisms behind FCRL3-associated autoimmunity, which we’ll discuss later.

A clinical trial of nearly 2,000 UK subjects confirmed the link between rs7528684-G and Graves’ disease (GD) in Europeans. Carriers of this allele had 17% higher GD rates. Another FCRL3 variant, rs3761959-T, showed an even stronger association and correlated with 20% higher disease rates [R].

In 2,500 people of European ancestry, scientists identified another SNP associated with Graves’ disease: people with the “C” allele at rs7522061 had 25% higher GD incidence. According to the study, rs7522061 is a “twin” SNP of rs3761959 rather than a separate factor [R].

Two Chinese studies of 20,000 total participants came to similar conclusions for two primary SNPs: rs3761959-T and rs7528684-G correlated with 22-23% higher rates of Graves’ disease [R, R].

The above variations also correlated with Graves’ ophthalmopathy (GO), a complication that attacks the eyes, in another Chinese study of 1,200 people [R].

In different populations across the globe, they’ve been associated with other autoimmune conditions, such as [R, R, R]:

• Rheumatoid arthritis
• Lupus
• Type 1 diabetes
• Multiple sclerosis

However, it’s important to note that the risk/beneficial alleles are not the same for each disease. In other words, those with a specific FCRL3 variant can be prone to one condition but protected against another.

Three FCRL3 variants —rs7528684, rs3761959, and rs7522061— correlate with Graves’ disease and other autoimmune conditions in European and Asian populations.

How It Works

The SNPs discussed above belong to a “block” of four variations that are almost always inherited together. In other words, they act as a single genetic factor.

After detailed experiments, scientists concluded that rs7528684 is likely a functional SNP driving the connection with Graves’ disease. The “G” allele increases FCRL3 expression by enhancing its interaction with NF-kB, a major inflammatory transcription factor [R, R].

Increased FCRL3 expression causes B-cells to “break the tolerance” — it allows the survival of self-attacking B-cells that create antibodies to healthy thyroid structures, such as the TSH receptor [R, R].

The Role of Tregs

Regulatory T cells (Tregs) play a central role in suppressing an overactive immune response. Surprisingly, Tregs with FCRL3 on their surface have a reduced ability to inhibit T cells. This phenomenon lowers immune tolerance and opens the door to autoimmunity [R, R, R].

Scientists are still investigating if other SNPs in this block have separate functional roles that impact the immune system regulation.

The “G” allele at rs7528684 increases FCRL3 expression by allowing NF-kB to bind. This may contribute to autoimmunity by reducing B-cell tolerance and suppressing regulatory T cells.

You can see your genotype for key FCRL3 SNPs in the table below. However, keep in mind that these results are based on association studies, and more research will be needed to know what role (if any) these variants play in actually causing thyroid disorders. Also, many different factors — including other genetic and environmental factors — can influence thyroid health. Therefore, just because you have one of these genotypes does not necessarily mean you are at an increased risk of developing a thyroid disorder!

SNP Table

SNP Summary

Primary SNP:

FCRL3 rs7528684:

• “G” – correlates with Graves’ disease
• “A” – doesn’t correlate with Graves’ disease

Other important SNPs:

FCRL3 rs3761959:

• “T” – correlates with Graves’ disease
• “C” – doesn’t correlate with Graves’ disease

FCRL3 rs7522061:

• “C” – correlates with Graves’ disease
• “T” – doesn’t correlate with Graves’ disease

Population Frequency 

As mentioned, these SNPs are almost always inherited together, so they act as a single genetic factor. Around 50% of European descendants carry one copy and 22-25% carry both copies of the alleles associated with Graves’ disease (G, T, and C, respectively).

These alleles are a bit less common in East Asian populations and a bit more common in African populations, compared with Europeans.  The “G” allele at rs7528684 is particularly common in African populations, where the other “A” allele is nearly non-existent.