How Crucial Autoimmunity Genes Impact Thyroid Health (HLA)

The human leukocyte antigen (HLA) system is a group of human genes encoding the major histocompatibility complex (MHC) proteins, or HLAs. HLAs are proteins or antigens on the surface of white blood cells. They help flag and remove external agents that may harm the body or cause infections [R].

HLA genes come in many different forms, and there are millions of their possible combinations. Their diversity ensures the protection against a wide array of external threats, but it can be a double-edged sword: some variants correlate with autoimmune disorders such as [R, R]:

• Autoimmune thyroid disorders (AITD)
• Diabetes type 1
• Lupus
• Inflammatory bowel disease (IBD)

HLA-DRB1

The HLA system has three groups or classes; HLA-DRB1, which we’ll focus on in this post, belongs to the class II. These proteins are expressed on antigen-presenting cells, and they present foreign peptides (antigens) to T-helper cells. Upon this signal, T-helpers stimulate B cells to make antibodies to specific antigens, which attack and neutralize them [R, R].

Along with HLA-B, HLA-DRB1 has the highest diversity in the entire human genome. Unfortunately, some variants can mistakenly “flag” the body’s components as external threats and initiate an autoimmune reaction [R].

Graves’ Disease

One of the earliest observed genetic associations with Graves’ disease (autoimmune hyperthyroidism) refers to a so-called “DR3-DQ2” haplotype (a group of genetic variants). It includes three alleles — DRB1*0301, DQB1*0201, and DQA1*0501 — and correlates with more than doubled GD rates [R, R].

Further analyses have shown that these variants are almost always inherited together in Caucasian (European) populations, so they act as a single genetic factor. DRB1*0301 is likely the lead variant responsible for the association with Graves’ disease [R]. 

In two studies of over 1,800 subjects, carriers of DRB1*0301 had 2.5-3x higher GD rates [R, R].

Studying its connection with other autoimmune conditions, scientists have identified a “tag” SNP for DRB1*0301: the “T” allele at rs2187668 [R].

The above haplotype is among the crucial genetic factors of celiac disease in European descendants, confirming a strong connection between gluten intolerance and autoimmune thyroid conditions. Other associated conditions include [R, R, R, R]:

• Systemic lupus erythematosus (SLE)
• Type 1 diabetes
• Idiopathic membranous nephropathy (kidney disease)

The HLA-DRB1*0301 variant is primarily responsible for the association between HLA genes and Graves’ disease (GD). People with this variant, tagged by rs2187668-T, may have up to 3x higher GD rates.

Hashimoto’s Disease

The connection between HLA alleles and Hashimoto’s disease (autoimmune hypothyroidism) is less clear but also points to a significant role of the HLA-DR3 group, which includes HLA-DRB1. According to a review of clinical trials, it correlates with 1.8x higher HD rates [R, R, R].

A study of over 39,000 participants found an SNP in the HLA-DRB1 gene slightly associated with low thyroid hormones. People with the “C” allele at rs2516049 had 15% higher rates of hypothyroidism [R].

Given the known role of HLA-DRB1 in autoimmunity, the affected people likely have Hashimoto’s disease. The same SNP is also associated with [R, R, R]:

• Epstein-Barr virus infection
• Asthma
• Ulcerative colitis

Different HLA-DRB1 variants, such as rs2516049-C, correlate with hypothyroidism and Hashimoto’s disease, confirming a significant role of this gene in thyroid autoimmunity.

How It Works

To determine precisely how HLA-DR variants contribute to thyroid autoimmunity, researchers studied their impact on protein structure and expression. According to their findings, a single amino acid is to be blamed!

Namely, DRB1*0301 replaces neutral amino acids (alanine or glycine) with the positively charged arginine in the beta-1 chain of the HLA-DR receptor (see the image above). This changes the receptor structure and causes it to bind specific thyroid peptides, signaling the production of antibodies against them [R, R, R].

As key controllers of T cell activation, regulatory T cells (Tregs) can prevent or reduce this harmful chain reaction. In animal models, increasing Tregs have suppressed autoimmune thyroid inflammation. On the other hand, mice depleted of Tregs were more susceptible to both Graves’ and Hashimoto’s disease [R, R, R].

HLA-DRB1 variants can change the receptor structure and cause it to confuse healthy thyroid peptides for harmful antigens. This error results in the production of thyroid autoantibodies, but regulatory T cells can prevent or reduce it.

Other HLA Variants in Thyroid Autoimmunity

Scientists didn’t expect HLA class I variants to be associated with thyroid autoimmunity because the class I receptors present bacterial and viral peptides from the cell interior (cytosol).

Still, a UK study of nearly 1,300 patients identified different HLA-C (class I) alleles as crucial factors behind the HLA and Graves’ disease connection [R].

In the previously mentioned study of almost 40,000 subjects, one variant near HLA-C was associated with low thyroid hormones. Carriers of the “A” allele at rs2517532 were less likely to have hypothyroidism [R].

The exact mechanism behind this connection is yet to be determined. A group of authors suggested the following: antibodies to viral or bacterial antigens presented by HLA-C can confuse thyroid structures for their real targets. This phenomenon is called “molecular mimicry” [R].

Some HLA-C (class I) variants, such as rs2517532, also correlate with thyroid autoimmunity. The exact mechanisms are still unknown, but they probably include antibodies to viral and bacterial antigens.

Other Populations

Different HLA variants have shown significant association with thyroid autoimmunity in non-Caucasian populations, such as Chinese and Korean, but they fall beyond the scope of this post. 

We are preparing a comprehensive report with all genetic factors that significantly impact thyroid health — stay tuned!

You can see your genotype for key HLA 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:

HLA-DRB1 rs2187668

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

Other important SNPs:

HLA-DRB1 rs2516049

• “T” – doesn’t correlate with autoimmune hypothyroidism
• “C” – correlates with higher rates of autoimmune hypothyroidism

HLA-C rs2517532

• “G” – doesn’t correlate with autoimmune hypothyroidism
• “A” – correlates with lower rates of autoimmune hypothyroidism

Population Frequency

For rs2187668, only 20% of people of European ancestry carry the “T” allele. Its frequency in other populations is even lower.

For rs2516049, about 42% of European descendants carry the hypothyroidism-associated “C” allele (12% have both copies). Its frequency is significantly lower in East Asian populations (24%).

For rs2517532, about 50% of European descendants have one copy and 17% have both copies of the protective “A” allele. In Asian populations, 25% of people carry both copies.