Is This Gene Connected To Autoimmunity And Thyroid Health? (SH2B3)

The SH2B3 gene codes for SH2B adapter protein 3 (SH2B3), or lymphocyte adapter protein (LNK). This protein has a wide variety of functions throughout the body, and helps regulate a wide range of important pathways including [R]:

• Inflammation and the immune response
• Blood cell formation (hematopoiesis)
• Cell growth and migration

Due to its wide range of functions, this gene has considerable significance for human health: studies have linked several SH2B3 mutations and variants with a number of autoimmune conditions, heart disease, blood disorders, and more [R, R].

In this post, we’ll be focusing on the role of SH2B3 in controlling inflammation and the immune system, and how this might relate to thyroid autoimmunity.

The SH2B3 gene helps regulate inflammation, blood cell formation, and other vital pathways. Certain variants in this gene have been associated with a wide range of health conditions, including autoimmune disorders.

Although we don’t know exactly how variants in this gene might lead to specific forms of thyroid disorders, scientists have proposed a few potential pathways in the immune system that might account for some of this gene’s effects.

Fine-Tuning The Immune System

When it comes to thyroid health, the main influence of this gene may stem from its ability to counteract the activity of different immune system components, such as T-cells, pro-inflammatory cytokines, and various growth factors [R].

For example, in thyroid autoimmunity, overactive T cells stimulate the production of different thyroid antibodies. SH2B3 acts to prevent this by keeping pro-inflammatory cytokines — such as TNF-alpha and IL-6 — in check [R, R, R].

Inflammation Damper

Some evidence suggests this gene may also be involved in suppressing or fine-tuning the inflammatory response. For example, a rare human case of a genetic SH2B3 loss resulted in early-onset Hashimoto’s disease, along with other developmental issues [R]. In mice without this protein, scientists have observed over-production of inflammatory cytokines [R].

These findings suggest a significant suppressive effect of the SH2B3 protein on cytokines that keeps inflammation in check. Hence, SH2B3 variants associated with thyroid autoimmunity probably reduce the activity of this gene, which then fails to suppress self-attacking antibodies. More research will be needed to clarify the exact mechanisms further.

SH2B3 keeps inflammation in check by suppressing cytokines such as TNF-alpha, IL-6, and IL-1b. Due to certain genetic variants, SH2B3 may fail to control an overactive immune response, opening the door to autoimmunity. Further research should clarify the exact mechanisms.

SH2B3 Variants And Thyroid Health

The above-discussed roles of SH2B3 in inflammation and autoimmunity can be crucial when it comes to thyroid health. Many thyroid disorders have an autoimmune background: autoimmune thyroid disorders are conditions in which the immune system targets the thyroid gland and alters its function. There are two main types [R]:

• Hashimoto’s disease: T-cells and antibodies target the thyroid gland and attack its tissues, resulting in thyroid hormone deficiency (hypothyroidism).
• Graves’ disease: antibodies bind to the thyroid gland causing it to be chronically stimulated, resulting in the over-production of thyroid hormones (hyperthyroidism).

Hashimoto’s Disease (Autoimmune Hypothyroidism)

A comprehensive study of nearly 40,000 participants identified one SH2B3 variant associated with low thyroid hormones (hypothyroidism). People with the ‘C’ allele for rs3184504 had significantly lower rates of this condition [R].

Another group of researchers investigated the connection between this variant and Hashimoto’s disease, an autoimmune disorder that lurks behind most cases of hypothyroidism. Once again, the ‘C’ allele showed a negative association with Hashimoto’s [R].

Graves’ Disease (Autoimmune Hyperthyroidism)

SH2B3 lies next to the ATXN2 gene, and they share certain variants. One of them, rs653178, was associated with Graves’ disease (autoimmune hyperthyroidism) in over 1,400 subjects. Carriers of the ‘C’ allele had 28% higher rates of GD [R].

Previously,  in a large trial of 18,000, rs653178-C correlated with the presence of antibodies to thyroid peroxidase (TPO-Ab). These antibodies are one of the hallmarks of thyroid autoimmunity, common in both Graves’ and Hashimoto’s disease patients [R, R].

However, one potential limitation of these studies is that scientists observed all of the above findings among people of European ancestry — and therefore it remains an open question whether these same genetic factors apply to other ethnic populations as well.

Other Conditions

Besides thyroid health, the above variants correlate with an array of conditions such as:

• Heart disease and high blood pressure (hypertension) [R, R]
• Diabetes (type-1) [R, R]
• Rheumatoid arthritis [R, R]
• Celiac disease [R, R]
• Multiple sclerosis [R]
• Colon and endometrial cancer [R]
• Blood disorders and blood cell counts [R, R, R]

You can see your genotype for several SH2B3 SNPs in the table below. However, note that the variants discussed below are just associated with some aspects of thyroid health. That does not mean they will necessarily make you more prone to thyroid disorders! More research will be needed to determine whether and how much they may directly contribute to the actual development of these thyroid conditions.

Primary SNPs:

SH2B3 rs3184504:

• ‘C’ = correlates with lower rates of hypothyroidism and Hashimoto’s disease
• ‘T’ = doesn’t correlate with hypothyroidism or Hashimoto’s disease

SH2B3 rs653178:

• ‘T’ = doesn’t correlate with Graves’ disease
• ‘C’ = correlates with higher rates of Graves’ disease

Population Frequency:

These two SNPs are almost always inherited together, which means that they essentially act as one single genetic factor.

Additionally, this also means that they have the same population frequencies: approximately 72% of European descendants have both of the “problematic” alleles (‘T’ and ‘C’, respectively), whereas the frequency of these alleles ranges from 1-12% in other groups, such as Asian and African populations.