How a Cell Structure Gene Impacts Thyroid Health (CAPZB)

_{Source: https://ghr.nlm.nih.gov/art/large/actin.jpeg} 

The story of CAPZB (capping actin protein of muscle Z-line subunit beta) begins in a cell skeleton.

Actin filaments are globe-shaped proteins that bind together to form a complex structure (helix), providing our cells with a backbone or skeleton. CAPZB encodes for a protein that binds to actin polymers and impacts their formation. More precisely, it caps the ends of these filaments, preventing their elongation, hence “capping actin protein” [R].

This process changes cell structure and controls different pathways, including thyroid function. In response to TSH, thyroid cells open up to ingest the colloid from their surrounding and supply thyroglobulin. This step, enabled and controlled by actin polymers, is essential for thyroid hormones (T3/T4) production [R, R].

Another vital mediator in this chain reaction is cAMP, which enables adequate thyroid stimulation by TSH and plays a central role in the shape and function of thyroid cells. According to different cell-based studies, cAMP modulates the activity of CapZ proteins [R, R, R].

CAPZB encodes for a protein that changes cell structure by capping actin filaments. In thyroid cells, this cAMP-dependent process impacts the production of thyroid hormones by controlling the uptake of thyroglobulin.

Hypothyroidism

In a clinical trial of nearly 40K participants, one CAPZB SNP showed a suggestive association with low thyroid hormones. Namely, people with the “C” allele at rs1472565 had 11% higher rates of hypothyroidism [R].

TSH Levels

Different CAPZB variants have shown a significant correlation with TSH, a key marker of thyroid health:

• In a meta-analysis of 2 studies and over 26K participants, the “A” allele at rs10799824 correlated with lower TSH levels [R].
• In a meta-analysis that included 3,736 European subjects, the “A” allele at rs10917477 correlated with lower TSH levels [R].
• In over 3,000 UK subjects, the “G” allele at rs10917469 correlated with lower TSH levels. People with the “GG” genotype had 0.5 mU/L lower levels, which can be a clinically significant difference [R].

We’ll discuss the potential mechanism behind these connections and their clinical relevance in more detail below.

Goiter

Goiter is a visible thyroid gland enlargement that can indicate both hypo- and hyperthyroidism. In nearly 5,000 participants of Caucasian (European) ancestry, different CAPZB SNPs correlated with thyroid volume and goiter. The main one is rs12138950, for which the carriers of the “C” allele had higher thyroid volume and higher rates of goiter [R].

Potential Mechanisms and Clinical Relevance

The exact mechanisms behind CAPZB variants and their clinical relevance for thyroid health are not fully understood, but the above study on goiter provides some valuable insights.

Based on its position and physiological effects, the main observed SNP, rs12138950, likely increases CAPZB expression. According to the authors, this leads to the stronger capping of actin filaments and reduces the ability of thyroid cells to ingest thyroglobulin in response to TSH/cAMP stimulation. This results in diminished T3/T4 release and a compensatory increase in thyroid volume (goiter) [R].

Interestingly, the authors discovered that the variants associated with goiter match those associated with lower TSH levels, and they are almost always inherited together. As it turns out, the compensatory increase in thyroid volume and hormone production results in lower TSH levels (negative feedback loop) [R].

In other words, low TSH levels may indicate a hindered production of thyroid hormones in this case, which is the opposite of a standard interpretation. Still, we should take the suggested mechanisms with a grain of salt until more research is done on the subject. 

The above CAPZB variants likely increase its expression and the capping of actin filaments. This may result in impaired thyroid hormone production and compensatory thyroid enlargement (goiter). The suggested mechanisms are yet to be confirmed.

Keep in mind that the clinical relevance of most CAPZB SNPs is still not fully clear. Do additional tests and consult with your doctor before taking any action based on your results for this gene.

Primary SNPs:

CAPZB rs1472565

• “T” doesn’t correlate with low thyroid hormones
• “C” weakly correlates with low thyroid hormones

CAPZB rs12138950

• “A” doesn’t correlate with goiter
• “C” correlates with goiter

Other important SNPs:

CAPZB rs10799824

• “G” doesn’t correlate with TSH levels
• “A” correlates with lower TSH levels

CAPZB rs10917477

• “G” doesn’t correlate with TSH levels
• “A” correlates with lower TSH levels

CAPZB rs10917469

• “A” doesn’t correlate with TSH levels
• “G” correlates with lower TSH levels

Population Frequency

For rs1472565, around 72% of European descendants carry the “problematic” C allele. The frequency of this allele in other populations is even higher.

Two of the other SNPs, rs10799824 and rs10917469, are always inherited together, so they act as a single genetic factor. Around 26% of European and up to 45% of African descendants have minor alleles (“A” and “G”, respectively). The available data for rs12138950 is incomplete, but it has a similar allele distribution like the previous two SNPs.

For rs10917477, up to 81% of people of European ancestry carry the “A” allele. Its frequency in other populations goes up to 93%, with a significant proportion of people carrying both copies.