The Genetic Basis of Autoimmune Thyroid Disease : A Bioinformatics Approach Project Done By: POUSALI MUKHERJEE M.Sc. In Genetic Engineering 2nd Year 4th Semester Roll No.:072101887019 Registration no.: 072101887201019 Institute of Genetic Engineering West Bengal University of Technology
Thyroid Gland The thyroid is one of the largest endocrine glands in the body. This gland is found in the neck inferior to (below) the thyroid cartilage (also known as the Adam’s Apple in men) and at approximately the same level as the cricoid cartilage The thyroid controls how quickly the body burns energy, makes proteins, and how sensitive the body should be to other hormones. The thyroid is controlled by the hypothalamus and pitutary.
The production of thyroxine and triiodothyronin is regulated by thyroid stimulating hormone (TSH), released by the anterior pitutary (that is in turn released as a result of TRH release by the hypothalamus). TSH production is suppressed when the T4 levels are high, and vice versa.
The TSH production itself is modulated by thyrotropin releasing hormone (TRH), which is produced by the hypothalamus and secreted at an increased rate in situations such as cold (in which an accelerated metabolism would generate more heat).
TSH production is blunted by Somatostatin, rising levels of glucocorticoids and sex hormones (estrogen and testesterone), and excessively high blood iodide concentration.
Graves’ Disease - This is the most common cause of hyperthyroidism.
It is a chronic disorder in which the affected person’s immune system produces antibodies that attack the thyroid, causing inflammation, damage, and the production of excessive amounts of thyroid hormone.
Hashimoto’s Thyroiditis – This is the most common cause of hypothyroidism in the United States.
Like Graves’ disease, it is a chronic autoimmune condition related to the production of antibodies that target the thyroid and cause inflammation and damage.
With Hashimoto’s thyroiditis, however, the body makes decreased amounts of thyroid hormone.
Thyroiditis — Thyroiditis is an inflammation of the thyroid gland. It may be associated with either hypo- or hyperthyroidism. It may be painful, feeling like a sore throat, or painless.
Thyroiditis may be due to autoimmune activity, an infection, exposure to a chemical that is toxic to the thyroid, or an unkown cause.
Depending on the cause, it can be acute but transient or chronic.
Thyroid Nodules — A thyroid nodule is a small lump on the thyroid gland that may be solid or a fluid-filled cyst. As many as 4% of women and 1% of men will have one or more thyroid nodules; however, the overwhelming majority of these nodules are harmless.
Occasionally, thyroid nodules can be cancerous and need to be treated.
Goiters — A thyroid goiter is a visible enlargement of the thyroid gland. In the past, this condition was relatively common and was due to a lack of iodine in the diet.
Iodine is a necessary component of thyroid hormone production.
Iodine-related goiters are common and represent the most common cause of hypothyroidism in some countries.
Any of the diseases listed above can also cause goiters. Goiters may compress vital structures of the neck, including the trachea and esophagus. This compression can make it difficult to breathe and swallow.
Autoimmunity is the failure of an organism to recognize its own constituent parts as self , which results in an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease .
Autoimmune Thyroid disease is associated with antibodies that block or stimulate the natural occurring thyroid stimulator, thyroid stimulating hormone, or TSH.
The Genetics of Autoimmune Thyroid Disease (AITD)
Autoimmune thyroid disease (AITD) comprises a series of interrelated conditions including hyperthyroid Graves’ disease , Hashimoto’s (goitrous) thyroiditis , atrophic autoimmune hypothyroidism , postpartum thyroiditis and thyroid-associated orbitopathy .
These different manifestations of AITD may occur synchronously.
Autoimmune thyroid diseases are the commonest autoimmune disorders in the population, affecting between 2% and 4% of women and up to 1% of men.
Autoimmune thyroid diseases prevalence increases with advancing age.
Is There Any Relationship Between AITD and Gender?
It is an observed fact that females are more affected than males.
From the early age to the later years (50-59 years) the thyroid dysfunction is predominant in females .
The age group that is mostly affected by the thyroid dysfunction is 40-49 years both in case of males and females
Relation of Thyroid Dysfunction With Age And Sex
The FOXP3 gene provides instructions for producing the forkhead box P3 (FOXP3) protein.
The FOXP3 protein attaches (binds) to specific regions of DNA and helps control the activity of genes that are involved in regulating the immune system.
On the basis of this role, the FOXP3 protein is called a transcription factor.
This protein is essential for the production and normal function of certain immune cells called regulatory T cells, which play an important role in preventing autoimmunity.
The FOXP3 protein is found primarily in an immune system gland called the thymus, where regulatory T cells are produced.
How are changes in the FOXP3 gene related to AITD?
At least 21 mutations in the FOXP3 gene have been found to cause auto immune diseases and X-linked (IPEX) syndrome.
Most mutations change one protein building block (amino acid) in the region of the FOXP3 protein that binds to DNA or lead to the production of an abnormally short, nonfunctional protein.
Mutations in the FOXP3 gene result in reduced numbers or a complete absence of regulatory T cells .
Without the proper number of regulatory T cells, the body cannot control immune responses. Normal body tissues and organs are attacked, causing the multiple autoimmune disorders.
Genomic regions, transcripts, and products of FOXP3 gene
FOXP3 gene and its relation with X-linked autoimmunity
The protein encoded by this gene is a member of the forkhead/winged-helix family of transcriptional regulators.
Defects in this gene are the cause X-linked autoimmunity
Genomic Size: 14392
Exon Count: 12
Coding Exon Count: 11
Front Side Top
Conserved domains on forkhead box P3 (FOXP3)isoform a [ Homo sapiens ]
Forkhead (FH), also known as a "winged helix".
FH is named for the Drosophila fork head protein, a transcription factor which promotes terminal rather than segmental development.
This family of transcription factor domains, which bind to B-DNA as monomers, are also found in the Hepatocyte nuclear factor (HNF) proteins, which provide tissue-specific gene regulation.
The structure contains 2 flexible loops or "wings" in the C-terminal region, hence the term winged helix.
Gene Model Information 2397 RNA size No Selenocysteine No Stop codon in genome Yes Has stop codon No Frame shift in genome Yes Has start codon No CDS single in intron: 1296 ORF size No CDS single in 3' UTR 12 Exon count No Nonsense-mediated-decay Coding Category
Previous reports suggest that polymorphisms of the FOXP3 gene may play a role in the genetic susceptibility to AITD in Caucasians, perhaps by altering FOXP3 function and/or expression ( Ban Y et al , 2007 ).
The prevalence of autoimmune thyroid disease is lowest in blacks and highest in whites.