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 thyroid participates in processes by producing thyroid hormones, principally thyroxine (T4) and triiodothyronine (T3).
These hormones regulate the rate of metabolism and affect the growth and rate of function of many other systems in the body .
Iodine is an essential component of both T3 and T4. The thyroid also produces the hormone calcitonin, which plays a role in calcium homeostasis.
The thyroid cells thus have three functions:
They collect and transport iodine
They synthesize thyroglobulin and secrets into the colloid and
They remove the thyroid hormones from thyroglobulin and secrete them into the circulation.
Thyroid Hormone Synthesis
T3 and T4 Regulation
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.
Thyroid disease occurs when the thyroid gland doesn't supply the proper amount of hormones needed by the body.
"Hyper" is from the Greek, meaning
"over or "above."
The body use up energy more
quickly than it should,
and chemical activity
(like metabolism) in the cells speeds up.
"Hypo" means "under" or "below."
The amount of hormone
released into the bloodstream is below normal,
the body uses up energy more slowly,
and chemical activity (metabolism)
in the cells slows down.
Types Thyroid Dysfunction
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.
Thyroid Dysfunction and Autoimmunity
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
Why Females are More Affected With AITD?
X-chromosome inactivation is a possible explanation for the female predominance in the prevalence of autoimmune thyroid diseases .
Women are more complex in that they have two similar X chromosomes.
This results in a double dose of often similar genes among the 1098 genes coded for on the X chromosome
XY XX X X XX Daughter
X-inactivation (also called lyonization) is a process by which one of the two copies of the X chromosome present in female mammals is inactivated.
The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin.
X-inactivation occurs so that the female, with two X chromosomes, does not have twice as many X chromosome gene products as the male, which only possess a single copy of the X chromosome.
A multifunctional domain on the X chromosome to be inactivated, called the X inactivation center (XIC), is present in the Xq13 region.
Using transgenic and knockout mice, this domain has been further refined to reveal the XIST gene.
Which encodes an untranslated RNA that coats the X chromosome and, together with some associated factors, silences it
Females frequently exhibit a random 50:50 ratio of the two cell lines
However deciding which chromosome becomes inactive is complex and appears to be mostly random
X-Chromosome Inactivation and AITD
Skewed X-Chromosome Inactivation (XCI) in the etiology of AITD explains the female preponderance of AITD.
A skewed XCI is a deviation from the original ratio and is arbitrarily defined, as a pattern where 80% or more of the cells inactivate the same X chromosome.
This can yield a situation in which self-antigens on one X chromosome may fail to be expressed at sufficiently high levels in the thymus.
FOXP3 is a key gene in the development of regulatory T cells
The FOXP3 gene is associated with thyroid autoimmunity which is among the typical autoimmune diseases that develop in individuals with FOXP3 mutations ( Yoshiyuki et al 2007 ).
Association of FOXP3 and AITD
FOXP3 gene can be a cause of autoimmune thyroid disease.
The FOXP3 gene is located within an X-chromosome locus (Xp11.23).
This region has been previously reported to be linked with autoimmune thyroid diseases (AITD).
The official name of this gene is “forkhead box P3.”
Location and Related SNPs Ideogram Genes/ 500kb mRNA Genotyped SNPs
What is the normal function of FOXP3 gene?
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
Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits.
But there is absence of an ortholog.
This absence may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
FOXP3 Gene and Ethnicity
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.
This study focuses on the predominance of autoimmune thyroid disease in females.
This predominance can be mostly explained by the X chromosome inactivation.
However, it has been previously reported that Xp11.23 is linked with autoimmune diseases.
Hence, a probable relation can be drawn between AITD and FOXP3 gene. The mutation of this gene results in the X-linked autoimmune disorders.
From this study this conclusion can be drawn that:
AITD is predominant in female of age group 40-49 years.
The most probable reason behind this is skewed X-chromosome inactivation.
This can be hypothesized that skewing of X-chromosome is due to the mutation in the FOXP3 gene.
The prevalence of autoimmune thyroid disease is however not estimated in Indian population till now.
Anderson’s Pathology, Volume-I, 8th-Edition.
Williams- A Text Book of Endocrinology, 6th edition
Ganong- Review of Medical Physiology, 22nd edition
Harrison's Principles of Internal Medicine, 17e Part Fifteen: Endocrinology and Metabolism > Section 1: Endocrinology >
Pathophysiology of Disease: An Introduction to Clinical Medicine, 5th Edition
J Clin June 2003, Polymorphism in Thyroid Hormone Pathway Genes, Endocrinol Metab 88(6):2880-2888
J Clin july 2004, Heritability of the Thyroid Hormones, Endocrinol Metab 89(7):3276–3284
W. Jean Dodds, Thyroid Disease and Autoimmune Thyroiditis, DVM 938 Stanford StreetSanta Monica, CA 90403
The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 12 5385-5397
Hot Thyroidology - Journal owned by the European Thyroid Association
Arch Dis Child 1998; 79: 242-245 ( September )
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