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Sequencing of HLA-DR3 gene suggest mutation providing disruption of amino acid collection causing autoimmune response developing Graves’ disease
Graves’ disease (GD) an autoimmune thyroid disease (AITD) suspected to be the result of gene malfunction and environmental factors (Jacobson, 2008). GD is an autoimmune disease that disrupts thyroid function, resulting in hyperthyroidism (Heward, et. al., 1998). Hyperthyroidism is the over expression of thyroid hormones. The specific cause for GD is not completely understood, but current autoimmune thyroid disease research suggest malfunction with the human leukocyte antigen (HLA) major histocompatibility complex (MHC) gene plays a major role in disease development (Jacobson et. al., 2008).
GD is the result of over production of thyroid hormones (T3 and/or T4), which cause many disruptions within the body and metabolism. Symptoms of GD include exophthalmos, tachycardia, weight loss, muscle wasting, tremors, sweating, oligomenorrhea (women only), and goiter. Diagnosis of GD starts with the recognition of the above sysptoms, but blood tests are conducted examining the current levels of thyroid stimulating hormone (TSH). TSH levels in GD patients drop below normal levels due to the negative feedback resulting from the high levels of T3 and T4 in the system.
Treatment for GD is focused in three main directions, decrease production, inactivation, or removing of the thyroid. Treatment one uses antithyroid drugs to lower T3 and T4 production, this treatment option is the lease invasive and potential will solve the problem. The theory of antithyroid treatment is to lower the production of hormones to normal levels, causing the thyroid to continue normal production after antithyroid treatment is completed. Hyperthyroidism may resume after treatment, which makes this treatment option unsuccessful. Inactivation of the thyroid is the second treatment option; thyroid hormone production is discontinued after radioactive iodine destroys thyroid function. Replacement thyroid drug therapy is then provided to the patient in synthetic form of thyroid hormone. Thyroid removal is the final treatment available, preventing all production of thyroid hormones, also resulting in synthetic drug replacement therapy.
Susceptibility Genes for Graves’ Disease
Evidence to support GD is influenced by genetic heritability is shown in a sibling risk ratio test conducted by Ban and Tomer (2005). Sibling risk ratio for AITD (GD and hashimoto’s thyoiditis (HT)) provided significant correlation when genetic analysis of the siblings conducted (Ban and Tomer, 2005). The research does not disprove environmental influences, but provided evidence to support that AITD are highly influenced by genetic heritability.
HLA genes are located on chromosome 6p21, believed to be associated with GD (Ban and Tomer, 2005). Chromosome 6p21 containd many different HLA genes, creating the likelihood of more then one gene malfunction causing development of GD. The research is unsure if one HLA gene malfunction could result in a cascade of HLA gene malfunctions.
Current GD research links high frequency of HLA-DR3 gene activation to GD patients; 40-55 percent of GD patients and 15-30 percent in general populations show high gene expression (Jacobson 2008). This allele is not the only mechanism for GD, but nearly 50 percent of 1800+ test subjects suggest HLA-DR3 was their genetic malfunction resulting in the development of GD.
The suggested mechanism for GD starts with a malfunction of the HLA gene on chromosome 6p21 (Ban and Tomer, 2005). Chromosome 6p21 contained many different HLA genes, creating the likelyhood of more than one gene malfunction responsible for GD. The amino acid sequencing of the HLA-DR gene suggested that GD patients contained a different aa on position 74 when compared to controls (Ban and Tomer, 2005). Normally Ala or Gln are present at position 74 on the peptide chain of the HLA-DR3 gene, but GD patients are suggested to have Arg in position 74 (Jacobson, et. al., 2008). Changing the aa from Ala or Gln to Arg switches from a neutral to positively charged aa.
Environmental Factors
Over iodine ingestion.
The most common developmental pathway for GD development?

Ban, Y, Tomer, Y. 2005. Susceptibility genes in thyroid autoimmunity. Clinical and Developmental Immunology 12(1):47-58.
Heward, J, et. al. 1998. Linkage Disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves’ disease: replication using a population case control and family-based study. Journal of clinical endocrinology and metabolism 83(10):3394-3397.
Jacobson, E, et. al. 2008. The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology. Journal of autoimmunity 30(1-2):58-62.

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