|(C;C)||0||Not a H63D hemochromatosis carrier.|
|(C;G)||3||One copy of H63D, carrier of hemochromatosis, likely unaffected unless also C282Y carrier.|
|(G;G)||4||Two copies of H63D, likely affected by mild form of hemochromatosis|
rs1799945, also known as H63D or His63Asp, represents a SNP that accounts for a mild form of hereditary hemochromatosis (HH), an iron overload condition in which mutations of certain genes involved in iron metabolism disrupt the body’s ability to regulate uptake of iron, causing increased intestinal iron absorption. The most common form is caused by mutations in the HFE gene, which are inherited recessively. The gene for HH is closely linked to the HLA-A3 locus on the short arm of chromosome 6 [PMID 1278715]. In 1996, HFE, a gene for HH, was found to have two missense mutations [PMID 8696333]. A mutation at amino acid 282 (C282Y) was found to be homozygous in 83 percent of patients with HH. This is a point mutation from guanine to adenine, resulting in a missense mutation from cysteine to tyrosine. Such mutations are commonly found in people with European ancestry, and is more rare in Asian and African populations. Among individuals of northern European descent, hereditary hemochromatosis is the most common inherited identified genetic disorder. However, penetrance differs between different populations.
The HFE gene encodes the human hemochromatosis protein, which is located on the short arm of chromosome 6 at 6p21.3. The protein regulates iron absorption by regulating the interaction of the transferrin receptor with transferrin. The HFE protein interacts with TFRC, the transferrin receptor protein 1, so its primary mode of action is through regulation of the iron storage hormone hepcidin.
Mutations in the HFE Gene
The three most common HH-causing mutations in the HFE gene (chromosome 6p21.3) are C282Y (A at rs1800562 instead of G), H63D (G at rs1799945 instead of C), and S65C (T at i3002468 instead of A). At least 17 other mutations in the HFE gene have been linked to HH. 60-90% of people with HH have two copies of the C282Y mutation. The H63D mutation is also quite common—about 20% of people carry a copy of the mutation, and about 3% have two copies. This mutation is not as severe as the C282Y mutation, and only causes symptoms when someone has both the H63D and the C282Y mutations. Even then, only a small fraction of people with one copy of each mutation actually exhibit evidence of iron overload. Additionally, those who have two copies of H63D do not exhibit any symptoms and are not at risk for iron overload. The S65C mutation is less common, and will also only cause symptoms if in combination with C282Y. For both H63D/C282Y and S65C/C282Y single mutation individuals, symptoms are usually mild if they develop at all.
Influence on Iron Levels
HH has four main pathophysiological mechanisms [PMID 21452290]: the increased absorption of dietary iron in the upper intestine, 2) decreased expression of hepcidin, 3) altered function of the HFE protein, and 4) tissue injury and fibrogenesis induced by iron. Since the HFE gene encodes for proteins that affect pathways centered around liver hepcidin synthesis, this mechanism will be further explained in more detail. The HFE gene regulates the liver protein hepcidin, which is considered to be the principal iron-regulatory hormone. Levels of hepcidin increase when iron levels increase in the blood, preventing intestinal cells and macrophages from releasing iron into the bloodstream. When iron builds up in the cells, signals are produced to reduce the iron absorption from food. Hepcidin levels decrease when the body needs more iron. Mutations in the HFE gene such as C282Y and H63D decrease hepcidin levels, causing intestinal cells to think more iron is needed. Thus, more iron is absorbed. Concentrations of hepcidin in the urine negatively correlate with the severity of HH.
Symptoms of Hereditary Hemochromatosis
The symptoms of HH depend on the person’s mutation as well as their sex and diet. The older a person, the more likely iron has accumulated in the body over time. Typically, complications may develop later in life between the ages of 40 and 60 in men and in post-menopausal women. If symptoms do develop, these are typically seen in the liver, skin, pancreas, heart, joints, and testes. At first, one may feel symptoms such as joint pain and stiffness, fatigue, abdominal pain, and weight loss. Later symptoms may lead to more serious conditions such as cirrhosis of the liver, cancer, liver failure, diabetes, congestive heart failure, and arthritis.
Symptomatic Findings in Patients with HH
- Liver- hepatomegaly, splenomegaly, liver failure
- Joints- arthritis, swelling, chondrocalcinosis
- Heart- dilated cardiomyopathy, CHF
- Skin- increased pigmentation
- Endocrine- testicular atrophy, hypogonadism
|Title||Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels|
|Odds Ratio||4.9500 [3.30-6.60] ug/dl decrease|
[PMID 22232660] Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene
|Title||Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.|
|Odds Ratio||0.6270 [NR] mmHg increase|
|Disease||Hemochromatosis type 1 Microvascular complications of diabetes 7 not specified not provided Hereditary hemochromatosis|
|CLNDBN||Hemochromatosis type 1 Microvascular complications of diabetes 7 not specified not provided Hereditary hemochromatosis|
|CLNSRC||OMIM Allelic Variant UniProtKB (protein)|
|CLNACC||RCV000000026.10, RCV000000027.4, RCV000117220.2, RCV000175607.2, RCV000394716.1,|
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