|(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|
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|
|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,|
[PMID 18194558] A hierarchical and modular approach to the discovery of robust associations in genome-wide association studies from pooled DNA samples.
[PMID 18603647] Functional genetic polymorphisms and female reproductive disorders: Part I: Polycystic ovary syndrome and ovarian response.
[PMID 18795173] Variants in iron metabolism genes predict higher blood lead levels in young children.
[PMID 19084217] Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels.
[PMID 19165391] Iron metabolism genes, low-level lead exposure, and QT interval.
[PMID 19237423] Is there an optimum endurance polygenic profile?
[PMID 19401444] Body iron stores and glucose intolerance in premenopausal women: role of hyperandrogenism, insulin resistance, and genomic variants related to inflammation, oxidative stress, and iron metabolism.
[PMID 19862010] Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.
[PMID 20659343] HFE gene variants modify the association between maternal lead burden and infant birthweight: a prospective birth cohort study in Mexico City, Mexico.
[PMID 21553046] Should we screen for hereditary hemochromatosis in healthy Lebanese: a pilot study.
[PMID 21679129] Genotyping of the hemochromatosis HFE p.H63D and p.C282Y mutations by high-resolution melting with the Rotor-Gene 6000(R) instrument.
[PMID 22611049] Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations.
|qualified_impact||Low clinical importance, Uncertain pathogenic|
|summary||There have been some hypotheses that this variant contributes to causing hereditary hemochromatosis, possibly as a compound heterozygote, but some others treat it as a polymorphism. Cys282Tyr is the classic causal variant and itself has very low penetrance. Mouse studies indicates this variant has a similar but weaker effect; if it has any effect at all its penetrance may be quite low and/or require modifier alleles.|
[PMID 23389292] Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study
[PMID 23792061] Meta-analyses of HFE variants in coronary heart disease
[PMID 22735619] Sample-to-SNP kit: a reliable, easy and fast tool for the detection of HFE p.H63D and p.C282Y variations associated to hereditary hemochromatosis.
[PMID 25085015] Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes
[PMID 25634189] Genetic Variant Coding for Iron Regulatory Protein HFE Contributes to Hypertension, the TAMRISK Study
[PMID 24663082] Influence of diet, menstruation and genetic factors on iron status: a cross-sectional study in Spanish women of childbearing age
[PMID 25880661] Decision Tree Analysis of Genetic Risk for Clinically Heterogeneous Alzheimer's Disease
[PMID 26024779] Association of genetic variants with response to iron supplements in pregnancy
[PMID 26597663] Genetic factors influencing ferritin levels in 14,126 blood donors: results from the Danish Blood Donor Study
[PMID 26690219] Association Studies of HFE C282Y and H63D Variants with Oral Cancer Risk and Iron Homeostasis Among Whites and Blacks.