HFE (Hereditary Hemochromatosis):

DEFECT: A substitution of Tyrosine for Cysteine at amino position 282 (Cys282Tyr). Frequency: 10% of the general population has at least one HFE mutation. Hereditary hemochromatosis affects 3 in 1,000 people in the US.

ASSOCIATED RISK: Mutations in the gene result in increased absorption of dietary iron. Excess iron over time can accumulate in the liver, pancreas, heart and other tissues, causing damage. Mode of action: Mutations in HFE lead to hereditary hemochromatosis, one of the most common genetic disorders in Americans of northern European descent. The features of hemochromatosis include cirrhosis of the liver, diabetes, hypermelanotic pigmentation of the skin, and heart failure.

METHOD OF DETECTION: Allele-specific PCR on DNA isolated from leukocytes found in whole blood.

POSSIBLE CLINICAL UTILITY: Tests should be done on people with a history of hemochromatosis. Others who should be tested include people with symptoms of fatigue, arthritis, sexual impotence, and abdominal pain. Hemochromatosis is a relatively easily treated disorder if diagnosed early.

COMMENT: Cardiac involvement in hemochromatosis typically results in congestive cardiomyopathy. A restrictive cardiomyopathy due to hemochromatosis is distinctly rare. (Cutler DJ, et al. Hemochromatosis heart disease: an unemphasized cause of potentially reversible restrictive cardiomyopathy. Am J Med 1980 Dec;69(6):923-8). Therefore, studies on HFE mutations and CAD are few. While some studies found an association between HFE and MI, others have found no association.

References:

1. Tuomainen TP, Kontula K, Nyyssonen K, Lakka TA, Helio T, Salonen JT.; Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation : a prospective cohort study in men in eastern Finland. Circulation 1999 Sep 21;100(12):1274-9

The aim of the study was to determine whether occurrence of the Cys282Tyr mutation was associated with increased risk of first acute myocardial infarction in 1150 healthy middle-aged men in a prospective cohort study. During a mean follow-up of 9 years, 8 (10.4%) of 77 carriers and 60 (5.6%) of 1073 noncarriers experienced an acute myocardial infarction. The carriers had a 2.3-fold (95% CI 1. 1 to 4.8; P=0.03) risk of acute myocardial infarction compared with noncarriers.

2. Roest M, van der Schouw YT, de Valk B, Marx JJ, Tempelman MJ, de Groot PG, Sixma JJ, Banga JD.; Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women. Circulation 1999 Sep 21;100(12):1268-73

The researchers studied the relation between HH heterozygosity (Cys282Tyr) and cardiovascular death in a cohort study among 12 239 women 51 to 69 years of age residing in Utrecht, the Netherlands. They found evidence that inherited variation in iron metabolism is involved in cardiovascular death in postmenopausal women, especially in women already carrying classic risk factors. The population-attributable risks of HH heterozygosity for myocardial infarction and cerebrovascular and total cardiovascular death were 3. 3%, 8.8%, and 4.0%, respectively.

3. Carella M, D'Ambrosio L, Totaro A, Grifa A, Valentino MA, Piperno A, Girelli D, Roetto A, Franco B, Gasparini P, Camaschella C.; Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am J Hum Genet 1997 Apr;60(4):828-32

Here they report that the Cys282Tyr change accounts for 69% of HH chromosomes in a series of 75 unrelated Italian patients who fulfilled well-defined criteria for HH diagnosis. Sixty-four percent of patients were Cys282Tyr homozygous, 10% were heterozygous, and 21% carried the normal allele. The same mutation was rare in normal controls. The His63Asp variant was less frequent but had a similar frequency among affected and normal chromosomes.

4. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Wolff RK, et al;
A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.
Nat Genet 1996 Aug;13(4):399-408

Using linkage-disequilibrium and full haplotype analysis, they have identified a 250-kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by-descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA-H (or HFE), containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class I-like proteins in iron metabolism.

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