FEATURE ARTICLE
Confounded:Widespread screening for hereditary hemochromatosis faces obstacles
By Maimon M. Cohen, PhD
Hereditary hemochromatosis (HH) is a common genetic disorder, especially among northern Europeans; one in 300 Britons are affected by HH.
The condition results from massive iron deposits in various organs. If untreated, HH leads to liver disease (cirrhosis), diabetes, cardiac disease, skin discoloration and decreased life span.
Although transferrin saturation, a non-molecular assay, is a commonly accepted screening test for HH, molecular approaches - such as polymerase chain reaction (PCR) - for the detection of mutations in the HFE gene which cause HH are coming into use.
For years, many public health experts and others have considered HH to be an ideal candidate disorder for widespread population molecular screening efforts. HH occurs at a relatively high frequency in a specified target population (Caucasians). It has a simple, cost-effective detection methodology and a successful treatment modality. These factors combine to make HH appear to be a good choice for wide-ranging screening.
However, reality is not that simple. Several factors have complicated attempts to implement a hemochromatosis screening program. (Many of these factors were discussed in the Summer issue of the journal, Genetic Testing, which was devoted entirely to widespread screening for hemochromatosis.)
For one, additional mutations and polymorphisms, which may affect the expression of disease-related alleles, can cause complications in the diagnosis of HH.
Approximately 20 alterations in the HFE gene, which may or may not be associated with disease, have been observed in either individual families or only in a few patients.
Although the C282Y mutation in the HFE gene is the most common cause of disease among members of northern European communities with a possible Celtic origin, a survey of 40 populations demonstrates a distinct north-south gradient of decreasing frequency across the continent.
It is estimated that the C282Y mutation first appeared 60 to 70 generations, or up to 800 years, ago. Another disease-associated mutation, H63D, believed to have evolved earlier than C282Y, has a more general distribution centered around the Mediterranean basin. These two mutations account for the molecular defect in more than nine in ten patients.
Patterns of emigration during the last 500 years have introduced both mutations into North America, New Zealand and South Africa in a predictable fashion.
Reinforcing this distribution pattern is a low frequency of the C282Y mutation among 1300 recently examined Italian newborns.This suggests that widespread screening in Italy would not be cost effective, but that instead, it might be useful in northern Italy with its Celt-derived populations.
Because mutation frequencies may differ considerably among the different components of a population of mixed national, racial, and ethnic composition,screening efficiency may be compromised.
Such approaches must be considered prior to instituting screening efforts in as diverse a population as exists in the US.
In addition to confounding technical issues, there are also ethical, legal and social implications of hemochromatosis screening, including the potential for genetic discrimination against carriers with regard to health, life and disability insurance, employment and blood donation.
Unresolved concerns surrounding HH population screening needing rapid clarification include:
reduced penetrance and variable expressivity of the HFE mutations,
genotype correlation with disease manifestation,
the growing multiracial, multiethnic composition of the US population,
who to screen and when,
how to test (biochemical vs. molecular approaches), and
a careful and detailed cost-benefit analysis of a population based program.
Answers to these open questions should be found through experimental pilot and demonstration projects prior to the design and implementation of a national hemochromatosis screening undertaking.
The Summer issue of the journal, Genetic Testing, is devoted entirely to the subject of hereditary hemochromatosis. Listed below are citations of and links to selected abstracts.
Lucotte G, Mercier G. Celtic origin of the C282Y mutation of hemochromatosis. 2000 Genet Test 4 (2):163-9. Medline abstract
Merryweather-Clarke AT, Pointon JJ, Jouanolle AM, Rochette J, Robson KJ. Geography of HFE C282Y and H63D mutations. 2000 Genet Test 4(2):183-98. Medline abstract
Restagno G, Gomez AM, Sbaiz L, De Gobbi M, Roetto A, Bertino E, Fabris C, Fiorucci GC, Fortina P, Camaschella C. A pilot C282Y hemochromatosis screening in Italian newborns by TaqMan technology. 2000 Genet Test 4(2):177-81. Medline abstract
Barash CI. Genetic discrimination and screening for hemochromatosis: then and now. 2000 Genet Test 4 (2):213-8. Medline abstract
Cohen MM, GeneLetter 1(9), October 2000.
All material on this website is protected by copyright.
Copyright © 1999 - 2001 by GeneSage Inc.
All rights reserved. This website also contains material
copyrighted by third parties.
Ma va!
Sara' un'altra ricerca "ovviamente" finanziata dalla Lega.Daltronde si sa che i Celti non sono mai esistiti.