A disease that was once thought to be the most common genetic disorder of Europeans has now been shown by scientists at The Scripps Research Institute (TSRI) to be relatively rare.
In what was one of the largest DNA-based genetic epidemiological studies ever conducted, TSRI researchers working with the Health Appraisal Clinic at Kaiser-Permanente in San Diego examined the DNA and clinical data of some 41,000 patients, looking for the genetic disease hereditary hemochromatosis, a metabolic disorder in which excessive amounts of iron are deposited in the liver, pancreas, and other organs. Hereditary hemochromatosis can lead to cirrhosis of the liver, diabetes, and cardiovascular disease, and the severe form of the disease can be lethal.
Although the mutation that causes hereditary hemochromatosis is common, the disease itself is rare, concludes study leader Ernest Beutler, M.D., who is Chairman of TSRI's Department of Molecular and Experimental Medicine and Professor, The Skaggs Institute for Chemical Biology. Even people with two copies of the genetic mutation that causes the disease hereditary hemochromatosis (so-called homozygotes) are very unlikely to become ill from it, the study finds.
A modest number of homozygotes do show minor abnormalities of liver function, but no symptoms. Most importantly, no difference was found in the life span of persons homozygous for the gene and those who do not carry it. The percentage of homozygotes in old people was the same as the percentage in young people, indicating that there is no attrition of homozygotes from the population. Presumably, other factors in addition to the gene mutation are required to cause the actual disease.
Beutler and his colleagues are careful to point out that it is very important to diagnose promptly those few patients who are severely affected because they can be treated quite simply and effectively by removing iron from the body by frequently drawing blood, as in blood donations.
About five out of every 1,000 Europeans and Americans of European descent are homozygotes for the mutation that causes the disease– they inherit the defect from both parents. The mutation is in a gene called "HFE"; which normally encodes a protein that helps regulate the uptake of iron by the body. In the mutation one of the DNA bases of the gene is altered, causing a corresponding change in one of the amino acids in the HFE protein. The amino acid cysteine is replaced with a leucine at position 282 in the protein (C282Y). This causes the HFE protein to misfold and malfunction, which can lead to increased iron absorption.
Virtually all of the people who have hemochromatosis are homozygotes for the defective HFE gene, and it was believed that up to 95 percent of the homozygotes would eventually develop clinical hemochromatosis.
However, Beutler points out that such estimates were based upon the occurrence of symptoms such as arthritis and diabetes that are also common in the normal population. An actual study of a large normal population had not previously been carried out. The study that Beutler led compared symptoms in homozygotes with the same symptoms in patients who had not inherited HFE mutations. In this controlled study, Beutler and his colleagues found that the actual number of homozygotes who eventually develop symptoms is only about one percent; most do not develop hemochromatosis.
Beutler is a highly respected expert in the fields of iron metabolism and genetics of blood diseases. He is a member of the National Academy of Sciences and edits the most widely used textbook in his field, "Williams Hematology". He says the results of this study were quite unexpected.
"When we initiated these investigations we knew that not everyone who was homozygous would develop full-blown hemochromatosis, but we expected that quite a few of the homozygotes would have signs of damage induced by the excess iron," he says. "Dr. Felitti, my collaborator from Kaiser, and I were quite surprised to find that this was true only in a very small proportion of the people who carry the mutation."
"Our findings recently have been confirmed," he adds, "in a large Scandinavian study, in which only 4 persons with liver fibrosis were found among more than 65,000 subjects who were screened by determining their blood iron levels."
Having the gene mutation alone apparently is not enough to trigger the disease process. "The low rate of iron-overload disease among people who have the genetic defect suggests that other stimuli are involved, which is common in other genetic diseases as well," says Griffin Rodgers, M.D., Deputy Director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "It will be important to determine what other genes or factors are in play and how to counter their effects to treat or prevent the disease."
Beutler's findings are significant because in recent years there has been much interest in the possible benefits of screening for mutations like the one that causes hemochromatosis in order to prescribe preventative therapy. The case for screening for hemochromatosis seemed particularly sound considering a 5/1,000 incidence of the homozygous state in the United States and a simple treatment that could remove the accumulated iron and presumably prevent further damage.
However, the cost-benefit ratio of screening normal populations for this disease now appears dramatically different in light of the results of this study. Despite the findings of this study, Beutler declined to take a position regarding the advisability of screening for hemochromatosis. "This decision depends on many factors that influence the cost/benefit ratio and is one that must be made by health policy planners," Beutler says. "The low prevalence of disease in homozygous subjects and their normal life span represents a vital part of this equation and must be taken into account when public policy is determined."
The research article "Penetrance of 845G-->(C282Y) HFE hereditary haemochromatosis mutation in the USA" by Ernest Beutler, Vincent J. Felitti, James A. Koziol, Ngoc J. Ho, and Terri Gelbart appears in the January 19, 2002 issue of The Lancet. The research was funded by the National Institutes of Health, the Centers for Disease Control and Prevention, the Stein Endowment Fund, and The Skaggs Institute for Chemical Biology.
Journal
The Lancet