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October 31, 2000
Common Kidney Disease Has a Genetic Basis
Researchers have located a gene that causes immunoglobulin A
nephropathy (IgAN), one of the most common kidney diseases. IgAN, which
was not previously recognized to be an inherited disorder, affects up
to one percent of the population worldwide and 100,000 people in the
United States. In discovering that the development of IgAN is
influenced by a gene on chromosome 6, the scientists have opened the
way to better understanding of the cause of IgAN and the possibility
that treatment aimed at the molecular cause of IgAN may one day prevent
kidney failure in patients with the disorder.
In a research article published in the November 2000 issue of
Nature Genetics, Howard Hughes Medical Institute investigator Richard
P. Lifton and his colleagues report that genetic analyses of 30
families in the United States and Italy indicate that IgAN is caused by
a gene located on chromosome 6. "Prior to this finding, IgA nephropathy
was recognized as the most common form of glomerulonephritis worldwide,
but its causes were unknown and were believed to be diverse," said
Lifton, who is at the Yale University School of Medicine.
“Until now, there was little suspicion that this disease would have a strong contribution from a single gene.”
Richard P. Lifton
Signs of the disease are commonly revealed by presence of blood in
the urine following an upper respiratory infection or cold, said
Lifton. As the disease progresses, deposits of the immune-related
antibody IgA, or immunoglobulin A, lead to scarring of the kidneys.
Ultimately, a substantial fraction of patients develop kidney failure,
and must rely on dialysis treatment or renal transplantation for
survival.
"Until now, there was little suspicion that this disease would have
a strong contribution from a single gene. It was recognized, however,
that the disease shows wide variation in incidence in different parts
of the world. For example, the disease is uncommon in some ethnic
groups, such as African-Americans, whereas it is very common in among
people from Southeast Asia. This ethnic variation, as well as studies
demonstrating that the disease sometimes recurs within families,
suggested that there was a genetic contribution to the disease," Lifton
said.
Lifton and Ali Gharavi at Yale and Mount Sinai Medical Schools,
teamed with clinical investigators who had studied families with IgAN,
including Francesco Scolari from Brescia, Italy; Paolo Schena from
Bari, Italy, Bruce Julian from University of Alabama at Birmingham, and
Robert Wyatt from University of Tennessee. In their search for a
genetic cause of IgAN, they studied 24 families in Italy and six in the
United States that had multiple members with the disease. Because IgA
deposits are obvious signs of the disease, the researchers first
screened for abnormalities in genes that govern the synthesis,
modification or clearance of IgA from the kidneys. They found no
evidence for abnormalities in those genes.
"So, we went on to take a less biased approach, and simply looked to
see whether there were any chromosomal sites in the human genome that
were inherited together with the disease more often than expected by
chance," said Lifton. "And, we found very strong evidence that a single
gene on chromosome 6 influences the disease in about 60 percent of
families we studied.
"Our analyses indicate an odds ratio of 400,000 to one in favor of a
linkage of this locus with the disease in the affected families. This
is surprisingly strong evidence for linkage," Lifton said. So far, the
scientists have shown that a single area of the chromosome, a region
called 6q22-23, is linked to the disease.
"We presume that this genetic finding will reflect the effects of a
single gene on chromosome 6," he said. "We don't know what that gene
is, but this finding tells us where to look and that the gene we find
is likely to have a large role in the development of IgA nephropathy,"
he said. The researchers are now trying to identify the gene involved
and are recruiting patients from different ethnic groups with IgAN. "It
will be of particular interest to determine whether the wide variation
in disease occurrence is due to different frequencies of the mutant
gene in different populations," Lifton said.
Discovery of the gene might yield clues to whether particular
environmental influences trigger the disease, said Lifton. Even though
there were no signs that known IgA-related genes were involved in the
disease, Lifton speculates that the culprit gene could still turn out
to influence IgA metabolism. The involvement of a key immune-related
protein, for example, might explain why the disease appears to be
triggered by an infection. "This interaction between a gene and an
environmental factor might explain why not everyone who inherits this
gene ends up getting the disease," he said.
Lifton believes that discovering the gene and tracing its
physiological effects will have an important impact on treatment.
"Right now there are no effective treatments for IgA nephropathy," he
said. "We hope that finding this gene will tell us what metabolic
pathways are involved, and give us some idea of how to intercede to try
to prevent affected patients from developing severe kidney damage."
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