alison chaiken

http://www.sciencemag.org/cgi/content/full/304/5668/185
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Science, Vol 304, Issue 5668, 185-187 , 9 April 2004

Two New Asthma Genes Uncovered
Jennifer Couzin

A painstaking, decade-long hunt spanning two continents has led a team
of Finnish scientists to two new asthma genes. Geneticists don't yet
know what role the genes play in asthma, which afflicts about 16
million people in the United States alone. But scientists say that the
work, described on page 300, has uncovered some of the most compelling
genetic associations yet for the disease.

Although researchers had previously linked three other genes to
asthma, those studies involved fewer individuals and mostly found a
relatively weak genetic effect in conferring susceptibility. Not only
are the current associations strong, but one of the new genes may be a
good target for novel antiasthma drugs. "One of the beauties of this
is that they came up with a drug target," says Jack Elias, a pulmonary
specialist at Yale University in New Haven, Connecticut.

The work also appears to validate the technique of using
geographically isolated populations, called founder populations, to
find genes for common complex diseases such as cancer and
diabetes. These diseases are tough to trace genetically because they
are apparently caused by combinations of genes, along with
environmental triggers. "People have said, 'Oh, you need thousands of
patients, and it's so difficult' " to identify genes for asthma and
other common disorders, says Scott Weiss, an asthma geneticist at
Harvard Medical School in Boston. But the discovery of these genes
"shows that you can do this," he notes.

The first clue to the genes' existence came in the mid-1990s when
molecular geneticist Juha Kere of the University of Helsinki and his
colleagues linked increased susceptibility to asthma to a massive,
20-million-base swath of chromosome 7. To find the culprit genes,
Kere, Helsinki colleague Tarja Laitinen, and others began collecting
blood samples from both healthy and asthmatic individuals in families
afflicted with asthma--a total of nearly 900 samples. The Finns, he
and others reasoned, were ideal for this sort of study: Geographically
isolated and genetically fairly uniform, their disease genes might be
easier to spot than those in more diverse populations.

By sequencing parts of the suspicious stretch of chromosome 7, Kere,
now at the Karolinska Institute in Stockholm, Sweden, and his team
found that both the healthy and asthmatic individuals, all of whom
lived in the same Finnish province near the Russian border, carried
one of seven possible variant DNA sequences, known as haplotypes, in
that chromosomal region. Certain haplotypes, many believe, predispose
to disease. In the Finnish case, this theory apparently held: Three of
the seven haplotypes Kere's group found were associated with asthma,
and more than half the asthma patients carried them as opposed to just
a third of the healthy people.

To make certain these haplotypes weren't unique to Finns, Kere teamed
up with Thomas Hudson, a haplotype expert at McGill University in
Montreal, Canada. Hudson had collected nearly 400 DNA samples from
asthmatics and nonasthmatics in Quebec. Close inspection revealed the
same seven haplotypes in this group as in the Finns and confirmed that
three are strongly linked to asthma susceptibility. The hazardous
haplotypes appear to boost asthma risk by up to 2.5 times normal.

Further comparisons of the haplotypes helped Kere's team uncover two
genes with alterations unique to the high-risk haplotypes. One of
these is a complete mystery. It doesn't appear to code for a protein,
and the scientists currently don't know what to make of it.

But the other, which the group labeled GPRA, has generated ripples of
excitement: It produces a so-called G protein-coupled receptor, which
belongs to a class of molecules that have proved their usefulness as
drug targets. Kere and his colleagues have launched a company, GeneOS
Ltd., and filed for patents on the GPRA protein, in the hope of
producing a drug to modulate its activity.

The researchers still need to pin down how a mutated GPRA gene
increases asthma susceptibility and whether it's widespread in
populations outside Quebec and Finland. But there are indications,
Kere says, that its role may not be limited to asthmatics who carry
the mutant gene. His team tested bronchial tissue from eight
asthmatics with unknown haplotypes; all showed high concentrations of
the protein, even though only half would be expected to carry the
mutant gene. Tissues from 10 healthy volunteers did not show elevated
amounts of GPRA.

There are also hints that the GPRA gene may be linked to
allergies. Human tissue samples revealed that the GPRA protein is
present in the air passages of normal lungs, although at much lower
concentrations than in the lungs of asthma patients, as well as in the
outer layers of the skin and the gut lining--all sites commonly
associated with allergic reactions.

--
Alison Chaiken "From:" address above is valid.
(650) 236-2231 [daytime] http://www.wsrcc.com/alison/
With how many things are we upon the brink of becoming acquainted, if
cowardice or carelessness did not restrain our enquiries. -- Mary
Shelley, _Frankenstein_