Contact: Elizabeth Crown
e-crown@northwestern.edu
312-503-8928
Northwestern University
Variations in detoxifying genes linked
to Lou Gehrig's disease
Genetic variations in three enzymes that
detoxify insecticides and nerve gas
agents as well as metabolize
cholesterol-lowering statin drugs may be
a risk factor for developing sporadic
amyotrophic lateral sclerosis (ALS, or
Lou Gehrig's disease), and possibly
responsible for a reported twofold
increased risk of ALS in Gulf War
veterans.
These findings, from a study led Teepu
Siddique, M.D., and colleagues at
Northwestern University, open the door
to investigating gene-environment
interactions as a cause of ALS and other
illnesses and to the development of
molecular targets for specific
treatments. The study was published in
the August 22 online issue (available
now) of the journal Neurology.
Siddique is Les Turner ALS
Foundation/Herbert C. Wenske Professor,
Davee Department of Neurology and
Clinical Neurosciences, professor of
cell and molecular biology and director
of the Neuromuscular Disorders Program
at Northwestern University Feinberg
School of Medicine.
ALS is a complex neurodegenerative
disorder of the motor neurons that
results in muscle weakness, difficulty
speaking, swallowing and breathing and
eventual total paralysis and death
generally within five years.
In 1993 Siddique and collaborators
determined that mutations in a gene
known as SOD1 account for 20 percent of
familial, or inherited, ALS (2 percent
of all cases of ALS). However, the cause
of sporadic ALS is still unknown.
In earlier research Siddique and other
researchers hypothesized that sporadic
ALS is modulated by variations in
multiple genes interacting with each
other and environmental exposures.
The genes for human paraoxanases (PON 1,
PON 2 and PON 3), which are located on
chromosome 7q21.3, code for the
production of detoxifying enzymes
involved in the metabolism of a variety
of drugs, organophosphate insecticides,
such as parathion, diazinon and
chlorpyrifos, and nerve gas agents such
as sarin.
Previous research described a possible
twofold increased risk for developing
ALS in veterans of the Gulf War,
indicating a war-related environmental
exposure to organophosphates and sarin
in genetically susceptible individuals
as a possible cause. PON gene cluster
variants have previously been associated
with other neurodegenerative and
vascular disorders, including
Alzheimer's disease, Parkinson's
disease, coronary artery disease and
stroke.
Although the Northwestern DNA study
samples were not analyzed for inclusion
of Gulf War veterans, Siddique and
co-researchers found significant
evidence that gene variations
(polymorphisms) on the chromosome region
encompassing PON2-PON3 were strongly
associated with sporadic ALS.
"Thus, single nucleotide polymorphism
genotyping in the intergenic regions of
the PON gene cluster, and replication,
gene expression, gene-gene interaction
and PON serum/enzymatic studies may help
elucidate the complexity of PON cluster
association with ALS," Siddique said.
Siddique hopes to study DNA samples from
Gulf War veterans with increased
incidence of sporadic ALS and has
applied for their DNA from the Veterans
Administration collection.
###
Collaborating with Siddique on this
research were Mohammad Saeed, M.D.;
Nailah Siddique; Wu-Yen Hung; Elena
Usacheva; Erdong Liu, M.D.; Robert L.
Sufit, M.D.; Scott L. Heller, M.D.,
Northwestern University Feinberg School
of Medicine; Jonathan L. Haines,
Vanderbilt University Medical Center;
and Margaret Pericak-Vance, Duke
University Medical Center.
