Northwestern University

Posted: July 6, 2006

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.

This study was supported by grants from the National Institute of
Neurological Disorders and Stroke; Les Turner ALS Foundation; V. E.
Schaff ALS Research Trust; Wenske Foundation; Harold Post
Professorship; Les Turner ALS Foundation/Herbert C. Wenske Foundation
Professorship; Falk Foundation Fund; and The David C. Asselin M.D.,
Memorial Fund.