Oct. 7, 2008
Enzyme Flaws Again Implicated In ALS Susceptibility
The search for genetic variations that predispose a person to developing ALS (amyotrophic lateral sclerosis) a paralyzing and ultimately fatal neurologic disease, has been complex and frustrating, although a few intriguing examples stand out as worthy of further investigation.
Among them are findings that particular variations in the PON (paraoxonase) genes, located together on chromosome 7 and carrying instructions for enzymes that detoxify certain chemicals, such as organophosphate pesticides, are found more often in people with ALS than in people who don't have the disease.
MDA grantee Guy Rouleau at the University of Montreal, and colleagues, have recently added to the evidence linking PON variants to ALS.
2006 studies link PON changes to ALS in Poland, N. America
In 2006, Agnieszka Slowik and colleagues found a combination of two variants, one in the PON1 gene and one in the PON2 gene, occurred 3.4 times more often in ALS-affected Polish subjects than it did in those without the disease.
At the same time, researchers in the laboratory of Teepu Siddique at Northwestern University in Chicago, with colleagues at Vanderbilt and Duke Universities, found a variant sequence of DNA lying between the PON2 and PON3 genes to be associated with ALS in a North American population. These researchers speculated that ALS risk might be altered by a PON "cluster," rather than by a single variant in a single gene. (See "Detox Enzyme DNA."
New results implicate PON changes elsewhere
Rouleau's group, which published its findings Aug. 12 in Neurology, studied PON genes in people with and without ALS in France, Sweden and the Canadian province Quebec. Their results, like the Siddique team's findings, suggest that a cluster of PON variations, not just one, may be responsible for an increase in ALS susceptibility.
The researchers looked at 20 locations in the three PON genes in 480 people with ALS and 475 without ALS in France; 159 people with ALS and 95 without in Quebec; and 558 people with ALS and 506 without in Sweden.
They didn't find any particular variant to be associated with ALS by itself in any group. However, they did find a cluster of PON gene variants was significantly associated with ALS in the French group, the Quebec group and the combined French, Quebec and Swedish groups.
In the Swedish group, the researchers found PON gene variants were not significantly different in the ALS and non-ALS populations.
They say the different results in the populations studied may mean that multiple combinations of PON gene changes have the potential to raise the likelihood of ALS development, but that different combinations accumulate over time in various populations.
The authors of the newest study say that "variants in the PON gene cluster must be seriously considered as a susceptibility factor to ALS." |
