No Smoking Gun

An analysis shows no single PON gene variant increases ALS risk, but doesn't rule out ALS-PON connections

by Quest Staff on July 9, 2009 - 5:00pm

A new meta-analysis combining data from 11 studies has found no connection between variations in genes for paraoxonase (PON) enzymes and an increased risk of developing amyotrophic lateral sclerosis (ALS).

As reported in the September 2008 issue of the ALS Newsmagazine, Some experts have speculated that variations in PON or other genes, combined with toxic exposures, may underlie an apparent increased incidence of ALS in veterans of the 1990-1991 Gulf War.

PON genes are the instructions for PON enzymes, which play a role in detoxifying certain poisons, such as organophosphate-based pesticides.

The meta-analysis (an overall analysis of several studies) rules out the theory that there’s a common PON genetic mechanism that raises ALS risk across worldwide populations. However, the analysis does not rule out the possibility that PON gene variations may raise ALS risk in people living in specific areas or who have had specific environmental exposures.

Simon Cronin of the Department of Neurology at Beaumont Hospital in Dublin, Ireland, was a principal investigator on the meta-analysis, which was published in the July 7, 2009, issue of the journal Neurology.

He says the most important aspect of the study is that it represents the first large-scale, multinational collaboration looking at genetic factors in sporadic (nonhereditary) ALS, the type of ALS that affects the vast majority of patients around the world.

Cronin says the meta-analysis doesn’t close the book on the role of PON genes in ALS. "It remains possible that PON genes play a role in ALS in groups with specific exposures or in limited geographical distributions."

Orla Hardiman, also of the Department of Neurology at Beaumont Hospital in Dublin, Ireland, was among the authors on the new meta-analysis. Hardiman’s MDA-supported analysis of PON gene variations in people with and without ALS in Ireland, published in 2007, was one of the included studies.

Several earlier, smaller studies suggested a connection between variations in PON genes and an increased risk of developing ALS in specific population groups.

The proposed connection between PON gene variants and an increased ALS risk has been widely cited as support for a "two-hit" model of ALS causation, one "hit" being genetic susceptibility and the other an environmental exposure. (See Gulf-War-associated increase in ALS and Variations in 'Detox' Enzymes.)

A conservative analysis

Lorene Nelson, an epidemiologist (expert in disease patterns) who has MDA support to study gene-environment interactions in ALS at Stanford (Calif.) University, says the meta-analysis was "very well done, included large numbers of subjects, and was accompanied by very careful analyses."

However, she said, the statistical methods the researchers used were extremely conservative, making it possible that in an effort to avoid "false positive" associations, they may have missed some actual associations between PON gene variants and ALS.

In addition, Nelson noted, "a negative result does not absolutely preclude the possibility that PON gene variants could be associated with ALS" either in the presence of gene-environment interactions or other factors not accounted for in the study.

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