This study confirms previous reports that genetic variants within the PON1 gene are associated with susceptibility to SALS. This association prompts consideration of the biological function of PON1 and mechanisms by which its variants may predispose to SALS. PON1 detoxifies several neurotoxic organophosphate compounds often found in insecticides, nerve gas, foods, and other household items[14
]. It therefore seemed reasonable at the outset of this study to postulate that decreased activity of PON1 increases ones risk with exposure to injurious neurotoxins, leading over time to SALS. This concept is consistent with studies showing that SALS is not fully explained by genetic factors (heritability=0.38–0.85)[12
], and by the epidemiological observations that ALS cases have an increased exposure to insecticides and pesticides and that some occupations confer a higher ALS risk (e.g. farmers [34
], members of the military in general and military personnel who were deployed in the first Gulf War [35
]). If indeed PON1 influences SALS susceptibility through capacity to detoxify specific toxins, then the identification of its environmental substrates as well as factors increasing the expression/activity of PON1 may illuminate aspects of the pathogenesis of SALS and ultimately be helpful in treating or reducing the risk of this disease.
Although the current study confirms the association of PON1 with sporadic ALS, it did not document a correlation between the disease-associated haplotype HAP1 and levels of PON1 activity, as measured by phenylacetate hydrolysis. This parallels our observation reported elsewhere that ALS sera also do not show reduced hydrolysis of paraoxon, diazoxon or phenylacetate compared to controls [37
]. These findings raise the possibility that the ALS-related genetic variants in PON1 alter activity towards some substrate other than phenylacetate or paraxon. Indeed, PON1 is highly promiscuous, hydrolyzing hundreds of substrates. Moreover, it is highly polymorphic with more than 160 known polymorphisms, many of which differentially affect hydrolysis of different substrates [38
We also note that PON1 is a potent inhibitor of lipid oxidation; it is tightly associated with HDL particles and is substantially anti-atherogenic[39
]. It may therefore also be that variations in the lipid anti-oxidant properties of ALS-associated PON1 polymorphisms underlie the SALS susceptibility. There are several lines of inquiry incriminating oxidative cytotoxicity as a causative factor in ALS, although this remains controversial. By analogy, heightened oxidative toxicity is reported in other neurodegenerative disorders (e.g. Alzheimer’s and Parkinson’s disease [42
]). Reports have also shown that the risk of SALS can be reduced by the intake of antioxidants [43
]. It is possible the detoxification and antioxidant properties both contribute to influencing the susceptibility of SALS. The study of PON1 variants that have lost their antioxidant properties, but not their detoxification properties, may be useful in dissecting this question.
This is the fifth report implicating variants in paraoxonases as susceptibility factors for SALS [23
]. It is potentially of importance that there are inconsistencies in these studies. Each study observed a different association peak; Two studies observed association peaks at differing PON1 amino acid variants, L55M and Q192R [23
], neither which were significant in our study. One study observed an association within the PON1 promoter region [24
] and one was within a PON3/PON2 haplotype [25
]. Thus, three of the previous reports implicate PON1 as an ALS risk factor while the fourth implicates PON2 and 3. Further, even among the reports associating PON1 with SALS there is no consistency in the linked variants. At least three factors may explain this. First, the SALS patients were derived from different populations in the studies (Poland, Australia, Ireland, North American Caucasians, USA/UK Caucasians). Conceivably, linkage disequilibrium patterns within the PON cluster may differ in each population, leading to divergent results. Second, it is possible that more than one variant in the PON1 gene can increase SALS susceptibility; differing observations may reflect the frequencies of the causal variants in that given population. And third, each population may differ in the patterns of exposure to environmental toxins and to compounds that influence paraoxonase expression. For example, smoking [44
], lipid-controlling medication exposure[46
] and organophosphate exposure [47
](both the amount and type) are all known to modify levels of PON1 expression; each is likely to vary among different populations. Thus, if a particular variant within the PON1 gene demonstrates a decreased activity in detoxifying cigarette smoke, the association with SALS may be more prominent in populations with high smoking rates. Obviously, the combination of several of these factors further complicates any dissection of the association.