PON1 Status in Relation to Gulf War Illness: Evidence of Gene–Exposure Interactions from a Multisite Case–Control Study…, 2024, Steele, Klimas+

Introduction

 

Methods
398 veterans from three pre-existing cohorts. 295 GWI cases and 103 controls

That sentence is slightly worrying. Hopefully the Gulf War veteran controls were actually healthy and not in some no mans land of being ill but not quite ticking the right boxes to be considered to have GWI.

One cohort was only asked to estimate their exposures during the war 9 to 15 years after the war, so that data may not be great.

That's important, although they haven't yet said what risk factors they considered.

 

PON1 status assays

I think they must have identified the actual PON1 genotype, but I'm not 100% sure. Ed. I don't think they determined PON1 genotype - reference 35 only talks about determining PON1 function using substrates. They definitely determined the function i.e. the enzyme activity in breaking down the toxins. That does mean that the different ages of some of the blood samples might be relevant.

 

Results
Demographics
Females accounted for 18% of GWI cases and 15% of veteran controls. I don't know if the selection of the cohorts was on a population basis or if there was some selection

If PON1 status is determined by PON1 function, then of course PON1 status is going to vary by PON1 function. They don't seem to have determined PON1 genotype. ?

I'm surprised about the finding that PON1 activity didn't vary by GWI case status, but Table 2 shows very clearly that it didn't.

 

3.4 Association of exposures with GWI case status
Table 4 shows that a range of exposures were associated with GWI case status.

E.g.
86% of GWI cases heard chemical alarms sound versus 64% of controls. Adjusted odds ratio of 1.7
83% of GWI cases took the pyridostigmine bromide versus 60% of controls. Adjusted odds ratio of 2.0
13% of GWI cases wore flea collars versus 1% of controls. Adjusted odds ratio of 9.8
73% of GWI cases used pesticide spray on skin versus 36% of controls. Adjusted odds ratio of 3.9

So, they are suggesting some interactions of the exposure factors.

3.5 GWI Status and Cholinergic Exposures by PON1 status
Table 5 gives the results of correlations between combinations of exposures and PON1 status on GWI status.

Hearing chemical alarms and having RR PON1 status is reported as giving the highest odds ratio (8.60). Having taken pyridostigmine bromide dramatically increased the odds in this groups of GWI (19.0).

Using pesticides on skin gave significant odds ratios for people with QQ and QR PON1 status (3.3. and 4.2). Having taken pyridostigmine bromide changed the odds ratios, increasing them in the QQ veterans to 6.3.

 

I'm sorry, I'm still confused how they determined PON1 status and what they mean by it. I think they just mean the functional phenotype.

Discussion
But, the good news - it seems their findings do fit with what is known about the biology of the PON1 forms.

That's something to hang onto. The combination of exposure to nerve gas and the RR genotype as a major risk factor for GWI seems to have been replicated - they suggest in 'multiple studies'.

And there does seem to be a coherent story about the increased risk for people with the Q alloform carriers with respect to pesticides:

 

This was interesting, for beyond the Gulf War:

They talk about how smoking can reduce PON1 efficiency and how that could explain some modification of risk associated with being a smoker.

They also talk about how the pyridostigmine bromide may have increase vulnerability for both RR veterans and QQ veterans.

It seems likely that a subset of people diagnosed with ME/CFS, people who aren't Gulf War veterans, have had cholinergic exposures that have caused their symptoms.