Mitochondrial and Nuclear Genes Together Determine Gulf War Illness Severity and Symptom Profile
Abstract
Overarching Challenges: • GWI subtyping: Replicates/extends evidence tying nuclear and mitochondrial genetics to Gulf War Illness (GWI) severity and clinical profile. • GWI treatment: 1. Gene relationships implicate mechanisms that provide targets for GWI treatment. 2. Including participants from a DoD GWI coenzyme Q10 (coQ10) trial enables the study to also define genetics of who benefits from coQ10 and at which dose. 3. Genetic data may also benefit future treatment studies. • Overarching challenges of GWI determinants (via testing gene-exposure interactions) and GWI consequences (by assessing gene relations to key GWI health consequences) are also touched upon. Objective: To validate and extend evidence that nuclear genetics (especially of detoxification) and mitochondrial genetics jointly predict GWI severity and clinical profile. Nuclear genetics are the Watson-Crick double helix genes inherited from both parents. Mitochondrial genes are circular, bacterial-style genes inherited only from the mother, with an important role in cell energy production. Our preliminary data show these each contribute strongly to predicting GWI severity and clinical profile. Rationale: Even Veterans with similar exposures develop widely differing GWI severity and clinical profile. Genetics have prospects to underlie these differences and it may be critical to consider the interplay of mitochondrial with nuclear genetics. A relative focus on detoxification genetics has an added benefit: toxin relations can be discounted as subject to recall/reporting bias but genes are objective and not subject to this challenge. If detoxification genetics (including Phase 2, e.g. antioxidant defense) coupled with mitochondrial genes are implicated, this reinforces the importance of toxin involvement. Our preliminary data show that nuclear detoxification genetics work together with mitochondrial genetics (including ancestral patterns of mitochondrial genes as well as mitochondrial DNA mutations) to powerfully predict GWI severity and to predict clinical features of GWI. The proposed study will validate those findings, extend to a larger sample and to the whole nuclear genome, and integrate with a funded coQ10 treatment trial to both leverage recruitment, and reap additional information from the study (i.e., genetic predictors of treatment benefit). Applicability: The strong relation of mitochondrial genetics supports continued focus on mitochondria as important in GWI, and on treatments targeted to this. Specific nuclear gene relationships implicate pathways that in turn guide prioritization for treatment candidates – for treatments addressing GWI overall (for genes tied to GWI severity), or for specific clinical outcomes (for genes tied to clinical features). Of note, we found a potent tie of a sluggish “acetylator” variant (of a “detoxification” enzyme called “NAT2”) to markedly greater GWI severity. This converges with evidence that impaired acetylation of tubulin (due to organophosphates) may impair mitochondrial transport by microtubules in GWI, to suggest that treatments seeking to enhance acetylation might merit prioritization for assessment in GWI. The fact that the sluggish acetylator variant worked together with mitochondrial genetics to predict GWI severity suggests that treatments enhancing acetylation might be most effective when coupled with mitochondrial support. (Safe, nutritional approaches to enhance acetylation are known.) Similarly, our findings tying impaired mitochondrial antioxidation (via adverse variant of SOD2, the mitochondrial-located superoxide dismutase – main mitochondrial antioxidant) to chemical sensitivity, adjusted for mitochondrial genetics, suggest approaches to mitochondrial antioxidation might mitigate this condition in GWI. Veterans found to have genes tied to outcomes of concern in GWV (e.g., the NAT2 slow acetylator variant that is also tied to Parkinson’s disease) might be able to initiate treatme
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110906
Entities
People
- Beatrice Golomb
Organizations
- United States Army
- University of California, San Diego