Combined Genetic Predisposition and Environmental Factors: The Causes of All Diseases.

In thinking about this blog I was originally planning to exclude trauma, but in fact this also pertains to trauma: the healing process and response to outside invaders (infectious organisms) are all affected by these two factors. In addition to other system predispositions that are not primarily immunologic, primarily neurological and cardiac. I recently wrote a blog about Damar Hamlin, focusing on the remarkably rapid and accurate health care response. Sudden death in young people engaged in strenuous physical activity, probably is most often due to the stimulation of a fatal cardiac arrhythmia that has at its basis a genetic predisposition to irregular heart rates.

The debate has raged for many decades: genes versus environment (nature vs nurture) for disease, and most other things (eg: abnormal behavior... also a genetic disease). In my opinion, it always is both. Now the importance of each component may vary between diseases and individuals, but they always both play a role. I think the most appropriate analogy I have used in the past which pertains to the profane yet clear life event: 'shit happens' is that many / everything is basically like playing a slot machine, sometime all 5 wheels come up with a lemon- what I have termed the anti-jackpot. When it comes to health some of those wheels are genetic and some environment. Take the case of cystic fibrosis, a devastating genetic disease: 4 of those wheels are genetic (and 3 fixed lemons), 1 is a variable genetic wheel, and the 5th is environment.

I had to think of this topic again, although in the past (and present) I have focused my attention on GDD, in this case the most recent reason I had to think of this health circumstance, was when hearing of the recent death of a woman due to an amoeba species (I had not heard of/ or remembered) due apparently to using tap water with a nasal lavage machine. Interesting though, to the present time the tap water has not been tested for this amoeba... which does not make any sense, especially since this has been considered the source. It has reported the mortality rate is extremely high, and that of the 70 or so reported cases in the last 30 years, there were only 2 survivors and she was not one of them. I have to suspect that more than 70 people have been exposed to this amoeba... maybe in the thousands or even 100s of thousands, but their immune systems effectively annihilated the protozoan before it developed any disease.

Abnormal reaction to an invading entity can be either not sufficient (under-reactive) immune reaction, which to the present time has been the major focus regarding most diseases, or too indiscriminate over-reactive. Probably with this amoeba the issue is that in her slot machine there were 3 wheels for genetic predisposition, maybe already all set at lemon for the ability to counteract this particular species of amoeba (possibly amoebas in general), and the two environment wheels locked into reaction: 1. lavage for sinus infection, and most importantly 2. exposure to the amoeba. My original theories on GDD and the distinction. from those who did not react to Gd retention (Gadolinium Storage Condition, GSC) was that GDD reacted with a vigorous self-destructive cytokine response and GSC individuals did not react at all, essentially ignored the Gd. Our cytokine data however revealed a different (and correct) finding: it is not that the immune system in GSC individuals do not react to Gd with a strong cytokine response, they actually do, but it is a response to calm down the immune system and essentially all other cells, whereas in GDD subjects that immune response is to a much larger extent pro-inflammatory (with a component of pro-fibrotic, but this response is the hallmark of NSF) which has become self-destructive, to a large extent due to the persistent harboring of Gd in the body. So the difference is not reaction vs no reaction (GDD vs GSC), is is imbalanced (destructive) reaction vs balanced (calming) reaction. The genetic aspect of GDD is that there almost certainly is a GDD gene, or gene cluster, but there are also co-genes (MTHFR variant for one, but also the as yet also unknown genes responsible for Multiple Chemical Sensitivity Syndrome (MCSS) and Mast Cell Activation Syndrome (MCAS) and other related genetic disorders that cause some form of immune mediated inflammatory disease[IMID]). An interesting uncommon genetic disease: Macrophage Activation Syndrome (MAS) - associated perforinopathy (perforin a type of protein made by the body) PRF1, has many of the features noted in GDD: reaction to vaccines, susceptibility to Lyme and other infections, and abnormal hyper-reactivity of macrophages and T cells to antigen stimulation with excess release of TNF-a, IL 6, and IL 8. (pro-inflammatory cytokines). This entity is associated with a gene variant: A91V PRF 1.

The environmental factors primarily relate to knocking the immune system balance off its feet. Recall the immune system acts in a multistep, multicell process, and one can readily imagine how easy it is to throw off balance a process that generally involves several orderly steps. If anything, it is remarkable how infrequently dramatic imbalance seems to occur. Examples as I previously reported are recent/current potent high dose antibiotic use, concurrent infection (eg: Lyme Disease), Flare effect of another IMID, dehydration, metabolic acidosis, and excessive exercise (maybe the explanation is the combination of dehydration and metabolic acidosis with extreme exercise early before or after GBCA administration). So 2 or 3 wheels are the GDD gene, 1 wheel the gene due to related conditions, and 1-2 wheels due to environmental factors. The steps to managing every insult/assault on the host are the same for essentially everything: destruction (often relatively indiscriminate), architecture construction (fibrosis one of the most common types), and remodelling. These 3 steps also all occur simultaneously at the same time, but in the normal process the proportions of each event vary as time goes along. These management steps also are largely directed by the immune system, and fall out of kilter in disease states such as GDD.

So, in summary and future direction, in my opinion all diseases reflect the combination of genetic predisposition and environmental factors. The obvious and simplest strategy is to control the environmental factors as best as possible (that is no more Gd, and remove Gd as best as possible in GDD). Is one of the genes for GDD A91V PRF1? In finding the responsible gene(s), is one of the obvious future treatment methods stem cell therapy or CRISPR gene insertion or substitution?

Richard Semelka, MD