Since learning I had this mutation (rs147859257) in Complement Component 3 (C3), many people in my family have tested their DNA to determine whether they share it as well. From analyzing which diseases and conditions people with the mutation have or had and excluding diseases also present in those who do not have the mutation, we’ve been able to postulate some disease associations. These associations are purely hypothetical at this point and mostly include diseases that could occur due to excessive inflammation. If you or others in your family have the C3 mutation, I would be interested in knowing if any of these diseases or others commonly occur in those with the mutation in your family. I am also considering organizing a study (though I still need to figure out the logistics). Please contact me if you’re interested in a study or just want to add to the information below.
Remember, C3 is an inflammatory gene, and this mutation causes three main consequences:
1. It causes excess, uncontrolled inflammation whenever inflammation occurs (likely linked to cancer (1-4), depression (5-8), AMD (9), leukemias (10), Post-Concussion Syndrome (11), etc.).
2. It does not kill certain pathogens well, which can lead to chronic sinus, middle ear, or outer ear infections, pelvic abscesses, and difficulty fighting certain bacterial or fungal infections in general.
3. It likely causes excess C3a to sit on the surface of mast cells, making them hyper-responsive to stimuli, which can lead to excessive histamine responses and can be involved in asthma, histamine intolerance, allergies (including “abnormal” allergies, nonallergic rhinitis, and sensitivities to foods, medicines, smoke, mold, pets, etc. without the typical IgE-allergic response on lab tests).
How do a person’s exposures and other genetics affect the risk of these diseases?
If one is lucky enough to experience life without any inciting inflammatory events, a person with this mutation might theoretically never experience some of the problems of out-of-control inflammation or even just excess C3. So, one’s exposures in life (smoking, alcohol, getting a concussion, surgery, antibiotics, inflammatory diet, toxins, loud noises, chalk dust; viral, bacterial & fungal infections, etc.) and other genetics (poor sinus and nasal anatomy, short eustachian tubes, a bad GI gene, etc.) will impact how this mutation ultimately affects people. For example, I have a petite face with small, poorly ventilated sinus cavities and nasal passages and have had chronic sinus infections my entire life, worsening over time. I’ve had 8 sinonasal surgeries and have been on hundreds of courses of antibiotics. My two siblings who have this mutation do not have my poor facial anatomy, have not had major sinus problems and have been on few antibiotics in their lives. The mutation does not manifest exactly the same from person to person, which is one reason, in addition to its rarity, that I believe it has not been definitively linked to more diseases as of yet, but whatever inflammation a person does have will likely lead to problems. Unfortunately, a person with this mutation will still not kill certain pathogens effectively (encapsulated bacteria, TB, fungi) and will have to remain cognizant of that and be proactive (get pneumonia and meningococcal vaccinations, etc.).
Why is this mutation implicated in cancer?
Chronic inflammation over a long period of time will lead to cancer eventually in most people. Out-of-control inflammation would theoretically lead to more cancer at younger ages. Also, having an out-of-control immune response triggers the bone marrow and immune system to be hyperactive. Over the years, I believe this can lead to dysregulation of those cells, possibly causing essential thrombocythemia, leukemia and multiple myeloma, among other disorders (early on it might start by showing small elevations in different components on a complete blood count, like in basophils and/or platelets).
This Mutation is likely from our English Ancestry
As a reminder, this mutation is found mostly in those with northern European ancestry. We are fairly certain this mutation descends from the full English side of our family tree, but until a few more distant family members are tested, we cannot be certain (the other options would be Irish or French). I will update this post and the below list whenever we have more data. Again, this list is hypothetical.
These are the diseases that might be linked to this mutation in our family:
1. Severe Post-Concussion Syndrome (PCS) with subsequent brain damage (see this post)
2. Age-related Macular Degeneration (AMD) — AMD was shown to be significantly linked to this C3 mutation in studies. It occurs in our family members with the mutation (one person is legally blind from AMD).
3. Dementia — Inflammation may be a driving component & having had PCS predisposes to it (12-14).
4. Hearing loss — several family members (other genetics are likely involved, but it is more severe and has occurred earlier in those with the C3 mutation)
5. Essential thrombocythemia (elevated platelets, sort of a pre-leukemia) — dysregulation likely due to excessive, chronic stimulation of the immune system
6. ?Multiple Myeloma
7. ?Early prostate cancer (late 50’s) — likely in the context of heavy alcohol exposure (any alcohol causes inflammation of the urethra which can lead to prostate cancer, but if you have out-of-control inflammation, I believe it can lead to this cancer at a younger age with less exposure).
8. ?Pancreatic cancer — theoretical, unable to test
9. ?Esophageal cancer at a young age (late 20’s) — theoretical, unable to test
10. Recurrent, chronic sinus infections
11. Recurrent middle ear infections
12. Recurrent outer ear infections (a competitive swimmer)
13. Inability to kill bacteria in pelvic cavity after prostate cancer surgery (abscess finally removed after 17 years, which shocked doctors and wreaked havoc on his immune system for those 17 years giving him Chronic Fatigue Syndrome/Myalgic Encephalopathy-like and Fibromyalgia-like symptoms)
14. More severe delayed-onset muscle soreness (DOMS) than teammates training with the same regimen and/or more swelling in muscles with extreme exertion
15. Recurrent pulmonary infections
16. Gastroesophageal Reflux Disease (GERD) — New understanding is that it could be an inflammatory illness (15)
17. ?Pulmonary fibrosis from exposure to chalk as a teacher — theoretical, unable to test
18. Abnormal allergies — many family members with and without the mutation show usual allergies, but some with the mutation also show allergies that do not show the typical IgE-mediated response
19. Glaucoma — recently an inflammatory mechanism was implicated (16)
20. Depression (present in family members with recurrent infections and inflammation, though may also be caused by altered microbiome from antibiotics)
21. Severe tissue necrosis after radiation therapy (much more than doctors expected)
22. Chronic Fatigue Syndrome/Myalgic Encephalopathy-like and Fibromyalgia-like symptoms
Remember that whether one acquires any of these diseases is related to exposures and other genetics. For example, in terms of dementia, even though I do not have the ApoE4 allele that predisposes for Alzheimer’s, I am more likely to develop dementia because of the damage I suffered from my concussion and the PCS in 2016. Hence, this “exposure” predisposes me to dementia.
More and more studies are showing that excess inflammation is implicated in cancer, dementia, depression, age-related macular degeneration and brain damage after a concussion. In a future post, I’ll discuss what we might be able to do to minimize the effects of having this mutation and to improve our health.
References:
1. https://www.ncbi.nlm.nih.gov/pubmed/15528423
Marx J. Inflammation and cancer: the link grows stronger. Science. 2004 Nov 5;306(5698):966-8.
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994795/
Rakoff-Nahoum S. Why cancer and inflammation?. Yale J Biol Med. 2007;79(3-4):123-30.
3. https://www.ncbi.nlm.nih.gov/pubmed/26243878
Fedeles BI, Freudenthal BD, Yau E, et al. Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer. Proc Natl Acad Sci U S A. 2015;112(33):E4571-80.
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372043/
Kiraly O, Gong G, Olipitz W, Muthupalani S, Engelward BP. Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo. PLoS Genet. 2015;11(2):e1004901.
5. https://www.ncbi.nlm.nih.gov/pubmed/26711676
Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16:22-34.
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050394/
Kohler O, Krogh J, Mors O, Benros ME. Inflammation in Depression and the Potential for Anti-Inflammatory Treatment. Curr Neuropharmacol. 2016;14(7):732-42.
7. https://www.ncbi.nlm.nih.gov/pubmed/27377015
Brundin L, Bryleva EY, Thirtamara Rajamani K. Role of inflammation in suicide: from mechanisms to treatment. Neuropsychopharmacol. 2017;42:271-283.
8. https://www.ncbi.nlm.nih.gov/pubmed/27337107
Soledad Cepeda M, Stang P, Makadia R. Depression Is Associated With High Levels of C-Reactive Protein and Low Levels of Fractional Exhaled Nitric Oxide: Results From the 2007-2012 National Health and Nutrition Examination Surveys. J Clin Psychiatry. 2016; 1666-71.
9. https://www.ncbi.nlm.nih.gov/pubmed/24036952
Seddon JM, Yu Y, Miller EC, et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nature Genetics. 2013; 45(11):1366-1370.
10. https://www.ncbi.nlm.nih.gov/pubmed/27666011
Zambetti NA, Ping Z, Chen S, et al. Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia. Cell Stem Cell 2016 Nov 3;19(5):613-627
11. https://www.ncbi.nlm.nih.gov/pubmed/29437855
Alawieh A, Langley EF, Weber S, et al. Identifying the role of complement in triggering neuroinflammation after traumatic brain injury. J Neurosci. 2018: 2197-17.
12. https://www.ncbi.nlm.nih.gov/pubmed/25792098
Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer’s Disease. The Lancet 2015;14:388-405.
13. https://www.ncbi.nlm.nih.gov/pubmed/29093073
Walker KA, Hoogeveen RC, Folsom AR, et al. Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study. Neurology. 2017 Nov 28;89(22):2262-2270.
14. https://www.ncbi.nlm.nih.gov/pubmed/29293211
Venegas C, Kumar S, Franklin BS, et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature, 2017; 552 (7685): 355.
15. https://www.ncbi.nlm.nih.gov/pubmed/30320456
Nejat Pish-Kenari F, Qujeq D, Maghsoudi H. Some of the effective factors in the pathogenesis of gastro-oesophageal reflux disease. J Cell Mol Med. 2018 Oct 15.
16. https://www.ncbi.nlm.nih.gov/pubmed/30097565
Chen H, Cho KS, Vu THK, et al. Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma. Nat Commun. 2018;9(1):3209.
Tags: Age-related macular degeneration, Allergies, Bad Mutation, C3 mutation, Cancer, Complement Component 3, Concussion, Depression, Inflammation