Inflammation is the body’s normal defence mechanism against injury or infection. It is usually short-lived, however when it lasts too long it can become chronic. Chronic inflammation plays a crucial role in the development of conditions such as obesity, type 2 diabetes, rheumatoid arthritis, asthma, and even cancer.1,2
Genetic information obtained from a DNA test provides an insightful tool that can help manage and bring clarity to a patient’s clinical picture. In particular, DNA testing can bring insight into three aspects of inflammation:
1. Uncovering the root cause of chronic inflammation by highlighting genetic predispositions to oxidative stress;
2. Reducing inflammation by identifying genetic weaknesses in cytokine pathways and unveiling specific anti/pro-inflammatory nutrient requirements; and
3. Contributing to understanding the body’s ability to resolve inflammation by identifying genetic requirements for pro-resolving mediator lipids.
The following information explains how identifying genetic polymorphisms can assist in identifying underlying causes to your health condition. Never mind if some of the scientific language seems difficult, our Naturopath will be able to explain what all the test results mean and how they relate to your health. True Medicine recommends only quality DNA testing and prefers to use 3×4 Genetics.
1. DNA TESTING AND ROOT CAUSE OF INFLAMMATION
As practitioners, it is not uncommon to deal with complex cases, where the patient presents with inflammatory traits but has not improved with conventional management. This can be frustrating both for the patient and the practitioner. DNA testing allows practitioners to focus on the predisposition to oxidative stress, a crucial aspect of inflammation. In fact, metabolically there is a tight and fundamental cross-talk between oxidative stress, DNA damage and inflammation. Genetic polymorphisms can influence the susceptibility to and how the body reacts to oxidative stress and DNA damage. Looking into key SNPs in genes linked to Glutathione, Nitric Oxide, Catalase, Superoxide dismutase and more gives the practitioner a wider understanding of the patient’s genetic weaknesses and strengths that have an impact on the inflammatory response. Each of these SNPs can contribute to understanding the root cause of their condition and guide treatment recommendations.
Under inflammatory conditions, nitric oxide is generated from nitric oxide synthases such as NOS1 and NOS2. Sustained production of nitric oxide produces oxidative stress and can cause DNA damage.
Variants in NOS1 and NOS2 have an impact on oxidative stress and therefore on inflammation pathways.3,4 Knowing an individual’s NOS1 and NOS2 genetic makeup can help understand their predisposition to oxidative stress upon inflammation and provide guidance on specific nutrients that can improve their function. Carotenoids, polyphenols, and DHA can improve NOS1 and NOS2 function.4,5 These nutrients may be recommended to a patient with variants in these genes to help re-establish balance in their antioxidant and inflammatory pathways.
Another important player is Glutathione, which is involved in oxidative stress, detoxification and immunity. Several genetic polymorphisms in Glutathione genes including GPX1, GSTM1, and GSTP1 may predispose to low Glutathione levels, higher oxidative stress and reduced antioxidant protection.6,7,11,12 This in turn causes too many free radicals that can damage healthy cells, leading to inflammation.
If your patient has a genetic profile with several risk variants in Glutathione-related genes, this might indicate their oxidative stress level may be causing or contributing to chronic inflammation. In this case, specific nutrients supported by the evidence that target Glutathione genes can be recommended. For example, curcumin, ginger and quercetin have the ability to induce GSTP1 expression.13,14,15 Studies have shown that cruciferous vegetables may be beneficial for GTSM1 risk allele carriers to improve their antioxidant abilities.6,13 Exposure to cold temperatures, vitamin C, vitamin E, and ginger can all assist GPX1 function.7,8,9,10
As Glycine and Cysteine are the major amino acids for Glutathione production, it’s important to provide these amino acids to protect the body from oxidative damage during the immune response. A gene related to Glycine requirements is COL1A1 whose polymorphisms are associated with low type-1 collagen production, and therefore also increase Glycine requirements.16,17 Another gene is CTH1 which converts cystathionine into cysteine and therefore has an influence on Cysteine availability. The functionality of both these genes contributes to the influence of Glutathione levels.12 Foods rich in Cysteine such as meat, eggs, nuts and legumes are recommended for risk allele carriers of CTH1, and collagen protein from bone broth, gelatin, and meat with the skin can be recommended to increase dietary Glycine, and ultimately support Glutathione production.19,20
Boosting Glutathione can also be accomplished with Selenium, which supports GPX1 function.7 Interestingly, Glutathione has been found to increase significantly with deep breathing practices like Tai Chi or yoga, as well as a combination of aerobic exercise and circuit weight training.21,22,23
2. DNA TESTING AND REDUCING INFLAMMATION
Inflammation in the body can be reduced or resolved, and these are two distinct mechanisms.
A series of immunoregulatory molecules called cytokines, together with receptors and inhibitors, control the pro- and anti-inflammatory response. Perturbations of the dynamic balance between pro- and anti-inflammatory cytokines may be due to genetic, environmental or other causes.24 A DNA test can identify disruptions in genes affecting cytokine balance. For example, polymorphisms in the genes encoding pro-inflammatory cytokine receptor TNF-α and cytokine IL6 might contribute to a genetic predisposition to inflammation.25,26
Other genetic variants may influence the anti-inflammatory ability of a patient, as is the case for PEMT which catalyses the synthesis of phosphatidylcholine. Choline is a methyl-donor that plays an important role in healthy cell membranes to protect against inflammation.27 A patient with polymorphisms in PEMT may have an increased requirement for dietary choline which is needed to help reduce inflammation.28
3. DNA TESTING AND RESOLVING INFLAMMATION
Complete resolution of an inflammatory response is essential for health. Resolution is an active process during which pro-resolution lipid mediators are generated. These mediators include molecules derived from the omega-3 essential fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).29 EPA and DHA play a crucial role in the inflammation process. Evidence shows that changing the composition of arachidonic acid, EPA and DHA in the cells involved in inflammation appears to be especially important.30 Therefore, having adequate levels of EPA and DHA is crucial not only for anti-inflammatory but also pro-resolving processes.
Currently, the published evidence reports several clinical studies still in progress aimed at identifying the main genes for the resolution of inflammation. What’s known so far is that FADS1 and FADS2 genes are involved in fatty acid metabolism. Variants in these genes may influence the ability to convert alpha linolenic acid (ALA) to EPA, which has an impact on EPA and DHA requirements.31 Therefore, considering a patient’s genetic profile for the FADS genes can add value in understanding their inflammatory status and assist in making nutritional recommendations.
REFERENCES
1. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2017 Dec 14;9(6):7204-7218. doi: 10.18632/oncotarget.23208. https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC5805548/ -.
2. Kawanishi S, Ohnishi S, Ma N, Hiraku Y, Murata M. Crosstalk between DNA damage and inflammation in the multiple steps of carcinogenesis. Int J Mol Sci. 2017 Aug 19;18(8):1808. doi: 10.3390/ijms18081808. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578195/ –
3. Duma D, Fernandes D, Bonini M et al. NOS-1-derived NO is an essential triggering signal for the development of systemic inflammatory responses. Eur J Pharmacol. 2011;668(1-2):285-292. https://www.sciencedirect.com/science/article/pii/S0014299911006480?via%…
4. Han X, Zheng T, Lan Q, Zhang Y, Kilfoy BA, Qin Q, et al. Genetic polymorphisms in nitric oxide synthase genes modify the relationship between vegetable and fruit intake and risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1429-38. doi: 10.1158/1055-9965.EPI-09-0001. https://pubmed.ncbi.nlm.nih.gov/19423521/
5. Balakumar P, Taneja G. Fish oil and vascular endothelial protection: bench to bedside. Free Radic Biol Med. 2012 Jul 15;53(2):271-9. doi: 10.1016/j.freeradbiomed.2012.05.005.
6. Carlsten C, Sagoo GS, Frodsham AJ, Burke W, Higgins JP. Glutathione S-transferase M1 (GSTM1) polymorphisms and lung cancer: a literature-based systematic HuGE review and meta-analysis. Am J Epidemiol. 2008 Apr 1;167(7):759-74. doi: 10.1093/aje/kwm383. https://academic.oup.com/aje/article/167/7/759/84189
7. Gholinejad. Association of glutathione peroxidase 1 gene polymorphism (rs1050450) with Hashimoto’s thyroiditis in Northwest Iran. Meta Gene. 2018;17:216-22. https://www.sciencedirect.com/science/article/pii/S2214540018301440
8. Wozniak A, Wozniak B, Drewa G, Mila-Kierzenkowska C. The effect of whole-body cryostimulation on the prooxidantantioxidant balance in blood of elite kayakers after training. Eur J Appl Physiol. 2007 Nov;101(5):533-7. doi: 10.1007/s00421-007-
0524-6.
9. Michalak, M. Plant-derived antioxidants: significance in skin health and the ageing process. Int J Mol Sci. 2022;23:585. https:// doi.org/10.3390/ijms23020585
10. Sheikhhossein F, Borazjani M, Jafari A, Askari M, Vataniyan E, Gholami F, Amini MR. Effects of ginger supplementation on biomarkers of oxidative stress: A systematic review and meta-analysis of randomized controlled trials. Clin Nutr ESPEN. 2021 Oct;45:111-119. doi: 10.1016/j.clnesp.2021.07.010.
11. Reszka E, Czekaj P, Adamska J, Wasowicz W. Relevance of glutathione S-transferase M1 and cytochrome P450 1A1 genetic polymorphisms to the development of head and neck cancers. Clin Chem Lab Med. 2008;46(8):1090-6. doi: 10.1515/CCLM.2008.227. https://www.degruyter.com/view/journals/cclm/46/8/article-p1090.xml
12. Ye Z, Song H. Glutathione s-transferase polymorphisms (GSTM1, GSTP1 and GSTT1) and the risk of acute leukaemia: a systematic review and meta-analysis. Eur J Cancer. 2005 May;41(7):980-9. doi: 10.1016/j.ejca.2005.01.014. https://pubmed.ncbi.nlm.nih.gov/15862746/
13. Wang LI, Giovannucci EL, Hunter D, Neuberg D, Su L, Christiani DC. Dietary intake of cruciferous vegetables, Glutathione S-transferase (GST) polymorphisms and lung cancer risk in a Caucasian population. Cancer Causes Control. 2004 Dec;15(10):977-85. doi: 10.1007/s10552-004-1093-1. https://pubmed.ncbi.nlm.nih.gov/15801482/
14. Nishinaka T, Ichijo Y, Ito M, Kimura M, Katsuyama M, Iwata K, et al. Curcumin activates human glutathione S-transferase P1 expression through antioxidant response element. Toxicol Lett. 2007 May 15;170(3):238-47. doi: 10.1016/j.toxlet.2007.03.011.
15. Schadich E, Hlaváč J, Volná T, Varanasi L, Hajdúch M, Džubák P. Effects of ginger phenylpropanoids and quercetin on Nrf2-ARE pathway in human BJ fibroblasts and HaCaT keratinocytes. Biomed Res Int. 2016;2016:2173275. doi: 10.1155/2016/2173275.
16. Clifford T, Ventress M, Allerton DM, Stansfield S, Tang JCY, Fraser WD, et al. The effects of collagen peptides on muscle damage, inflammation and bone turnover following exercise: a randomized, controlled trial. Amino Acids. 2019 Apr;51(4):691-704. doi:10.1007/s00726-019-02706-5. https://pubmed.ncbi.nlm.nih.gov/30783776/
17. Posthumus M, September AV, Keegan M, O’Cuinneagain D, Van der Merwe W, Schwellnus MP, et al. Genetic risk factors for anterior cruciate ligament ruptures: COL1A1 gene variant. Br J Sports Med. 2009 May;43(5):352-6. doi: 10.1136/bjsm.2008.056150. https://pubmed.ncbi.nlm.nih.gov/19193663/
18. Wang J, Huff AM, Spence JD, Hegele RA. Single nucleotide polymorphism in CTH associated with variation in plasma homocysteine concentration. Clin Genet. 2004 Jun;65(6):483-6. doi: 10.1111/j.1399-0004.2004.00250.x. https://pubmed.ncbi.nlm.nih.gov/15151507/
19. Ishii I, Akahoshi N, Yamada H, Nakano S, Izumi T, Suematsu M. Cystathionine gamma-Lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury. J Biol Chem. 2010 Aug 20;285(34):26358-68. doi:10.1074/jbc.M110.147439.
20. McCarty MF, O’Keefe JH, DiNicolantonio JJ. Dietary glycine is rate-limiting for glutathione synthesis and may have broad potential for health protection. Ochsner J. 2018 Spring;18(1):81-87.
21. Rosado-Pérez J, Castelán-Martínez OD, Mújica-Calderón AJ, Sánchez-Rodríguez MA, Mendoza-Núñez VM. Effect of tai chi on markers of oxidative stress: systematic review and meta-analysis. Int J Environ Res Public Health. 2021 Mar 26;18(7):3458. doi:10.3390/ijerph18073458. https://pubmed.ncbi.nlm.nih.gov/33810466/
22. Patil SG, Dhanakshirur GB, Aithala MR, Naregal G, Das KK. Effect of yoga on oxidative stress in elderly with grade-I hypertension: a randomized controlled study. J Clin Diagn Res. 2014 Jul;8(7):BC04-7. doi: 10.7860/JCDR/2014/9498.4586. Epub 2014 Jul 20. PMID: 25177555; PMCID: PMC4149061.
23. Elokda AS, Nielsen DH. Effects of exercise training on the glutathione antioxidant system. Eur J Cardiovasc Prev Rehabil. 2007 Oct;14(5):630-7. doi: 10.1097/HJR.0b013e32828622d7.
24. Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest. 2000 Apr;117(4):1162-72. doi: 10.1378/chest.117.4.1162. https://pubmed.ncbi.nlm.nih.gov/10767254/
25. England A, Valdes AM, Slater-Jefferies JL, Gill R, Howell WM, Calder PC, et al. Variants in the genes encoding TNF-α, IL-10, and GSTP1 influence the effect of α-tocopherol on inflammatory cell responses in healthy men. Am J Clin Nutr. 2012 Jun;95(6):1461-7.
doi: 10.3945/ajcn.111.012781. https://pubmed.ncbi.nlm.nih.gov/22572643/
26. Pereira DS, Mateo EC, de Queiroz BZ, Assumpção AM, Miranda AS, Felício DC, et al. TNF-α, IL6, and IL10 polymorphisms and the effect of physical exercise on inflammatory parameters and physical performance in elderly women. Age (Dordr). 2013 Dec;35(6):2455-63. doi: 10.1007/s11357-013-9515-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824985/
27. Wiedeman AM, Barr SI, Green TJ, Xu Z, Innis SM, Kitts DD. Dietary choline intake: current state of knowledge across the life cycle. Nutrients. 2018 Oct 16;10(10):1513. doi: 10.3390/nu10101513. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213596/
28. Piras IS, Raju A, Don J, Schork NJ, Gerhard GS et al. Hepatic PEMT Expression Decreases with Increasing NAFLD Severity. Int J Mol Sci. 2022 Aug 18;23(16):9296. doi: 10.3390/ijms23169296.
29. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008 May;8(5):349-61. doi: 10.1038/nri2294. https://www.nature.com/articles/nri2294
30. Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients. 2010 Mar;2(3):355-374. doi: 10.3390/nu2030355. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257651/
31. Bokor S, Dumont J, Spinneker A, Gonzalez-Gross M, Nova E, Widhalm K, et al. Single nucleotide polymorphisms in the FADS gene cluster are associated with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios. J Lipid Res. 2010 Aug;51(8):2325-33. doi: 10.1194/jlr.M006205. www.ncbi.nlm.nih.gov/pmc/articles/PMC2903808/