Inflammation is the body's natural defence mechanism against injury and infection, a process that typically promotes healing. However, when inflammation persists and becomes chronic, it can trigger a range of serious health issues, including autoimmune diseases, cardiovascular problems, and metabolic disorders. While factors such as diet, stress, and environmental toxins significantly influence inflammation levels, genetics also plays a crucial role in determining your susceptibility to inflammatory conditions. This article delves into twelve specific genetic variants linked to an increased risk of chronic inflammation, offering
insights into your genetic predisposition and how to tailor health strategies to mitigate these risks effectively.
Overview of Inflammation
Inflammation is a fundamental response of the immune system designed to protect the body from injury, infection, or harmful stimuli. This complex process involves multiple cellular and molecular interactions that help repair damaged tissues and eliminate pathogens. When an injury occurs, immune cells such as macrophages and mast cells are among the first responders, releasing signalling molecules called cytokines and chemokines that recruit additional immune cells to the site of injury. This rapid influx of immune cells increases blood flow, causing the characteristic signs of inflammation: redness, swelling, heat and pain.
Key Players: Cytokines
Cytokines are small proteins that play crucial roles in cell signalling during inflammation. They can be pro-inflammatory, promoting inflammation and attracting more immune cells to the site, or anti-inflammatory, helping to resolve inflammation and promote healing. Key pro-inflammatory cytokines include interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1). These molecules act like alarms, triggering an immune response and modulating the activity of various immune cells.
Cytokines are produced by a variety of cell types, including macrophages, T cells and endothelial cells. For instance, during an infection, macrophages detect pathogens and release cytokines that signal other immune cells to come to the site of inflammation. This process helps to eliminate the invaders but can also lead to tissue damage if the response is excessive or prolonged.
In a healthy response, inflammation serves as a protective mechanism, facilitating tissue repair and returning the body to homeostasis. However, when inflammation becomes chronic, it can lead to various health issues. Chronic inflammation is characterised by a prolonged inflammatory response that does not resolve, leading to tissue damage and contributing to the development of diseases such as autoimmune disorders, heart disease,
diabetes and cancer.
Macrophages are pivotal players in the inflammatory process. They not only help engulf and destroy pathogens but also secrete a variety of cytokines that regulate inflammation. Macrophages can adopt different phenotypes depending on the signals they receive from their environment. Classically activated macrophages (M1 macrophages) are involved in pro-inflammatory responses, while alternatively activated macrophages (M2 macrophages) help resolve inflammation and promote tissue repair.
When activated, M1 macrophages produce large amounts of pro-inflammatory cytokines, contributing to the inflammation and attracting more immune cells to the site. In contrast, M2 macrophages secrete anti-inflammatory cytokines that help resolve the inflammation and restore tissue homeostasis. This balance between M1 and M2 macrophages is crucial for maintaining health; an imbalance can lead to chronic inflammation and disease.
The impact of oxidative stress
Oxidative stress plays a significant role in inflammation. It occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify these reactive intermediates. Elevated levels of ROS can damage cellular components, including lipids, proteins and DNA, triggering an inflammatory response. Chronic oxidative stress can perpetuate inflammation, leading to a cycle of damage
and repair that contributes to various chronic diseases.
Chronic inflammation: A double-edged sword
While acute inflammation is a protective response, chronic inflammation can have severe consequences for health. It can lead to tissue damage, organ dysfunction and the development of several chronic diseases. For example, conditions such as rheumatoid arthritis, inflammatory bowel disease and asthma are characterised by persistent inflammation that damages healthy tissues.
Additionally, chronic inflammation is implicated in the pathogenesis of metabolic disorders like obesity and type 2 diabetes, where low-grade inflammation contributes to insulin resistance and metabolic dysregulation. Understanding the complex mechanisms behind inflammation is vital for developing targeted therapies and personalised health strategies aimed at mitigating its harmful effects.
Adiponectin and Inflammation (ADIPOQ, rs17366568)
- What the ADIPOQ gene does: The ADIPOQ gene encodes adiponectin, an anti-inflammatory hormone produced by fat cells. This hormone plays a pivotal role in regulating glucose levels and fatty acid breakdown, contributing to metabolic health.
- Link to Inflammation: Variants such as GA or AA may indicate low adiponectin levels, while the GG variant is associated with higher levels (protective). Lower adiponectin levels have been linked to increased inflammation and a higher risk of developing cardiovascular diseases. By enhancing insulin sensitivity and exerting anti-inflammatory effects, adiponectin helps to modulate inflammatory responses in the body, highlighting the importance of maintaining optimal adiponectin levels for overall health.
Interleukin 6 and Inflammation (IL6, rs1800795)
- What the IL6 gene does: The IL6 gene encodes interleukin 6 (IL-6), a pro-inflammatory cytokine that acts as a key player in the immune response. It is involved in inflammation, infection response, and the regulation of metabolic processes.
- Link to Inflammation: The GG or GC variants are associated with higher IL-6 levels, while the CC variant may indicate elevated levels. High IL-6 levels are considered a biomarker for inflammation and have been linked to various inflammatory conditions, including cardiovascular diseases and autoimmune disorders. Elevated IL-6 can stimulate the acute phase response, leading to increased inflammation, highlighting the need for monitoring IL-6 levels to assess and manage inflammation effectively, especially in inflammatory and autoimmune conditions.
Vitamin B12 and Inflammation (FUT2)
- What the FUT2 Gene does: The FUT2 gene produces an enzyme called fucosyltransferase 2, which is essential for the absorption and transport of vitamin B12 (also known as cobalamin). Certain variants of this gene, particularly the GG or GA variants, can lead to lower blood levels of vitamin B12. This is especially common in individuals following vegetarian or vegan diets, making them more susceptible to deficiency.
- Link to Inflammation: Vitamin B12 deficiency has been linked to increased levels of inflammatory markers in the body. This can worsen conditions like megaloblastic anaemia, which is characterised by the production of large, ineffective red blood cells. Symptoms of this deficiency may include fatigue, weakness and irritability.
- Research indicates that higher levels of circulating vitamin B12 are associated with lower levels of two key inflammatory markers: IL-6 and C-reactive protein (CRP). In studies involving humans and mice, vitamin B12 has shown potential anti-inflammatory effects by helping to modulate these pro-inflammatory molecules.
- Additionally, vitamin B12 plays a crucial role in converting homocysteine (a marker linked to inflammation and cardiovascular risk) into methionine, an essential amino acid. A deficiency in B12 can lead to elevated homocysteine levels, contributing to inflammation. Furthermore, vitamin B12 is vital for the production of myelin, the protective sheath around nerve fibres. A lack of B12 can result in demyelination, which may trigger inflammatory responses in the central nervous system.
In summary, maintaining sufficient levels of vitamin B12 is essential for cellular health, immune function and optimising the body’s ability to combat inflammation.
Test your B12 levels HERE
Folate and Inflammation (MTHFR, rs1801133)
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What the MTHFR gene does: The MTHFR gene (methylenetetrahydrofolate reductase) encodes an enzyme critical for converting dietary folate into its biologically active form, 5-methyltetrahydrofolate, which is essential for various cellular processes. Genetic variants such as CT or TT reduce the activity of this enzyme, leading to inefficient folate utilisation and an increased risk of deficiency.
- Link to Inflammation: Low folate levels are directly linked to elevated inflammatory markers, which can contribute to the development of cardiovascular diseases and other inflammatory conditions. Individuals carrying these genetic variants may exhibit heightened inflammatory responses, emphasising the need to monitor folate status. Optimal levels of folate are crucial for regulating inflammation as they can help reduceendothelial dysfunction (the impaired functioning of the inner lining of blood vessels) and influence inflammatory processes through mechanisms such as DNA methylation (a process that modifies gene expression) and cell proliferation (the process by which cells divide and multiply). Furthermore, emerging research suggests that adequate concentrations of both folate and vitamin B12 are vital for managing oxidative damage and inflammation, affecting both systemic health and the function of the central nervous system (CNS).
Gluten and Inflammation (HLA, rs2187668 & rs7454108)
- What the HLA genes do: The HLA genes (human leukocyte antigen) encode proteins that comprise the HLA complex, which is essential for proper immune system function. This complex enables the body to differentiate between its own proteins and potentially harmful foreign proteins. Variants such as DQ2 and DQ8 are significant genetic predictors of gluten intolerance, with approximately 99% of individuals diagnosed with coeliac disease and 60% of those with non-coeliac gluten sensitivity (NCGS) carrying these risk alleles.
- Link to Inflammation: Individuals with coeliac disease and NCGS frequently exhibit elevated inflammatory responses, leading to a range of symptoms, including digestive issues, fatigue and suboptimal nutrient absorption. Understanding the connection between these genetic variants and inflammation is crucial for identifying individuals at risk for gluten-related disorders. This knowledge can inform dietary modifications that may alleviate symptoms and improve overall health outcomes.
Test for Coeliac Disease/Gluten Sensitivity HERE
Triglyceride Regulation and Inflammation (ANGPTL3, rs10889353)
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What the ANGPTL3 gene does: The ANGPTL3 gene regulates lipid metabolism by inhibiting the activity of lipoprotein lipase, an enzyme crucial for breaking down triglycerides in the blood.
- Link to Inflammation: Variants such as rs10889353 can lead to elevated triglyceride levels, which are associated with increased inflammatory responses in the body. High triglyceride levels contribute to the development of metabolic syndrome and cardiovascular diseases, underscoring the importance of ANGPTL3 in both lipid regulation and inflammation. Monitoring triglyceride levels is essential for understanding and managing systemic inflammation, providing insights into potential health risks.
Test your Lipid and Cholesterol HERE
Cholesterol Metabolism and Inflammation (APOA5, rs662799)
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What the APOA5 gene does: The APOA5 gene encodes a protein that is essential for the transport and metabolism of lipids, particularly triglycerides and cholesterol, influencing lipid levels in the bloodstream.
- Link to Inflammation: Abnormal cholesterol levels, especially elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, are associated with increased systemic inflammation. Individuals with dysregulated cholesterol metabolism often exhibit high levels of inflammatory markers, highlighting the APOA5 gene's significance in cardiovascular health and its potential involvement in inflammatory processes. Understanding this connection can provide insights into managing inflammation-related health risks.
Test your Lipid and Cholesterol HERE
Glucose Regulation and Chronic Inflammation (ADCY5, rs11708067)
- What the ADCY5 gene does: The ADCY5 gene is involved in glucose metabolism and the secretion of insulin, a hormone that helps regulate blood glucose levels.
- Link to Inflammation: Variants such as rs11708067 can impair an individual's ability to effectively manage blood glucose levels. Poor glucose control is a significant contributor to chronic inflammation, particularly in metabolic disorders like type 2 diabetes. Elevated blood glucose levels can activate inflammatory pathways, leading to the development of insulin resistance and related health complications. This highlights the critical role of ADCY5 in metabolic health and its connection to inflammation.
Test your HbA1C (Blood Glucose Marker) HERE
Insulin Signalling and Inflammation (IRS1, rs2943641)
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What the IRS1 gene does: The IRS1 gene encodes an insulin receptor substrate that is essential for effective insulin signalling and glucose metabolism.
- Link to Inflammation: Variants such as rs2943641 can disrupt insulin signalling, leading to poor glucose control and an increased risk of insulin resistance. This impairment is often associated with chronic inflammation, particularly in individuals with metabolic disorders like type 2 diabetes, where disrupted insulin signalling is prevalent. Understanding the connection between IRS1, insulin resistance, and inflammation can inform strategies to address chronic inflammatory conditions related to metabolic health.
Test your HbA1C (Blood Glucose Marker) HERE
SOD2 Gene: Superoxide Dismutase 2 and Inflammation-Related Oxidative Stress
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What the SOD2 gene does: The SOD2 gene encodes a vital antioxidant enzyme responsible for protecting cells from oxidative stress by converting superoxide radicals into less harmful molecules. However, individuals carrying the CT or TT variants may have reduced activity of the SOD2 enzyme, impairing the body's antioxidant defences.
- Link to Inflammation: When SOD2 activity is diminished, the accumulation of superoxide radicals can lead to increased oxidative stress, which in turn triggers a heightened inflammatory response. This elevated oxidative stress is linked to the development and progression of various inflammatory conditions, including cardiovascular disease and neurodegenerative disorders. Consequently, the SOD2 gene is essential for maintaining cellular health and regulating inflammation, underscoring its significance in preventing chronic inflammatory diseases.
Test your Glutathione Status (master antioxidant which gives an indication of antioxidant capacity) HERE
References
Anthocyanins and Human Health—A Focus on Oxidative Stress, Inflammation and Disease
https://www.mdpi.com/2076-3921/9/5/366
● Assessment of Markers of Gut Integrity and Inflammation in Non-Celiac Gluten Sensitivity After a Gluten Free-Diet https://www.tandfonline.com/doi/full/10.2147/IJGM.S333078
● Chronic tissue inflammation and metabolic disease
https://genesdev.cshlp.org/content/35/5-6/307.short
● Dual role of ANGPTL4 in inflammation https://link.springer.com/article/10.1007/s00011-023-01753-9
● Effects of Whole-Body Adenylyl Cyclase 5 (Adcy5) Deficiency on Systemic Insulin Sensitivity and Adipose Tissue https://www.mdpi.com/1422-0067/22/9/4353
● Folate and Inflammation – links between folate and features of inflammatory conditions
https://www.sciencedirect.com/science/article/pii/S2352385919300209
● Gluten consumption and inflammation affect the development of celiac disease in at‑risk children https://www.nature.com/articles/s41598-022-09232-7.pdf
● Higher circulating vitamin B12 is associated with lower levels of inflammatory markers in individuals at high cardiovascular risk and in naturally aged mice
https://scijournals.onlinelibrary.wiley.com/doi/10.1002/jsfa.12976
● Interleukin-6 signalling in health and disease https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443778/
● Liver X Receptors: Regulators of Cholesterol Metabolism, Inflammation, Autoimmunity, and Cancer
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.584303/full
● Multifaceted Physiological Roles of Adiponectin in Inflammation and Diseases
https://www.mdpi.com/1422-0067/21/4/1219
● Novel relationships between B12, folate and markers of inflammation, oxidative stress and NAD(H) levels, systemically and in the CNS of a healthy human cohort
https://www.tandfonline.com/doi/abs/10.1179/1476830515Y.0000000041
● Pro-Inflammatory Markers Negatively Regulate IRS1 in Endometrial Cells and Endometrium from Women with Obesity and PCOS https://link.springer.com/article/10.1007/s43032-019-00026-3
● The Dietary Intake of Wheat and other Cereal Grains and Their Role in Inflammation
https://www.mdpi.com/2072-6643/5/3/771
● Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages https://www.pnas.org/doi/abs/10.1073/pnas.2114739119
