What you carry at this position in your DNA and what research says about it.
Infection and Immune Response: 5/10 evidence, 56 publications.
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Sample genotype (not yours): C/C
Typical Infection Risk and Standard Immune Response
Standard Toll-like receptor activity ensures a fully functional early-warning system against bacterial pathogens. This keeps the risk of severe infections and complications at baseline levels.
What this genotype means: Typical susceptibility to bacterial and viral infections; Standard response to anti-inflammatory medications.
Sample genotype (not yours): C/T
Altered Immune Response and Higher Infection Risk
A single copy of the variant dampens the immediate inflammatory response to bacteria. This reduces chronic vascular inflammation but increases susceptibility to severe infections.
What this genotype means: Increased risk of bacterial and respiratory infections; Slightly lower risk of carotid artery narrowing; Potentially reduced response to prednisolone.
Sample genotype (not yours): T/T
Dampened Immune Response and Elevated Infection Risk
Two copies of the variant significantly blunt the body's early response to bacterial toxins. This offers protection against arterial narrowing but raises the risk of severe infections.
What this genotype means: Higher susceptibility to severe bacterial infections and septic shock; Lower risk of carotid artery narrowing; Reduced response to prednisolone.
Gene function and biological role
Gene Function: The TLR4 gene encodes Toll-like receptor 4, a critical pattern recognition receptor in the innate immune system [1]. This receptor is primarily responsible for detecting lipopolysaccharides, which are major components of Gram-negative bacterial cell walls [1]. Upon activation, it triggers intracellular signaling cascades that lead to the production of pro-inflammatory cytokines [2]. This rapid response is essential for initiating the body's defense against bacterial pathogens and coordinating adaptive immunity. However, excessive or dysregulated TLR4 signaling can contribute to chronic inflammatory diseases and sepsis.
Variant Impact: The rs4986791 variant results in a missense mutation that changes the amino acid at position 399 of the TLR4 protein from threonine to isoleucine [1]. This structural alteration occurs in the extracellular domain of the receptor, directly affecting its ability to interact with bacterial endotoxins [1]. As a result, the variant receptor exhibits a blunted response to microbial triggers, leading to a state of endotoxin hyporesponsiveness [1]. This altered signaling profile influences susceptibility to various infectious diseases, inflammatory conditions, and certain drug responses [3].
Key Insight: This variant causes a structural change in the immune system's early warning system, making the body less sensitive to bacterial toxins. While this dampens the immediate inflammatory response and protects against some chronic vascular diseases, it increases vulnerability to severe infections.
Location: TLR4. Chromosome 9 · 9q33.1 · 117.7 Mb
Estimated prevalence by population
Global 90.5%; European 87.6%; African 96.9%; East Asian 99.8%; South Asian 78.7%; Americas 92.0%; Ashkenazi 90.0%; Finnish 81.7%; Middle Eastern 93.3%; Amish 92.9%.
Estimated CC genotype frequency.
Global 9.2%; European 12.0%; African 3.0%; East Asian 0.2%; South Asian 20.0%; Americas 7.8%; Ashkenazi 9.7%; Finnish 17.4%; Middle Eastern 6.6%; Amish 7.0%.
Estimated CT genotype frequency.
Global 0.3%; European 0.4%; African < 0.1%; East Asian < 0.1%; South Asian 1.3%; Americas 0.2%; Ashkenazi 0.3%; Finnish 0.9%; Middle Eastern 0.1%; Amish 0.1%.
Estimated TT genotype frequency.
Showing effects for C/C genotype
Immunity & Inflammation
Infection Susceptibility & Resistance
Bacterial Infection Risk. Evidence: 3/10. Source: PMID 23867959. Typical Risk.
Septic Shock. Evidence: 3/10. Source: PMID 20525286. Typical Risk.
Respiratory Virus Risk. Evidence: 3/10. Source: PMID 21837802. Typical Risk.
Pharmacogenomics
Immunosuppressant & Biologic Response
Prednisolone Response. Evidence: 5/10. Source: PMID 37638833. Typical Response.
Cardiovascular & Metabolic
Vascular Health & Aneurysm
Carotid Stenosis. Evidence: 3/10. Source: PMID 12124407. Typical Risk.
Showing effects for C/T genotype
Bacterial Infection Risk. Evidence: 3/10. Source: PMID 23867959. Increased Risk.
Septic Shock. Evidence: 3/10. Source: PMID 20525286. Increased Risk.
Respiratory Virus Risk. Evidence: 3/10. Source: PMID 21837802. Increased Risk.
Prednisolone Response. Evidence: 5/10. Source: PMID 37638833. Poorer Response.
Carotid Stenosis. Evidence: 3/10. Source: PMID 12124407. Lower Risk.
Showing effects for T/T genotype
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Standard Toll-like receptor 4 activity ensures a robust, typical response to bacterial endotoxins and other pathogens [1]. This active defense mechanism helps clear infections efficiently, keeping the risk of severe complications like septic shock at baseline levels [2]. While a strong immune response is generally protective against external threats, it can also contribute to typical levels of systemic inflammation, which is a standard factor in long-term cardiovascular health [3]. Innate immune cells utilize this fully functional receptor to quickly detect Gram-negative bacteria. This allows immune cells to quickly release cytokines to recruit help and contain localized infections before they spread. However, this highly active response can sometimes lead to more severe symptoms during minor infections as the body mounts a vigorous defense. In terms of medical treatments, this standard receptor structure is associated with a typical, expected response to anti-inflammatory medications like prednisolone [4]. Overall, this represents the most common and evolutionary balanced immune profile.
Typical susceptibility to bacterial and viral infections; Standard response to anti-inflammatory medications.
Sample genotype: CT (Heterozygous)
A single copy of the isoleucine variant alters the structure of the Toll-like receptor 4, leading to a milder inflammatory response when encountering bacterial endotoxins [1]. This reduced sensitivity can make it harder for the body to quickly detect and clear certain pathogens, resulting in an increased susceptibility to severe bacterial infections and respiratory viruses [2]. However, this dampened inflammatory signaling may offer a protective effect against chronic inflammatory conditions, such as a lower risk of carotid artery narrowing [3]. Immune cells carrying this mixed receptor profile show a blunted release of inflammatory cytokines when exposed to environmental triggers. While this helps prevent the blood vessels from developing severe plaque buildup, it leaves the respiratory and urinary tracts more vulnerable to persistent colonization. Clinical studies also suggest that this altered receptor structure might correlate with a poorer response to corticosteroid therapies like prednisolone [4]. Pregnant individuals with this genetic profile may also face a slightly higher risk of premature birth due to altered local inflammatory regulation in the reproductive tract. This combination of traits represents a classic evolutionary trade-off between acute infectious defense and long-term inflammatory protection.
Increased risk of bacterial and respiratory infections; Slightly lower risk of carotid artery narrowing; Potentially reduced response to prednisolone.
Sample genotype: TT (Homozygous)
Presence of two copies of the isoleucine variant significantly dampens the body's innate immune response to bacterial endotoxins [1]. This state of hyporesponsiveness reduces the immediate inflammatory surge but increases the risk of deep-seated bacterial infections, respiratory syncytial virus, and septic shock [2]. On the other hand, the reduction in chronic vascular inflammation is associated with a lower incidence of carotid stenosis, demonstrating a clear trade-off between acute defense and long-term inflammatory wear [3]. The structural change in the receptor prevents it from binding effectively to microbial components, which delays the activation of downstream inflammatory pathways. Because the immune system does not sound the alarm quickly, pathogens can multiply more easily before a full defense is mounted. This genetic profile is also linked to a significantly reduced response to prednisolone, meaning standard anti-inflammatory treatments may be less effective [4]. Additionally, the altered inflammatory environment in the reproductive tract is associated with an elevated risk of premature birth. Ultimately, this genotype represents the most pronounced shift away from standard immune surveillance toward a highly dampened inflammatory state.
Higher susceptibility to severe bacterial infections and septic shock; Lower risk of carotid artery narrowing; Reduced response to prednisolone.
Variants with shared genetic architecture
rs1928295 · TLR4 Gene · Chr 9 · Weight and Obesity Risk
rs4986790 · TLR4 Gene · Chr 9 · Infection and Heart Risk
rs1927911 · TLR4 Gene · Chr 9 · Heart Attack Risk
TLR4 mutations are associated with endotoxin hyporesponsiveness in humans.
Toll-like receptor 4 polymorphisms and atherogenesis.
Content updated August 2026.
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