What you carry at this position in your DNA and what research says about it.
Infection and Heart Risk: 8/10 evidence, 66 publications.
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Sample genotype (not yours): A/A
Typical Inflammatory Response
This genotype represents the standard, fully functional version of the TLR4 receptor. It provides robust defense against bacterial infections but maintains typical baseline levels of inflammation.
What this genotype means: Robust defense against bacterial pathogens; Typical baseline risk of chronic inflammatory conditions; Standard response to statin medications.
Sample genotype (not yours): A/G
Dampened Inflammation and Higher Infection Risk
Carrying one copy of the G allele results in a blunted inflammatory response. This provides protection against heart disease but increases susceptibility to severe bacterial infections.
What this genotype means: Lower risk of chronic vascular inflammation; Increased susceptibility to severe bacterial infections; Enhanced cardiovascular benefit from pravastatin therapy.
Sample genotype (not yours): G/G
Significantly Dampened Inflammation and Higher Infection Risk
Carrying two copies of the G allele significantly blunts your body's inflammatory response. This offers strong protection against cardiovascular disease but elevates the risk of severe infections.
What this genotype means: Significantly reduced vascular inflammation; Elevated risk of severe bacterial and viral infections; Altered response to statins and immunosuppressive therapies.
Gene function and biological role
Gene Function: The TLR4 gene encodes toll-like receptor 4, a critical sentinel of the innate immune system [1]. This receptor detects lipopolysaccharide, a component found on the outer membrane of Gram-negative bacteria [1]. Upon activation, TLR4 triggers a signaling cascade that releases pro-inflammatory cytokines to fight off the invading pathogens [2]. However, excessive or prolonged TLR4 activation can lead to systemic inflammation, which contributes to chronic conditions like cardiovascular disease [3]. Thus, TLR4 acts as a double-edged sword, balancing defense against infections with the risk of inflammatory tissue damage.
Variant Impact: The rs4986790 variant, also known as Asp299Gly, is a missense mutation in the third exon of the TLR4 gene [1]. This genetic change replaces the amino acid aspartate with glycine at position 299 of the receptor's extracellular domain [1]. This structural alteration blunts the receptor's ability to recognize bacterial endotoxins, resulting in a dampened inflammatory response [3]. Consequently, individuals carrying this variant exhibit lower levels of systemic inflammation but may have a reduced capacity to clear certain pathogens [3]. This functional shift influences susceptibility to both infectious diseases and chronic inflammatory conditions [4].
Key Insight: This variant represents an evolutionary trade-off where a dampened immune response protects the cardiovascular system from chronic inflammatory damage but leaves the body more vulnerable to severe bacterial infections.
Location: TLR4. Chromosome 9 · 9q33.1 · 117.7 Mb
Origin Story: The Asp299Gly variant is highly prevalent in sub-Saharan Africa, where evolutionary pressure from malaria is thought to have selected for it because carriers have a lower risk of dying from cerebral malaria, despite having higher overall parasite levels.
Estimated prevalence by population
Global 87.3%; European 88.1%; African 85.2%; East Asian 99.8%; South Asian 77.4%; Americas 91.0%; Ashkenazi 86.5%; Finnish 81.9%; Middle Eastern 93.3%; Amish 99.8%.
Estimated AA genotype frequency.
Global 12.2%; European 11.5%; African 14.2%; East Asian 0.2%; South Asian 21.2%; Americas 8.8%; Ashkenazi 13.0%; Finnish 17.2%; Middle Eastern 6.6%; Amish 0.2%.
Estimated AG genotype frequency.
Global 0.5%; European 0.4%; African 0.6%; East Asian < 0.1%; South Asian 1.4%; Americas 0.2%; Ashkenazi 0.5%; Finnish 0.9%; Middle Eastern 0.1%; Amish < 0.1%.
Estimated GG genotype frequency.
Showing effects for A/A genotype
Cardiovascular & Metabolic
Heart Disease
Heart Disease. Evidence: 3/10. Source: PMID 12124407. Typical Risk.
Immunity & Inflammation
Infection Susceptibility & Resistance
Bacterial Infection Risk. Evidence: 3/10. Source: PMID 10835634. Typical Risk.
Chronic Inflammatory Diseases
Inflammatory Bowel Disease. Evidence: 8/10. Source: PMID 26974007. Typical Risk.
Pharmacogenomics
Lipid-Lowering Drug Response
Statin Response. Evidence: 5/10. Source: PMID 12742999. Typical Response.
Showing effects for A/G genotype
Heart Disease. Evidence: 3/10. Source: PMID 12124407. Lower Risk.
Bacterial Infection Risk. Evidence: 3/10. Source: PMID 10835634. Increased Risk.
Inflammatory Bowel Disease. Evidence: 8/10. Source: PMID 26974007. Altered Risk.
Statin Response. Evidence: 5/10. Source: PMID 12742999. Enhanced Benefit.
Showing effects for G/G genotype
What this genotype means for the people who carry it
Sample genotype: AA (Homozygous)
Having two copies of the common A allele means your body produces the standard toll-like receptor 4 protein [1]. This receptor responds fully to bacterial endotoxins, mounting a strong and rapid inflammatory defense when pathogens are detected [1]. While this active immune response is highly effective at clearing infections, it can also contribute to chronic vascular inflammation over time [2]. Studies suggest that individuals with this typical genotype do not experience the reduced risk of atherosclerosis seen in variant carriers [2]. Additionally, standard cardiovascular therapies like statins show typical, expected efficacy without the modified risk profiles observed in other genotypes [3].
Robust defense against bacterial pathogens; Typical baseline risk of chronic inflammatory conditions; Standard response to statin medications.
Sample genotype: AG (Heterozygous)
Carrying one copy of the G allele alters the structure of the TLR4 receptor, leading to a blunted response to bacterial endotoxins [1]. This dampened inflammatory state is associated with a lower risk of developing atherosclerosis and coronary artery disease [2]. However, the weaker immune response makes carriers more vulnerable to severe infections, such as Gram-negative bacterial sepsis and respiratory syncytial virus [1]. Clinical studies also indicate that G allele carriers may experience a significantly greater reduction in cardiovascular events when taking pravastatin [3]. On the other hand, this genotype is linked to an increased risk of side effects from medications like methotrexate [4].
Lower risk of chronic vascular inflammation; Increased susceptibility to severe bacterial infections; Enhanced cardiovascular benefit from pravastatin therapy.
Sample genotype: GG (Homozygous)
Having two copies of the G allele means all of your TLR4 receptors have the altered Asp299Gly structure, leading to a highly blunted response to bacterial endotoxins [1]. This significantly reduces systemic inflammation, which is highly protective against chronic conditions like atherosclerosis and heart attacks [2]. However, this compromised immune signaling substantially increases the risk of severe Gram-negative bacterial infections and septic shock [1]. Research also shows that individuals with this genotype may have a modified response to certain drugs, including a higher risk of side effects from methotrexate [3]. Furthermore, studies indicate that G/G carriers may experience an enhanced protective effect against cardiovascular events when treated with statins like pravastatin [4].
Significantly reduced vascular inflammation; Elevated risk of severe bacterial and viral infections; Altered response to statins and immunosuppressive therapies.
Variants with shared genetic architecture
rs1928295 · TLR4 Gene · Chr 9 · Weight and Obesity Risk
rs1927911 · TLR4 Gene · Chr 9 · Heart Attack Risk
rs4986791 · TLR4 Gene · Chr 9 · Infection and Immune Response
TLR4 mutations are associated with endotoxin hyporesponsiveness in humans.
Toll-like receptor 4 polymorphisms and atherogenesis.
Role of Toll-like receptor 4 in acute myocardial infarction and longevity.
Functional polymorphisms and methotrexate treatment outcome in recent-onset rheumatoid arthritis.
Content updated August 2026.
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