What you carry at this position in your DNA and what research says about it.
Bone and Heart Health: 8/10 evidence, 58 publications.
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Sample genotype (not yours): T/T
Lower Heart Risk and Better Drug Response
Estrogen receptors function at a baseline level that supports cardiovascular protection. This genotype is associated with a lower risk of coronary artery disease and better responses to certain medications.
What this genotype means: Lower risk of coronary artery disease; Better response to leflunomide; Typical risk of joint pain on aromatase inhibitors.
Sample genotype (not yours): C/C
Higher Bone Density but Elevated Heart Risk
Estrogen receptor sensitivity is shifted to favor bone strength over cardiovascular protection. This genotype presents a clear trade-off between stronger bones and higher heart risks.
What this genotype means: Higher bone mineral density; Increased risk of myocardial infarction; Increased risk of musculoskeletal pain on aromatase inhibitors.
Sample genotype (not yours): T/C
Intermediate Heart Risk and Bone Density
Estrogen sensitivity is moderately altered, balancing bone and heart phenotypes. This genotype presents a blend of typical bone density and slightly elevated cardiovascular risk.
What this genotype means: Slightly higher bone mineral density; Slightly elevated risk of coronary artery disease; Increased risk of musculoskeletal pain on aromatase inhibitors.
Gene function and biological role
Gene Function: The ESR1 gene encodes estrogen receptor alpha, a key protein that mediates the biological effects of estrogen in the body [1]. Estrogen signaling through this receptor is essential for maintaining bone mineral density and regulating bone remodeling [2]. In the cardiovascular system, the receptor helps protect blood vessels and regulate lipid levels [3]. It also plays a significant role in reproductive health, metabolic function, and emotional well-being [4].
Variant Impact: Located in the first intron of the ESR1 gene, rs2234693 is a common genetic change often referred to as the PvuII variation [5]. While it does not change the structure of the estrogen receptor protein itself, it is thought to alter gene expression and mRNA splicing [6]. This alteration changes how sensitive tissues are to circulating estrogen levels [7]. As a result, this variant is widely studied for its influence on bone strength, heart health, and response to hormone-related medications [8].
Key Insight: This single genetic letter change acts as a biological trade-off, where the version that protects heart health also leads to slightly lower bone density.
Location: ESR1. Chromosome 6 · 6q25.1 · 151.8 Mb
Estimated prevalence by population
Global 28.9%; European 28.9%; African 21.3%; East Asian 36.5%; South Asian 32.5%; Americas 40.3%; Ashkenazi 29.5%; Finnish 36.4%; Middle Eastern 31.2%; Amish 24.0%.
Estimated TT genotype frequency.
Global 49.1%; European 49.7%; African 49.7%; East Asian 47.8%; South Asian 49.0%; Americas 46.3%; Ashkenazi 49.6%; Finnish 47.9%; Middle Eastern 49.3%; Amish 50.0%.
Estimated TC genotype frequency.
Global 22.0%; European 21.4%; African 29.0%; East Asian 15.6%; South Asian 18.5%; Americas 13.3%; Ashkenazi 20.9%; Finnish 15.7%; Middle Eastern 19.5%; Amish 26.0%.
Estimated CC genotype frequency.
Showing effects for T/T genotype
Organ Systems
Bone, Joint & Connective Tissue Health
Bone Mineral Density. Evidence: 8/10. Source: PMID 30048462. Typical Density.
Cardiovascular & Metabolic
Heart Disease
Heart Disease. Evidence: 4/10. Source: PMID 32682401. Lower Risk.
Pharmacogenomics
Chemotherapy Response
Aromatase Inhibitor Joint Pain. Evidence: 5/10. Source: PMID 23894347. Typical Risk.
Immunosuppressant & Biologic Response
Leflunomide Response. Evidence: 5/10. Source: PMID 21174621. Stronger Response.
Showing effects for C/C genotype
Bone Mineral Density. Evidence: 8/10. Source: PMID 30048462. Higher Density.
Heart Disease. Evidence: 4/10. Source: PMID 32682401. Higher Risk.
Aromatase Inhibitor Joint Pain. Evidence: 5/10. Source: PMID 23894347. Increased Pain Risk.
Leflunomide Response. Evidence: 5/10. Source: PMID 21174621. Typical Response.
Showing effects for T/C genotype
Bone Mineral Density. Evidence: 8/10. Source: PMID 30048462. Slightly Higher.
Heart Disease. Evidence: 4/10. Source: PMID 32682401. Slightly Higher Risk.
What this genotype means for the people who carry it
Sample genotype: TT (Homozygous)
Cardiovascular health is highly supported by this genotype, which is consistently linked to a lower risk of myocardial infarction and coronary artery disease [1]. Research indicates that blood vessels maintain typical endothelial function and healthy lipid profiles with this genetic profile [2]. While bone mineral density may be slightly lower compared to other genotypes, the overall risk of fractures remains within typical ranges [3]. Additionally, individuals with this genotype show a significantly better therapeutic response to the rheumatoid arthritis medication leflunomide [4]. There is also a lower likelihood of experiencing joint and muscle pain if taking aromatase inhibitors for breast cancer therapy [5].
Lower risk of coronary artery disease; Better response to leflunomide; Typical risk of joint pain on aromatase inhibitors.
Sample genotype: CC (Homozygous)
Skeletal strength is highly supported by this genotype, which is strongly associated with higher heel bone mineral density and a lower risk of osteoporosis [1]. However, this benefit comes with a trade-off, as the C allele is a recognized risk factor for myocardial infarction and coronary artery disease [2]. Estrogen's protective effects on the blood vessel walls may be less pronounced with this variation [3]. Furthermore, individuals with this genotype are more susceptible to severe joint and muscle pain when taking aromatase inhibitors for breast cancer [4]. Response to rheumatoid arthritis treatments like leflunomide is also typical rather than enhanced [5].
Higher bone mineral density; Increased risk of myocardial infarction; Increased risk of musculoskeletal pain on aromatase inhibitors.
Sample genotype: TC (Heterozygous)
A balanced genetic profile is observed here, showing intermediate effects across both bone and cardiovascular systems [1]. Bone mineral density is slightly higher than the baseline genotype, providing moderate skeletal support [2]. However, there is a minor increase in the risk of coronary artery disease compared to the T/T genotype [3]. If undergoing breast cancer treatment with aromatase inhibitors like anastrozole or letrozole, there is an increased risk of developing musculoskeletal pain [4]. Response to other medications, such as leflunomide for rheumatoid arthritis, is generally typical rather than enhanced [5].
Slightly higher bone mineral density; Slightly elevated risk of coronary artery disease; Increased risk of musculoskeletal pain on aromatase inhibitors.
Variants with shared genetic architecture
rs2046210 · ESR1 Gene · Chr 6 · Breast Cancer Risk
rs2077647 · ESR1 Gene · Chr 6 · Blood Pressure
rs2228480 · ESR1 Gene · Chr 6 · Estrogen Receptor Health
An atlas of genetic influences on osteoporosis in humans and mice.
Estrogen receptor gene variants are associated with anxiety disorders in older women.
Association between estrogen receptor alpha gene variation and cardiovascular disease.
Content updated August 2026.
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