What you carry at this position in your DNA and what research says about it.
Heart Disease Risk: 8/10 evidence, 56 publications.
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Sample genotype (not yours): C/C
Lower Cholesterol and Heart Risk
Carrying two copies of the protective C allele is linked to significantly lower LDL cholesterol levels. This genotype is also associated with a reduced risk of heart disease and a better response to statin medications.
What this genotype means: Significantly lower LDL cholesterol levels; Reduced risk of coronary artery disease; Enhanced response to statin therapy.
Sample genotype (not yours): C/T
Carrying one copy of the protective C allele is associated with lower LDL cholesterol levels. This genotype is linked to a reduced risk of heart disease and improved response to statin therapy compared to the typical genotype.
What this genotype means: Lower LDL and total cholesterol; Decreased risk of cardiovascular events; Improved response to statins.
Sample genotype (not yours): T/T
Typical Cholesterol and Higher Heart Risk
Carrying two copies of the T allele is associated with higher LDL cholesterol and a 1.2x increased risk of coronary artery disease. This common genotype represents the baseline response to statin medications.
What this genotype means: Higher circulating LDL cholesterol; Increased risk of coronary artery disease; Standard response to statin therapy.
Gene function and biological role
Gene Function: The CELSR2 gene is located in a highly studied region on chromosome 1p13.3 that also contains the PSRC1 and SORT1 genes [1]. This specific gene cluster is widely recognized for having the strongest genetic influence on blood cholesterol levels in the human genome [2]. CELSR2 is co-expressed with sortilin, a protein that plays a critical role in sorting and transporting lipids within liver cells [3]. Changes in this gene cluster directly alter how efficiently the liver clears low-density lipoprotein (LDL) cholesterol from the bloodstream [4].
Variant Impact: The rs646776 variant is a DNA change located downstream of the CELSR2 gene that acts as a powerful regulator of neighboring genes, particularly SORT1 [3]. The major T allele is associated with lower liver expression of sortilin, which reduces the liver's ability to clear LDL cholesterol from circulation [4]. Conversely, the minor C allele increases sortilin expression, leading to more efficient cholesterol clearance [1]. This single nucleotide change has a cascading effect on multiple lipid markers and overall cardiovascular health [5].
Key Insight: This variant belongs to the 1p13.3 locus, which has the strongest known association with LDL cholesterol levels in the entire human genome. Carrying the protective C allele not only lowers baseline cholesterol but also enhances the cholesterol-lowering efficacy of statin medications.
Location: CELSR2. Chromosome 1 · 1p13.3 · 109.3 Mb
Estimated prevalence by population
Global 6.9%; European 4.9%; African 12.5%; East Asian 0.4%; South Asian 6.1%; Americas 5.0%; Ashkenazi 2.9%; Finnish 4.9%; Middle Eastern 1.3%; Amish 10.8%.
Estimated CC genotype frequency.
Global 36.7%; European 34.5%; African 45.7%; East Asian 11.9%; South Asian 37.1%; Americas 34.7%; Ashkenazi 28.2%; Finnish 34.5%; Middle Eastern 19.9%; Amish 44.1%.
Estimated CT genotype frequency.
Global 56.4%; European 60.6%; African 41.8%; East Asian 87.7%; South Asian 56.8%; Americas 60.4%; Ashkenazi 68.9%; Finnish 60.6%; Middle Eastern 78.8%; Amish 45.2%.
Estimated TT genotype frequency.
Showing effects for C/C genotype
Cardiovascular & Metabolic
Lipids & Cholesterol
LDL Cholesterol. Evidence: 10/10. Source: PMID 18193044. Lower LDL.
Heart Disease
Coronary Artery Disease. Evidence: 8/10. Source: PMID 21239051. Reduced Risk.
Heart Attack. Evidence: 8/10. Source: PMID 19198609. Reduced Risk.
Pharmacogenomics
Lipid-Lowering Drug Response
Statin Response. Evidence: 8/10. Source: PMID 25350695. Stronger Response.
Showing effects for C/T genotype
Showing effects for T/T genotype
LDL Cholesterol. Evidence: 10/10. Source: PMID 18193044. ~0.17 mmol/L Higher.
Coronary Artery Disease. Evidence: 8/10. Source: PMID 21239051. ~1.2x Increased Risk.
Heart Attack. Evidence: 8/10. Source: PMID 19198609. ~1.19x Increased Risk.
Statin Response. Evidence: 8/10. Source: PMID 25350695. Typical Response.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Having two copies of the protective C allele is associated with highly efficient clearance of low-density lipoprotein (LDL) cholesterol from the blood [1]. This efficient clearance is driven by increased expression of the sortilin protein in the liver, which helps remove cholesterol-carrying particles from circulation [2]. As a result, individuals with this genotype typically have lower total cholesterol and triglyceride levels [3]. This favorable lipid profile translates into a significantly reduced risk of coronary artery disease and heart attacks [4]. Additionally, clinical studies suggest that carriers of this protective allele experience a more pronounced reduction in LDL cholesterol when treated with statin medications [5].
Significantly lower LDL cholesterol levels; Reduced risk of coronary artery disease; Enhanced response to statin therapy.
Sample genotype: CT (Heterozygous)
Carrying one copy of the protective C allele provides a significant advantage in lipid metabolism compared to the common T/T genotype [1]. This genetic profile is associated with lower circulating levels of LDL cholesterol and total cholesterol [2]. The presence of the C allele increases the liver's expression of sortilin, enhancing its capacity to bind and clear atherogenic lipoproteins [3]. Consequently, individuals with this genotype have a lower risk of developing coronary artery disease and experiencing myocardial infarction [4]. Furthermore, research indicates that this genotype is associated with a better therapeutic response to HMG-CoA reductase inhibitors, commonly known as statins [5].
Lower LDL and total cholesterol; Decreased risk of cardiovascular events; Improved response to statins.
Sample genotype: TT (Homozygous)
Carrying two copies of the T allele is the most common genetic profile globally and is associated with higher levels of circulating LDL cholesterol [1]. This genotype leads to lower expression of sortilin in the liver, which reduces the rate at which cholesterol-carrying particles are cleared from the bloodstream [2]. Over time, elevated LDL and total cholesterol levels contribute to the buildup of arterial plaque [3]. Consequently, this genotype is associated with a 1.2-fold increased risk of coronary artery disease and a higher likelihood of myocardial infarction [4]. While this represents the typical baseline risk, individuals with this genotype may require more proactive lifestyle or therapeutic interventions to maintain optimal cardiovascular health [5].
Higher circulating LDL cholesterol; Increased risk of coronary artery disease; Standard response to statin therapy.
Variants with shared genetic architecture
rs12740374 · CELSR2 Gene · Chr 1 · Heart Disease and Cholesterol
rs629301 · CELSR2 Gene · Chr 1 · Cholesterol and Heart Risk
rs660240 · CELSR2 Gene · Chr 1 · LDL Cholesterol Levels
Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.
Content updated August 2026.
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