What you carry at this position in your DNA and what research says about it.
Cholesterol and Statin Response: 10/10 evidence, 24 publications.
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Sample genotype (not yours): A/A
Lower Cholesterol and Enhanced Statin Benefit
This genotype is associated with naturally lower LDL cholesterol levels. It also predicts a significantly stronger reduction in colorectal cancer risk when taking statins.
What this genotype means: Lower baseline LDL cholesterol; Enhanced protective response to statins.
Sample genotype (not yours): A/T
Typical Cholesterol and Moderate Statin Benefit
This genotype is linked to average baseline cholesterol levels. It is associated with a moderate, typical protective benefit from statin therapy.
What this genotype means: Typical baseline cholesterol levels; Standard response to statin therapy.
Sample genotype (not yours): T/T
Higher Cholesterol and Weaker Statin Benefit
This genotype is associated with higher baseline LDL cholesterol levels. It also predicts a less pronounced reduction in colorectal cancer risk from statins.
What this genotype means: Higher baseline LDL cholesterol; Attenuated protective response to statins.
Gene function and biological role
Gene Function: The HMGCR gene encodes 3-hydroxy-3-methylglutaryl-CoA reductase, which is the rate-limiting enzyme in cholesterol biosynthesis [1]. This enzyme is the primary therapeutic target for statins, a widely prescribed class of lipid-lowering medications [2]. By inhibiting HMGCR, statins reduce endogenous cholesterol production in the liver and increase the clearance of circulating low-density lipoprotein [2]. Beyond cardiovascular health, HMGCR activity and its inhibition by statins have been implicated in modifying the risk of certain cancers, particularly colorectal cancer [2].
Variant Impact: The rs12654264 variant is an intronic change within the HMGCR gene that is strongly associated with circulating lipid levels [1]. This genetic variation is in tight linkage disequilibrium with functional variants that alter the alternative splicing of HMGCR mRNA [1]. Specifically, it influences the splicing of exon 12 and exon 13, which are critical components of the statin-binding domain of the enzyme [2]. Consequently, this single nucleotide polymorphism modifies both baseline cholesterol levels and individual sensitivity to statin therapy [2].
Key Insight: This variant acts as a genetic modifier that determines how effectively statins can lower colorectal cancer risk, showing that cardiovascular drugs can have profound chemopreventive interactions based on your DNA.
Location: HMGCR. Chromosome 5 · 5q13.3 · 75.4 Mb
Estimated prevalence by population
Global 38.5%; European 38.5%; African 45.6%; East Asian 21.9%; South Asian 17.6%; Americas 37.9%; Ashkenazi 29.1%; Finnish 31.4%; Middle Eastern 45.8%; Amish 38.8%.
Estimated AA genotype frequency.
Global 46.6%; European 47.1%; African 43.8%; East Asian 49.8%; South Asian 48.7%; Americas 47.3%; Ashkenazi 49.7%; Finnish 49.3%; Middle Eastern 43.7%; Amish 47.0%.
Estimated AT genotype frequency.
Global 14.9%; European 14.4%; African 10.5%; East Asian 28.3%; South Asian 33.6%; Americas 14.7%; Ashkenazi 21.2%; Finnish 19.3%; Middle Eastern 10.4%; Amish 14.2%.
Estimated TT genotype frequency.
Showing effects for A/A genotype
Cardiovascular & Metabolic
Lipids & Cholesterol
LDL Cholesterol. Evidence: 10/10. Source: PMID 18193044. Lower LDL.
Total Cholesterol. Evidence: 10/10. Source: PMID 31217584. Lower Total.
VLDL Cholesterol. Evidence: 8/10. Source: PMID 38448586. Lower VLDL.
Pharmacogenomics
Lipid-Lowering Drug Response
Statin Cancer Benefit. Evidence: 5/10. Source: PMID 20403997. Stronger Benefit.
Showing effects for A/T genotype
LDL Cholesterol. Evidence: 10/10. Source: PMID 18193044. Typical LDL.
Total Cholesterol. Evidence: 10/10. Source: PMID 31217584. Typical Total.
VLDL Cholesterol. Evidence: 8/10. Source: PMID 38448586. Typical VLDL.
Statin Cancer Benefit. Evidence: 5/10. Source: PMID 20403997. Moderate Benefit.
Showing effects for T/T genotype
LDL Cholesterol. Evidence: 10/10. Source: PMID 18193044. Higher LDL.
Total Cholesterol. Evidence: 10/10. Source: PMID 31217584. Higher Total.
VLDL Cholesterol. Evidence: 8/10. Source: PMID 38448586. Higher VLDL.
Statin Cancer Benefit. Evidence: 5/10. Source: PMID 20403997. Weaker Benefit.
What this genotype means for the people who carry it
Sample genotype: AA (Homozygous)
Clinical studies show that individuals with the A/A genotype tend to have lower baseline levels of low-density lipoprotein and total cholesterol [1]. When treated with statins, cells with this genotype demonstrate a highly pronounced reduction in cholesterol synthesis [2]. This enhanced sensitivity translates to a substantial clinical advantage. Research indicates that long-term statin users with the A/A genotype experience an impressive seventy percent reduction in colorectal cancer risk compared to non-users [2]. This protective effect is much stronger than that observed in individuals carrying the T allele [2].
Lower baseline LDL cholesterol; Enhanced protective response to statins.
Sample genotype: AT (Heterozygous)
Carrying one copy of each allele generally results in intermediate baseline lipid profiles [1]. Low-density lipoprotein and total cholesterol levels typically fall within the average range for the population [1]. In terms of pharmacogenomics, individuals with the A/T genotype experience a moderate reduction in colorectal cancer risk when taking statins [2]. This response lies between the highly sensitive A/A genotype and the less responsive T/T genotype [2]. Standard cardiovascular benefits from statin therapy remain highly effective for this group [2].
Typical baseline cholesterol levels; Standard response to statin therapy.
Sample genotype: TT (Homozygous)
Individuals carrying two copies of the T allele typically exhibit higher baseline levels of circulating low-density lipoprotein and total cholesterol [1]. This increase is driven by alternative splicing of the HMGCR gene, which affects the statin-binding domain of the enzyme [1]. Consequently, the T/T genotype is associated with reduced sensitivity to the lipid-lowering and chemopreventive mechanisms of statins [2]. While statins still provide cardiovascular protection, the associated reduction in colorectal cancer risk is significantly weaker in T/T carriers compared to those with the A/A genotype [2]. Managing cholesterol through comprehensive lifestyle and therapeutic strategies remains important for this group [2].
Higher baseline LDL cholesterol; Attenuated protective response to statins.
Variants with shared genetic architecture
rs12916 · HMGCR Gene · Chr 5 · LDL Cholesterol Levels
rs3846662 · HMGCR Gene · Chr 5 · Cholesterol and Statin Response
rs3846663 · HMGCR Gene · Chr 5 · Cholesterol Levels
Content updated August 2026.
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