What you carry at this position in your DNA and what research says about it.
Cholesterol and Statin Response: 10/10 evidence, 15 publications.
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Sample genotype (not yours): A/A
Lower Baseline Cholesterol and Reduced Statin Response
Naturally lower LDL and total cholesterol levels characterize this genetic profile. However, a reduced response to statin medications is also common.
What this genotype means: Naturally lower LDL cholesterol levels; Lower risk of late-onset Alzheimer's disease; Reduced cholesterol-lowering response to statins.
Sample genotype (not yours): A/G
Typical Cholesterol Levels and Standard Statin Response
Typical baseline cholesterol levels and a standard response to statin medications are expected. Standard cardiovascular prevention strategies remain highly effective.
What this genotype means: Typical baseline LDL cholesterol levels; Standard response to statin medications; Average risk of late-onset Alzheimer's disease.
Sample genotype (not yours): G/G
Higher Baseline Cholesterol and Excellent Statin Response
Higher baseline LDL cholesterol levels and an increased risk of Alzheimer's disease are associated with this profile. Fortunately, response to statin medications is typically excellent.
What this genotype means: Higher baseline LDL cholesterol levels; Increased risk of late-onset Alzheimer's disease; Highly effective response to statin medications.
Gene function and biological role
Gene Function: The HMGCR gene encodes 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis [1]. This enzyme is the primary cellular target for statins, a widely prescribed class of cholesterol-lowering medications [2]. By inhibiting HMGCR, statins reduce intracellular cholesterol production, which prompts cells to clear more low-density lipoprotein (LDL) cholesterol from the bloodstream [2]. Beyond cardiovascular health, HMGCR activity in the brain is increasingly recognized for its role in maintaining neural cell membranes and modulating neurodegenerative processes [3].
Variant Impact: Alternative splicing of exon 13 in the HMGCR gene is heavily influenced by the rs3846662 variant [4]. The presence of the A allele promotes the skipping of exon 13, which encodes a critical portion of the enzyme's catalytic and statin-binding domain [4]. This alternative splicing results in a spliced enzyme variant with reduced baseline activity, leading to lower circulating LDL cholesterol levels [1]. Conversely, the G allele favors the retention of exon 13, producing the full-length, highly active enzyme that increases baseline cholesterol levels but also makes the enzyme more sensitive to statin inhibition [4] [5].
Key Insight: The same genetic variant that naturally lowers your baseline cholesterol also makes you less responsive to cholesterol-lowering statin drugs.
Location: HMGCR. Chromosome 5 · 5q13.3 · 75.4 Mb
Estimated prevalence by population
Global 22.0%; European 32.3%; African 1.6%; East Asian 22.0%; South Asian 17.0%; Americas 26.9%; Ashkenazi 23.5%; Finnish 28.7%; Middle Eastern 31.5%; Amish 36.6%.
Estimated AA genotype frequency.
Global 41.8%; European 49.1%; African 22.3%; East Asian 49.8%; South Asian 48.5%; Americas 49.9%; Ashkenazi 50.0%; Finnish 49.7%; Middle Eastern 49.3%; Amish 47.8%.
Estimated AG genotype frequency.
Global 36.1%; European 18.6%; African 76.1%; East Asian 28.2%; South Asian 34.5%; Americas 23.2%; Ashkenazi 26.6%; Finnish 21.6%; Middle Eastern 19.3%; Amish 15.6%.
Estimated GG genotype frequency.
Showing effects for A/A genotype
Cardiovascular & Metabolic
Lipids & Cholesterol
LDL Cholesterol. Evidence: 10/10. Source: PMID 19060911. Lower LDL.
Total Cholesterol. Evidence: 10/10. Source: PMID 19060911. Lower Cholesterol.
Neurology & Mental Health
Neurodegenerative Diseases
Alzheimer's Disease. Evidence: 3/10. Source: PMID 21867541. Lower Risk.
Pharmacogenomics
Lipid-Lowering Drug Response
Statin Response. Evidence: 5/10. Source: PMID 26466344. Reduced Response.
Showing effects for A/G genotype
LDL Cholesterol. Evidence: 10/10. Source: PMID 19060911. Typical LDL.
Total Cholesterol. Evidence: 10/10. Source: PMID 19060911. Typical Cholesterol.
Alzheimer's Disease. Evidence: 3/10. Source: PMID 21867541. Typical Risk.
Statin Response. Evidence: 5/10. Source: PMID 26466344. Typical Response.
Showing effects for G/G genotype
LDL Cholesterol. Evidence: 10/10. Source: PMID 19060911. Higher LDL.
Total Cholesterol. Evidence: 10/10. Source: PMID 19060911. Higher Cholesterol.
Alzheimer's Disease. Evidence: 3/10. Source: PMID 21867541. Higher Risk.
Statin Response. Evidence: 5/10. Source: PMID 26466344. Excellent Response.
What this genotype means for the people who carry it
Sample genotype: AA (Homozygous)
Presence of the AA genotype promotes alternative splicing of the HMGCR gene, which naturally reduces the activity of the cholesterol-producing enzyme [1]. As a result, individuals with this genotype tend to have lower baseline levels of LDL and total cholesterol, which is generally protective for cardiovascular health [2]. This natural reduction in cholesterol is also linked to a delayed onset and lower risk of late-onset Alzheimer's disease [3]. However, because the spliced enzyme lacks the primary binding site for statins, individuals with this genotype often experience a less pronounced reduction in cholesterol when taking statin medications [4]. If statin therapy is required, alternative lipid-lowering strategies or different dosages may be discussed with a healthcare provider [4].
Naturally lower LDL cholesterol levels; Lower risk of late-onset Alzheimer's disease; Reduced cholesterol-lowering response to statins.
Sample genotype: AG (Heterozygous)
A heterozygous AG genotype produces a balanced mix of full-length and spliced HMGCR enzymes. Consequently, baseline LDL and total cholesterol levels are generally typical and close to population averages [1]. The risk for late-onset Alzheimer's disease associated with this genotype is also typical [2]. When prescribed statin medications, individuals with this genotype usually show a standard, moderate reduction in cholesterol levels [3]. This balanced genetic profile means that standard cardiovascular prevention and treatment guidelines are typically highly effective [3].
Typical baseline LDL cholesterol levels; Standard response to statin medications; Average risk of late-onset Alzheimer's disease.
Sample genotype: GG (Homozygous)
Presence of the GG genotype prevents the skipping of exon 13, leading to maximum production of the full-length, highly active HMGCR enzyme [1]. This high enzymatic activity results in naturally higher baseline levels of LDL and total cholesterol, which can increase long-term cardiovascular risk [2]. Additionally, the higher circulating cholesterol levels associated with this genotype are linked to an increased risk and earlier onset of late-onset Alzheimer's disease [3]. Fortunately, because this genotype produces the full-length enzyme, it provides the ideal target for statin medications [4]. Individuals with this genotype typically experience an excellent, highly effective reduction in LDL cholesterol when treated with statins [4].
Higher baseline LDL cholesterol levels; Increased risk of late-onset Alzheimer's disease; Highly effective response to statin medications.
Variants with shared genetic architecture
rs12654264 · HMGCR Gene · Chr 5 · Cholesterol and Statin Response
rs12916 · HMGCR Gene · Chr 5 · LDL Cholesterol Levels
rs3846663 · HMGCR Gene · Chr 5 · Cholesterol Levels
HNRNPA1 regulates HMGCR alternative splicing and modulates cellular cholesterol metabolism.
Content updated August 2026.
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