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From SNPedia

Geno Mag Summary
(A;A) 0 Normal/Average risk for Alzheimer's
(A;G) 2 ~3x increased Alzheimer's risk; 1.4x increased heart disease risk ; increased LDL cholesterol
(G;G) 3 2x+ increased Alzheimer's risk, further genotyping suggested ; increased LDL cholesterol
ReferenceGRCh38 38.1/141
is asnp
is mentioned by
dbSNP (classic)rs4420638
1000 genomesrs4420638
GWAS Ctlgrs4420638
Max Magnitude3
? (A;A) (A;G) (G;G) 28

Apolipoprotein E ApoE status is technically defined by two different SNPs, rs429358 and rs7412. This SNP, rs4420638, is situated about 14kb away in the adjacent ApoC1 gene and is co-inherited with ApoE and thus associated with late-onset Alzheimer's disease.[PMID 17192785]

rs4420638 (the proxy SNP) is not independent of rs429358. These two SNPs are correlated with each other and it's believed that most of the association with AD at rs4420638 is due to its proximity to rs429358. That said, rs4420638 is not a perfect proxy for rs429358 either -- rs4420638 correlates better for certain genotypes and for certain ethnicities. For example, if you have the genotype at rs4420638 that is more correlated with the e4 allele of APOE, you still only have a 50% chance of actually having the e4 allele. And rs4420638 is not very predictive for any genotype in African populations.

The (G;G) form of this SNP indicates increased risk of Alzheimer's disease, however the probability and amount of increased risk is subject to some disagreement. The initial report concerning this SNP indicated a high likelihood that rs4420638(G;G) homozygotes were predictably ApoE4/ApoE4 homozygotes and thus at significantly (15 fold or higher) risk for Alzheimer's. However, one testing service has estimated [pers. communication] that 25% to 50% of people with the (G;G) are *not* actually ApoE4 homozygotes, and are more likely to be at ~2-3x increased risk based on being ApoE3/ApoE4 heterozygotes.

If you were tested on deCODEme or 23andMe v3 platform, ignore this proxy and just check your status at rs429358 and rs7412. 23andme added rs429358 for people who tested on the v3 platform on 04/14/2011, so you should re-download your data if you haven't.

This AlzForum.org article suggests that ApoE4/ApoE4 homozygotes have a ~15-fold increased risk for developing the disease compared to ApoE3/ApoE3 carriers, whereas rs4420638(A;G) individuals have a ~3-fold increased risk.

ApoE4 status is notable as being the variation that several well known scientists, including Nobel Prize winner James Watson, request not to learn when having their own genomes analyzed.

Meta-analyses have also supported the association between the ApoE4 allele and somewhat increased risk for heart disease, with an odds ratio of 1.42 (CI: 1.26 - 1.61).[15488874?dopt=Abstract PMID 15488874]

23andMe blog each rs4420638(G) lowered CRP by 21.8% also associated with higher total cholesterol, LDL choelsterol and triglycerides, and lower HDL cholesterol

Note: the Affymetrix 500K chip is said to poorly tag (ie assay) this particular SNP. [PMID 17554300OA-icon.png]

According to a 23andMe discussion This is one of the SNPs which were re-analyzed April 2009. Customers with older data may wish to redownload. SNPs effected rs4420638, rs34276300, rs3091244, rs34601266, rs2033003, rs7900194, rs9332239, rs28371685, rs1229984, and rs28399504.

G allele is associated with 6.61mg/dl increase in LDL cholesterol (bad cholesterol). [PMID 18193043OA-icon.png]

GWAS snp
PMID [PMID 19060906OA-icon.png]
Trait LDL cholesterol
Title Common variants at 30 loci contribute to polygenic dyslipidemia
Risk Allele G
P-val 4E-27
Odds Ratio 0.29 [0.17-0.41] SD increase
GWAS snp
PMID [PMID 18802019OA-icon.png]
Trait LDL cholesterol
Title Common SNPs in HMGCR in Micronesians and Whites Associated With LDL-Cholesterol Levels Affect Alternative Splicing of Exon13
Risk Allele
P-val 2E-7
Odds Ratio NR NR
GWAS snp
PMID [PMID 18262040OA-icon.png]
Trait LDL cholesterol
Title LDL-cholesterol concentrations: a genome-wide association study
Risk Allele G
P-val 9.9999999999999995E-21
Odds Ratio 0.06 [0.04-0.08] mmol/L increase
GWAS snp
PMID [PMID 18193044OA-icon.png]
Trait LDL cholesterol
Title Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans
Risk Allele G
P-val 9.9999999999999997E-61
Odds Ratio 0.19 [0.15-0.23] % SD higher
GWAS snp
PMID [PMID 18193043OA-icon.png]
Trait LDL cholesterol
Title Newly identified loci that influence lipid concentrations and risk of coronary artery disease
Risk Allele G
P-val 3E-43
Odds Ratio 6.61 [NR] mg/dl higher
GWAS snp
PMID [PMID 17998437]
Trait Alzheimer's disease
Title Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease
Risk Allele
P-val 1.9999999999999999E-44
Odds Ratio NR NR
GWAS snp
PMID [PMID 17975299]
Trait Alzheimer's disease
Title Sorl1 as an Alzheimer's disease predisposition gene?
Risk Allele
P-val 9.9999999999999993E-40
Odds Ratio NR NR
GWAS snp
PMID [PMID 17463246]
Trait Triglycerides
Title Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
Risk Allele G
P-val 2.9999999999999998E-13
Odds Ratio 2.40 % [NR] of variance explained
GWAS snp
PMID [PMID 17474819]
Trait Late onset Alzheimer's disease
Title A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease
Risk Allele
P-val 9.9999999999999993E-40
Odds Ratio 4.01 [NR]

[PMID 19567438OA-icon.png] Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease


[PMID 19818961OA-icon.png] Apolipoprotein E genotype is associated with serum C-reactive protein but not abdominal aortic aneurysm

GWAS snp
PMID [PMID 19197348OA-icon.png]
Trait Quantitative traits
Title Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae
Risk Allele G
P-val 3E-7
Odds Ratio 0.28 [NR] mg/dL increase

[PMID 19773416OA-icon.png] A gene score of nine LDL and HDL regulating genes is associated with fluvastatin-induced cholesterol changes in women

GWAS snp
PMID [PMID 20442857OA-icon.png]
Trait Lipoprotein-associated phospholipase A2 activity and mass
Title Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study
Risk Allele G
P-val 6E-24
Odds Ratio 8.00 [NR] nmol/ml/min increase
GWAS snp
PMID [PMID 20864672OA-icon.png]
Title Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease
Risk Allele G
P-val 2E-40
Odds Ratio 0.06 [0.05-0.07] unit increase
GWAS snp
PMID [PMID 21196492]
Title Genome-wide association study for C-reactive protein levels identified pleiotropic associations in the IL6 locus
Risk Allele A
P-val 3E-7
Odds Ratio 0.1360 [0.09-0.19] unit increase
GWAS snp
PMID [PMID 21300955OA-icon.png]
Title Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels
Risk Allele A
P-val 0
Odds Ratio 0.2360 [0.22-0.26] unit increase

[PMID 21149302OA-icon.png] Effects of genetic variants on lipid parameters and dyslipidemia in a Chinese population

GWAS snp
PMID [PMID 21740922]
Title A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals.
Risk Allele
P-val 2E-16
Odds Ratio None None
GWAS snp
PMID [PMID 22054870OA-icon.png]
Title A genome-wide scan for common variants affecting the rate of age-related cognitive decline.
Risk Allele
P-val 4E-27
Odds Ratio None None
GWAS snp
PMID [PMID 22005931OA-icon.png]
Title Genome-wide association analysis of age-at-onset in Alzheimer's disease.
Risk Allele
P-val 1E-12
Odds Ratio None None
GWAS snp
PMID [PMID 22003152OA-icon.png]
Title Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies.
Risk Allele A
P-val 5E-30
Odds Ratio 0.0540 None
GWAS snp
PMID [PMID 20686565OA-icon.png]
Title Biological, clinical and population relevance of 95 loci for blood lipids.
Risk Allele G
P-val 4E-21
Odds Ratio 1.0600 None

[PMID 18161859OA-icon.png] Does APOE explain the linkage of Alzheimer's disease to chromosome 19q13?

[PMID 18179892OA-icon.png] Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.

[PMID 18852197OA-icon.png] Metabolic and cardiovascular traits: an abundance of recently identified common genetic variants.

[PMID 19060910OA-icon.png] Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.

[PMID 19161620OA-icon.png] An open access database of genome-wide association results.

[PMID 19204163OA-icon.png] GAB2 as an Alzheimer disease susceptibility gene: follow-up of genomewide association results.

[PMID 19265542OA-icon.png] Performance of random forest when SNPs are in linkage disequilibrium.

[PMID 19336475OA-icon.png] Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk.

[PMID 19336575] Genetic analysis of coronary artery disease single-nucleotide polymorphisms in diabetic nephropathy.

[PMID 19389868] The coronary artery disease SNP, rs4420638, is associated with diabetic nephropathy rather than end-stage renal disease.

[PMID 19474294OA-icon.png] Potential etiologic and functional implications of genome-wide association loci for human diseases and traits.

[PMID 19557197OA-icon.png] NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.

[PMID 19569043OA-icon.png] Genome-wide association studies and the genetic dissection of complex traits.

[PMID 19750184OA-icon.png] Genome-wide association studies for atherosclerotic vascular disease and its risk factors.

[PMID 19756043OA-icon.png] A simple and efficient algorithm for genome-wide homozygosity analysis in disease.

[PMID 19951432OA-icon.png] Analysis of recently identified dyslipidemia alleles reveals two loci that contribute to risk for carotid artery disease.

[PMID 20018036OA-icon.png] Using a latent growth curve model for an integrative assessment of the effects of genetic and environmental factors on multiple phenotypes.

[PMID 20339536OA-icon.png] Genome-wide association of lipid-lowering response to statins in combined study populations.

[PMID 20679960] Pharmacogenetic analysis of lipid responses to rosuvastatin in Chinese patients.

[PMID 20972250] Genetic loci associated with lipid concentrations and cardiovascular risk factors in the Korean population.

[PMID 22368281OA-icon.png] Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a).

GWAS snp
PMID [PMID 22832961OA-icon.png]
Title Genome-wide association study of Alzheimer's disease.
Risk Allele
P-val 0
Odds Ratio 3.4500 None

[PMID 23098650] Impact of variants within seven candidate genes on statin treatment efficacy

[PMID 23119086OA-icon.png] Variants Identified in a GWAS Meta-Analysis for Blood Lipids Are Associated with the Lipid Response to Fenofibrate

[PMID 23588940] Association of Polymorphisms Modulating Low-density Lipoprotein Cholesterol with Susceptibility, Severity, and Progression of Rheumatoid Arthritis

GWAS snp
PMID [PMID 23455636OA-icon.png]
Trait Age-related macular degeneration
Title Seven new loci associated with age-related macular degeneration.
Risk Allele A
P-val 2E-20
Odds Ratio 1.30 [1.24-1.36]

[PMID 24160669OA-icon.png] Impact of APOE gene polymorphisms on the lipid profile in an Algerian population

[PMID 23100282OA-icon.png] Impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection Study.

[PMID 23286790OA-icon.png] Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study.

[PMID 24922540OA-icon.png] Genetic Determinants of Long-Term Changes in Blood Lipid Concentrations: 10-Year Follow-Up of the GLACIER Study

GWAS snp
PMID [PMID 24688116OA-icon.png]
Trait Longevity (85 years and older)
Title Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.
Risk Allele
P-val 2E-26
Odds Ratio 1.22 [1.18-1.27]
GWAS snp
PMID [PMID 24097068OA-icon.png]
Trait Cholesterol, total
Title Discovery and refinement of loci associated with lipid levels.
Risk Allele G
P-val 1E-149
Odds Ratio .20 [NR] unit increase
GWAS snp
PMID [PMID 24023261OA-icon.png]
Trait Lipid traits
Title THOC5: a novel gene involved in HDL-cholesterol metabolism.
Risk Allele G
P-val 1E-14
Odds Ratio .25 unit increase

[PMID 26535656] Significant interaction of APOE rs4420638 polymorphism with HDL-C and APOA-I levels in coronary heart disease in Han Chinese men

Risk Rs4420638(G;G)
Alt Rs4420638(G;G)
Reference Rs4420638(A;A)
Significance Untested
Disease not provided
Variation info
Gene APOC1
CLNDBN not provided
Reversed 0
HGVS NC_000019.9:g.45422946A>G
CLNACC RCV000190314.1,

[PMID 27707806OA-icon.png] Replication of Genome-Wide Association Study Findings of Longevity in White, African American, and Hispanic Women: The Women's Health Initiative.

[PMID 27805002OA-icon.png] Performance Metrics for Selecting Single Nucleotide Polymorphisms in Late-onset Alzheimer's Disease.

[PMID 29390587OA-icon.png] Prospective association of a genetic risk score with major adverse cardiovascular events in patients with coronary artery disease.

[PMID 29410832OA-icon.png] Prediction of cholesterol ratios within a Korean population.

[PMID 29942042OA-icon.png] A decade in psychiatric GWAS research.

[PMID 33163038OA-icon.png] Lack of association between genetic variants in the 19q13.32 region and CHD risk in the Algerian population: a population-based nested case-control study.