rs4420638

Orientation

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Stabilized

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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

Reference

GRCh38 38.1/141

Chromosome

19

Position

44919689

Gene

APOC1

is a	snp
is	mentioned by
dbSNP	rs4420638
dbSNP (classic)	rs4420638
ClinGen	rs4420638
ebi	rs4420638
HLI	rs4420638
Exac	rs4420638
Gnomad	rs4420638
Varsome	rs4420638
LitVar	rs4420638
Map	rs4420638
PheGenI	rs4420638
Biobank	rs4420638
1000 genomes	rs4420638
hgdp	rs4420638
ensembl	rs4420638
geneview	rs4420638
scholar	rs4420638
google	rs4420638
pharmgkb	rs4420638
gwascentral	rs4420638
openSNP	rs4420638
23andMe	rs4420638
SNPshot	rs4420638
SNPdbe	rs4420638
MSV3d	rs4420638
GWAS Ctlg	rs4420638

GMAF

0.1635

Max Magnitude

3

?	(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 17554300]

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 18193043]

GWAS snp
PMID	[PMID 19060906]
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 18802019]
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 18262040]
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 18193044]
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 18193043]
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 19567438] Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease

OMIM	107741
Desc	APOLIPOPROTEIN E; APOE
Variant
Related	also

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

GWAS snp
PMID	[PMID 19197348]
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 19773416] A gene score of nine LDL and HDL regulating genes is associated with fluvastatin-induced cholesterol changes in women

GWAS snp
PMID	[PMID 20442857]
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 20864672]
Trait
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]
Trait
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 21300955]
Trait
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 21149302] Effects of genetic variants on lipid parameters and dyslipidemia in a Chinese population

GWAS snp
PMID	[PMID 21740922]
Trait
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 22054870]
Trait
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 22005931]
Trait
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 22003152]
Trait
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 20686565]
Trait
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 18161859] Does APOE explain the linkage of Alzheimer's disease to chromosome 19q13?

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

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

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

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

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

[PMID 19265542] Performance of random forest when SNPs are in linkage disequilibrium.

[PMID 19336475] 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 19474294] Potential etiologic and functional implications of genome-wide association loci for human diseases and traits.

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

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

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

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

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

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

[PMID 20339536] 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 22368281] Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a).

GWAS snp
PMID	[PMID 22832961]
Trait
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 23119086] 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 23455636]
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 24160669] Impact of APOE gene polymorphisms on the lipid profile in an Algerian population

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

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

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

GWAS snp
PMID	[PMID 24688116]
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 24097068]
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 24023261]
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

ClinVar
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
CLNSRC
CLNACC	RCV000190314.1,

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

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

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

[PMID 29410832] Prediction of cholesterol ratios within a Korean population.

[PMID 29942042] A decade in psychiatric GWAS research.

[PMID 33163038] 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.