Rs4420638

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).[PMID 15488874]

spittoon 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

[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