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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.
23andMe blog each rs4420638(G) lowered CRP by 21.8% also associated with higher total cholesterol, LDL choelsterol and triglycerides, and lower HDL cholesterol
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.
|Title||Common variants at 30 loci contribute to polygenic dyslipidemia|
|Odds Ratio||0.29 [0.17-0.41] SD increase|
|Title||Common SNPs in HMGCR in Micronesians and Whites Associated With LDL-Cholesterol Levels Affect Alternative Splicing of Exon13|
|Odds Ratio||NR NR|
|Title||LDL-cholesterol concentrations: a genome-wide association study|
|Odds Ratio||0.06 [0.04-0.08] mmol/L increase|
|Title||Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans|
|Odds Ratio||0.19 [0.15-0.23] % SD higher|
|Title||Newly identified loci that influence lipid concentrations and risk of coronary artery disease|
|Odds Ratio||6.61 [NR] mg/dl higher|
|Title||Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease|
|Odds Ratio||NR NR|
|Title||Sorl1 as an Alzheimer's disease predisposition gene?|
|Odds Ratio||NR NR|
|Title||Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels|
|Odds Ratio||2.40 % [NR] of variance explained|
|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|
|Odds Ratio||4.01 [NR]|
[PMID 19818961] Apolipoprotein E genotype is associated with serum C-reactive protein but not abdominal aortic aneurysm
[PMID 19567438] Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease
|Title||Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae|
|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
|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|
|Odds Ratio||8.00 [NR] nmol/ml/min increase|
|Title||Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease|
|Odds Ratio||0.06 [0.05-0.07] unit increase|
|Title||Genome-wide association study for C-reactive protein levels identified pleiotropic associations in the IL6 locus|
|Odds Ratio||0.1360 [0.09-0.19] unit increase|
|Title||Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels|
|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
|Title||A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals.|
|Odds Ratio||None None|
|Title||A genome-wide scan for common variants affecting the rate of age-related cognitive decline.|
|Odds Ratio||None None|
|Title||Genome-wide association analysis of age-at-onset in Alzheimer's disease.|
|Odds Ratio||None None|
|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.|
|Odds Ratio||0.0540 None|
|Title||Biological, clinical and population relevance of 95 loci for blood lipids.|
|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).
|Title||Genome-wide association study of Alzheimer's disease.|
|Odds Ratio||3.4500 None|
|qualified_impact||Insufficiently evaluated pathogenic|
[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
|Trait||Age-related macular degeneration|
|Title||Seven new loci associated with age-related macular degeneration.|
|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
|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.|
|Odds Ratio||1.22 [1.18-1.27]|
|Title||Discovery and refinement of loci associated with lipid levels.|
|Odds Ratio||.20 [NR] unit increase|
|Title||THOC5: a novel gene involved in HDL-cholesterol metabolism.|
|Odds Ratio||.25 unit increase|