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.

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).

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.

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).