Allelic expression of APOE in human brain: effects of epsilon status

[Orangeblossom]

As a 3/4 for APOE I was interested in how the different alleles were expressed and the affects on AD. I was reading these which were interesting and just thought I would share in case others found them of interest too. I didn't realise that the different alleles of APOE are not equally expressed and had assumed they were.

Allelic expression of APOE in human brain: effects of epsilon status and promoter haplotypes
https://academic.oup.com/hmg/article/13/22/2885/610242

"The APOE ε4 allele is a strong genetic susceptibility factor for Alzheimer's disease. Interaction with other biological factors may modulate the effect of the apoE isoforms. However, previous work suggested that other genetic variability within the APOE locus, influencing the effect of the ε 4 allele, may exist. Such variability could modify the expression of the APOE gene and, in particular, the level of expression of APOE alleles could be an important determinant of disease pathogenesis. To test this hypothesis we examined the levels of expression of APOE in heterozygotes with AD and in controls, using a new method of semi-quantitation. We report that relative ε4 mRNA expression is increased in AD compared with controls and suggest that genetic variability in the neural expression of APOE contributes to disease risk."

Distortion of Allelic Expression of Apolipoprotein E in Alzheimer's Disease https://academic.oup.com/hmg/article/6/12/2151/2357263

"There are two major findings in our work. First, that the expression of the ε3 allele is consistently higher than the expression of the ε4 allele. Second, that the expression of the ε4 allele beyond a certain level seems to greatly influence the vulnerability of an individual to Alzheimer's disease."

[Orangeblossom]

The first paper is the more recent one, showing increased expression of E4 to E3 in heterozygotes.

i'm not sure if I have it right about the promoter alleles. If you were double GG for the first promoter mentioned, (the -219 G) this would increase the general levels of APOE (both 3 and 4 in a 3,4) but if you were hetero for the promoter, it seems in 85% of cases this would increase the APOE3? (as it is on the same side). I think! (but would welcome clarification).

[SusanJ]

Orange, interesting finds. Look forward to reading them when I have a spare moment.

[Orangeblossom]

Further to this, I found the promoter polymorphism mentioned seems to be in linkage disequilibrium with APOE4. Linkage disequilibrium refers to the non-random association of alleles at two or more loci in a general population.

Anyway this paper mentions the influence of this combination on the APOE4 expression, might be of interest. (about how different combinations would affect the expression). Maybe I'm unusual then as have not got this G-T polymorphism but do have a APOE4. So I'm guessing, with mine having GG this would increase both 4 and 3 activity.

https://academic.oup.com/hmg/article/7/3/533/2901476

Abstract
The ε4 allele of the Apolipoprotein E gene (APOE), one of the main allele of APOE polymorphism, is a major risk factor for the development of Alzheimer's disease. However, several data suggest that genetic factors, within the APOE locus, may also modulate the risk associated with this polymorphism. We look for new mutations in the APOE promoter, susceptible to modify the risk associated with the APOE ε4 allele. We characterised a G→T mutation at −186 bp of the APOE gene TATA box, named Th1/E47cs. This new polymorphism is located in a consensus sequence of a potential transcriptional (Th1/E47) factor binding site. We studied the impact of this new polymorphism with those of other markers of the APOE locus in a large case-control study and observed that Th1/E47cs modulated the influence of the APOE ε4 allele on the risk of Alzheimer's disease.

"If we assume that the level of expression of the APOE alleles is increased due to cis mutations in the promoter region, this hypothesis has three major implications: (i) the promoter mutation may modulate the expression of the APOE alleles leading to an increased deleterious risk for ε4 and to an increased protective effect for ε2; (ii) given that what determines the risk is the importance of the relative level of expression of both alleles of the APOE, this promoter mutation will have a differential effect in APOE heterozygous and homozygous genotypes; (iii) the effect of the cis mutation in heterozygous individuals will depend on the phase of this polymorphism with the APOE ε alleles (i.e., the haplotype). In heterozygous Th1/E47cs and APOE ε4 genotype bearers, the ε4 allele may be combined either with the Th1/E47cs T or G allele. One of these combinations may increase the relative expression level of the ε4 allele and decrease the relative expression level of the ε3 allele, the other combination having the inverse influence. Thus, in the ε3/ε4 genotype bearers, the risk of developing AD will be different between the Th1/E47cs heterozygous and homozygous individuals."

"In conclusion, The Th1/E47cs polymorphism, located within a putative regulatory element of the APOE promoter could contribute to the APOE expression level but other polymorphisms in the regulatory sequences of this gene may exist and a more extended screening of these regulatory regions needs to be developed. The regulation of the APOE gene could be very important for deciphering the mechanisms of the involvement of the APOE alleles, in particular to better define subjects at higher risk of developing AD."

This paper https://www.sciencedirect.com/science/a ... 4098005679 is more about the strong linkage disequilibrium between the promoter polymorphism and APOE4. This isn't the case with me though, so a bit confused. If something has strong linkage does this mean happens in all cases or just the majority I wonder. I wondered if the other promoter/s are also in linkage but couldn't find that out, yet. It would be interesting of more than one of them were also and might be a link with levels of APOE found in the different genotypes, given that APOE 4 levels are usually less than APOE3...

[Orangeblossom]

Aha, this paper mentions a LD between all the promoter polymorphisms...

"a strong linkage disequilibrium was observed between the alleles of these promoter region polymorphisms and the APOE coding region alleles". I can't seem to find my result for the other one on Prometheus, not sure why.

https://www.nature.com/articles/5200513

Feel like I'm on the verge of working out a pattern here but not quite sure. If these promoters are all in LD with APOE4 and cause less of it, could that result in the lower E4 levels observed. or is it not that simple...

Here is another one which seems to say that as well.. (for the -219 T/G one anyway)

https://journals.lww.com/neuroreport/Ab ... 2M.39.aspx

Our results showed that APOE genotype was the only informative marker of AD risk contrary to −219T/G and A2M/A2Mdel polymorphism. In AD patients however, a strong linkage disequilibrium was observed between the T allele of −219T/G polymorphism and APOE4 allele. This result indicates that −219T/G APOE promoter polymorphism is a risk factor for AD by increasing the APOE4-associated risk.

This recent one gives a sort of score based on the promoters and APOE...but seems to be based on a small sample so unsure how correct that is...

The algorithm for Alzheimer risk assessment based on APOE promoter polymorphisms https://alzres.biomedcentral.com/articl ... 016-0187-9

Ok from this it seems they may all be in LD...

"LD between loci rs449647, rs405509 and rs440446 on one side, and the APOE exon 4 loci coding for epsilon variants (distant by 3 kb) on the other, was observed. Of all SNPs analysed, the strongest LD was observed for rs440446 and rs429358 (Lewontin coefficient D′ 0.956, logarithm of [base 10] odds [LOD] 11.51, r 2 = 0.127). The rs440446 locus was simultaneously linked with promoter SNPs, too, for instance with rs405509".

and "LD may vary significantly depending on ethnic background." Interesting.

Also https://www.researchgate.net/publicatio ... 7s_Disease

I can't get my results for rs449647 or rs440446 from either 23andme or Promethease. Has anyone else had that problem too I wonder or anyway to find it out? It's all a bit new to me...

I noticed this links into this topic on APPE levels here viewtopic.php?f=4&t=1155&hilit=promoters