What do we know about Apo. E? I’m confused about Apo. E. And the more I read, the more I think I’m not alone. Of all the known genetic risk factors for late- onset Alzheimer disease, APOE genotype has by far the largest effect size — a single E4 allele increases your risk by ~3. X . If you believe, as I do, that human genetics is a valuable source of validation for therapeutic strategies, then it follows that Apo. E might be considered as one possible drug target for preventing Alzheimer disease.
People with the APOE e4 genetic variation have a greater number of sticky protein clumps, called beta-amyloid plaques, in the brain. Thus, a diet high in saturated. The trouble is, no one seems to know the mechanism by which the E4 allele increases Alzheimer risk. There is not even any agreement on whether E4 represents a gain of function or a loss of function, and therefore on whether one should strive to develop inhibitors or activators of Apo. ![]() E. Accordingly, people have taken approaches that are all over the map. Some think Apo. E is beneficial, and have sought to therapeutically upregulate APOE expression . Others view Apo. E as the enemy, and look to its knockdown or its inhibition with monoclonal antibodies as potential therapies . Still others believe that the answer is isoform- dependent, and that one should seek to downregulate the risk- increasing E4 isoform and/or upregulate the protective E2 isoform . And it’s not for lack of interest. One of the studies mentioned above . ![]() Paradoxically, all this literature makes my task harder, rather than easier. The literature is so crowded with different claims about APOE that it becomes incredibly difficult to tell what is real. For instance, in a quick Google Scholar search I spotted more than ten candidate gene studies proposing an association between APOE genotype and either the risk, age of onset, or phenotype of prion disease, even though in the largest prion disease GWAS to date . To believe everything in the literature, it seems, would be to believe this one protein is found in every subcellular compartment, interacts with every other protein, modulates every mouse phenotype, and is a risk factor for every neurological disease. I soon developed the following postulate: for every hypothesis that you can imagine about Apo. E, there exists a paper that claims it’s true. To try to sift through this morass, I figured I’d start with what I know best: human genetics. That’s not to say that human genetics papers about APOE are any more likely to be correct than papers about mouse models or cell biology or anything else, but rather, human genetics is a body of literature that I know how to read. I don’t always know a good mouse from a bad mouse or a representative image from a cherry- picked one, but I have at least a decent handle on the methods and statistical thresholds that pass for evidence in human genetics. So the question of this post, then: what does the human genetic data tell us about APOE? Be warned, even on this subject I’m far from an expert, so this post is very likely to contain mistakes and omissions. First, some general facts about APOE variation in humans. APOE consists of 3 exons located on chromosome 1. In terms of numbering, the coding sequence is 3. Two variants are common worldwide, C1. R (often called C1. R) and R1. 76. C (often R1. C), and another variant, R1. C (or R1. 45. C) has a frequency of 6% in Africans. ![]() ![]() And of course, as with any gene, there are loads of other less common variants — a total of 9. Ex. AC release. Other than the variants discussed above, plus one variant in the signal peptide (N1. K), none of these has an allele frequency greater than 1% in any large continental population. Note that, as is convention, the amino acid codes above are given in comparison to the reference genome, but in the case of C1. R, R is actually the ancestral allele, shared by chimpanzees and mice alike. ![]() ![]() This means that 1. C, which is the reference and the most common allele in all major world populations, actually arose in humans and swept to its current 7. Africa bottleneck. The R1. 58. C variant, which is found in cis with 1. C, must therefore have arisen later on that same new haplotype. People don’t often refer directly to these missense variants by their codon and resulting amino acid substitition as I’ve done above. Instead, one often hears a specific nomenclature for APOE variants, one which, as far as I can tell, arose by historical accident. Apo. E protein was studied using biochemical techniques years before DNA sequencing was in common use, and it was noticed early on that different versions of the protein had different isoelectric points and could be separated on 2. D gels. The term “E3” came to refer to the electrophoretic mobility of the protein encoded by the most common allele (now the reference). It turns out that most of the time, the underlying missense variants that gave rise to these differences were R1. C (E2) and C1. 12. R (E4), though there were exceptions: that common African R1. C variant mentioned above also has “E2” electrophoretic mobility, and there were other, rarer, variants as well, such as “E2 Fukuoka” (R2. Q) . As an additional historical curiosity, “E1” referred to Apo. E protein with two fewer positive charges than the reference E3 allele, and reported E1 alleles included K1. E . Nowadays, when people say E2 or E4, they’re no longer thinking of electrophoretic mobility, but instead are simply referring to R1. C and C1. 12. R respectively — and for the avoidance of confusion, I will refer directly to the missense variants in the rest of this post, with parenthetical reference to the “E” term in common use. Blood lipids and cardiovascular disease risk. Years before APOE was ever associated with Alzheimer disease, its protein product was known as a component of lipoprotein particles in the bloodstream. As far as I could find, the earliest reference to what we now call Apo. E may be the characterization of an “arginine- rich” (3. VLDL) particles in the blood of patients with a disorder called dysbetalipoproteinemia . Within a few years, the arginine- rich protein, christened Apo. ![]() ![]() E, was known to be present not just in VLDL, but also in chylomicrons and HDL . The APOE locus is reproducibly associated with LDL cholesterol levels in genome- wide association studies . None of those GWAS papers discussed the direction of effect nor whether the locus was also associated with coronary artery disease, but those issues were examined in detail in an enormous meta- analysis (~1. That study found that R1. C (E2) resulted in reduced LDL and reduced risk of coronary artery disease, while C1. R (E4) increased both. For LDL, R1. 58. C homozygotes (E2/E2) had 4. L lower LDL than C1. R homozygotes (E4/E4). In an allelic model, compared to the reference genome (E3), R1. C (E2) was associated with reduced risk of coronary artery disease (odds ratio = 0. C1. 12. R (E4) was associated with increased risk (OR = 1. At first glance, then, this all sounds straightforward: R1. C (E2) is good, and C1. R (E4) is bad. It’s not quite so simple, though. Although R1. 58. C (E2) on average is associated with reduced risk of cardiovascular disease, there seems to be a lot of variance in people’s outcomes, and the earliest studies of E2 actually examined its role in causing disease. It’s confusing, and I only wrapped my mind around it after finding one good thorough review . The R1. 58. C (E2) variant is described as being defective in receptor binding, thus causing Apo. Complete information for APOE gene (Protein Coding), Apolipoprotein E, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The. The lipoproteins page provides a detailed description of the structure and function of the lipoprotein particles found in the circulation as well as therapeutic means. E protein, which is found on chylomicrons, VLDL, IDL, HDL, to stay in the bloodstream and circulate longer. R1. 58. C (E2) is associated with increased levels of circulating Apo. E (associated with one or more of chylomicrons, VLDL, IDL, HDL) and decreased levels of circulating Apo. B (associated with LDL). So although LDL is apparently always decreased in these individuals, which is good, VLDL and other lipoprotein particles can be increased, sometimes pathologically so, such that a subset of R1. C homozygotes (E2/E2) actually suffer from a disorder called either dysbetalipoproteinemia or type 3 hyperlipoproteinemia. These people have very high total cholesterol, and develop xanthomas (visible deposits of cholesterol under their skin) and early- onset heart attacks. I couldn’t find any reference for what proportion of R1. C homozygotes (E2/E2) develop this condition, but it must be fairly small, since in the aggregate, even in a homozygous state, this variant appears to be associated with reduced risk of coronary artery disease . Individuals lacking a functional copy of APOE have low LDL but high levels of all other lipoprotein particle types, especially VLDL, which is increased by several- fold. This, at first, seemed incomprehensible to me: how could the absence of Apo. E cause the same disorder as homozygosity for R1. C (E2), which is associated with increased circulating Apo. ![]() E? Utermann speculates that any deficiency in Apo. E binding to its receptors, whether due to R1. C or due to total lack of Apo. E, results in upregulation of the LDL receptor (thus reducing LDL) but an inability to scavenge “remnant” lipoprotein particles such as VLDL and IDL (and thus an increase in levels of those particles). To date, several families with this recessive disease of APOE deficiency have been reported . There was also one individual with an “E1” missense allele in trans to a frameshift . Following the discovery of these families, Apoe knockout mice ? No one seems to know for sure. Certainly, the severe phenotypes of xanthomas and early onset atherosclerosis were only reported in double null individuals, and not in their heterozygote relatives. One proband did have an affected father, but he was deceased and his genotype was unknown, and 3 out of 6 of his children were affected . Some of the papers cited above do present VLDL, LDL, triglyceride and other blood lipid levels for one or two heterozygote relatives, but none of their numbers look to be glaringly outside the range in the general population, so it is not clear whether they are significantly shifted from the population distribution. One of the papers .
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. Archives
October 2017
Categories |