Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Position: (GRCh38/hg38):Chr19:44908783 C>T
Position: (GRCh37/hg19):Chr19:45412040 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs769455
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGT to TGT
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant has been associated with an increased risk of Alzheimer’s disease (AD) in individuals of African ancestry with an APOE3/E4 genotype (Le Guen et al., 2023, March news 2023). The findings emerged from a case-control study including nearly 32,000 participants of African ancestry from case-control, family-based, population-based, and longitudinal AD cohorts. In the discovery stage, which included nearly 3,000 AD patients and 5,000 controls, R163C was associated with an increased risk of AD (OR=3.01; 95% CI=1.87-4.85; p=6x10^-6) and a younger age at onset (β, −5.87 years; 95%CI, −8.35 to −3.4 years; P = 3.4 × 10⁻⁶). Secondary analyses of a replication cohort (OR=2.20) and an external validation cohort (OR=1.90) supported these findings. Also, R163C was tied to more rapid cognitive decline. Because R163C was found to be linked to APOE3, stratified analyses were limited to APOE2/E3, APOE3/E3 and APOE3/E4 genotypes. Significant associations were detected only in the APOE3/E4 group.

As noted by the authors, R163C is likely the causal variant underpinning these associations because the results persisted after adjusting for the presence of sequences shared amongst people of African ancestry at the APOE locus. Moreover, the findings were consistent with an earlier study in African Americans that found a weaker association between R163C and AD in a non-stratified analysis (Kunkle et al., 2021). Although another report failed to detect an association (Medway et al., 2014), it was likely due to low allele frequency. The only large group in this earlier study was composed of European Americans and R163C appears to be found only in individuals with African ancestry (see below).

Non-Neurological Conditions

The R163C mutation has long been known as a risk factor for hyperlipoproteinemia type III (HLPP3). The condition, also known as familial dysbetalipoproteinemia, is characterized by elevated cholesterol and triglyceride levels in blood, and early onset atherosclerosis and heart disease (Hopkins et al., 2014; Koopal et al., 2017). In addition to fulfilling one set of criteria for this disorder (non-high density lipoprotein cholesterol (HDLc)/ApoB≥1.7 and triglycerides/ApoB≥1.35), carriers of this mutation have been reported to have elevated levels of very low-density cholesterol (VLDLc) and an increased ratio of VLDLc to VLDL triglycerides (Bea et al., 2023).

The R163C variant was first described in two African Americans with HLPP3 (Rall et al., 1982). The ApoE proteins of both patients migrated on an isoelectric focusing gel to the position of the R176C (ApoE2) variant which previously had been associated, in its homozygous form, with HLPP3. However, the proteins’ receptor binding ability was observed to differ from that of ApoE2. Peptide mapping and amino acid analysis revealed one individual had a single copy of ApoE2, while his other allele carried the R163C substitution. The other subject had two copies of R163C with no copies of ApoE2.

In 1988, a woman from Utah with abnormal lipoprotein particle levels typical of HLPP3 was found to have the same heterozygous substitution and the mutation was sequenced at the DNA level (Emi et al., 1988).

The inheritance pattern of HLPP3 caused by R163C has been described as autosomal dominant with incomplete penetrance (deVilliers et al., 1997; Abou Ziki et al., 2014). The first indication of this pattern emerged from a South African study of 10 unrelated mutation carriers with HLPP3, and 10 affected family members who also carried the mutation. The cholesterol and triglyceride levels of these patients were similar in homozygotes and heterozygotes, suggesting a lack of an allele dosage effect (deVilliers et al., 1997). However, the clinical expression of the disease differed between the two groups. Whereas heart disease affected heterozygotes more often, fat deposits under the skin, known as xanthomas, occurred more often in homozygotes. Some mutation carriers may not develop the disease at all. A compilation of several reported cases identified 20 of 24 mutation carriers with diagnosed HLPP3 (Koopal et al., 2017).

The variant has also been identified in patients with other lipid disorders, including autosomal dominant hypercholesterolemia, also known as hyperlipoproteinemia type IIa (HLPP2a), and familial combined hyperlipidemia, also known as hyperlipoproteinemia type IIb (HLPP2b). Carriers with elevated cholesterol and low-density lipoprotein (LDL) cholesterol in blood, including four diagnosed with HLPP2a, have been reported (Wintjens et al., 2016, Sinnott and Mazzone, 2006, Abou Khalil et al., 2022, Bea et al., 2023), as well as three carriers with elevated triglyceride levels (Abou Khalil et al., 2022, Bea et al., 2023), two diagnosed with HLPP2b (Abou Khalil et al., 2022).

In one family, R163C was found together with E31K. All seven reported carriers of the compound mutation, referred to as ApoE4 Philadelphia based on its migration on an isoelectric focusing gel, had altered blood lipid profiles. The original proband, a 24-year-old homozygous female, suffered from HLPP3 (Lohse et al., 1991; Lohse et al., 1992). The other six carriers were heterozygotes and had only a moderate form of HLPP3, lacking clinical symptoms. The authors concluded the compound mutant exhibits incomplete dominance for HLPP3.

As assessed by local ancestry analysis, R163C is part of a haplotype—a stretch of DNA with variants that are inherited together—tied to African ancestry (Le Guen et al., 2023). This is consistent with previous studies showing a low frequency in European Americans, and a relatively high frequency in some African populations (Abou Ziki et al., 2014, Pirim et al., 2019). The variant’s global frequency in the gnomAD variant database was 0.002, with 339 of 393 heterozygote carriers of African ancestry (v2.1.1, May 2022). Seven homozygotes were also reported, all of African ancestry. Moreover, data from the 1000 Genomes Project indicated it is present in 5–12 percent of individuals in populations with sub-Saharan African ancestry (Abou Ziki et al., 2014). The mutation was also found in 17 percent of a Qatari population, which has a high prevalence of cardiovascular disease.

In these high prevalence populations, the variant might be a common cause of mild hypertriglyceridemia (Abou Ziki et al., 2014; Pirim et al., 2019). Consistently, several genome-wide association studies (GWAS) each including over 10,000 individuals of non-European ancestry, all reported associations with high triglyceride levels (Peloso et al., 2014; Hoffman et al., 2018; Wojcik et al., 2019; Hu et al., 2020). In two of the studies, reduced levels of cholesterol and LDL-C were also observed (Peloso et al., 2014; Wojcik et al., 2019).

Similar results were obtained in two smaller association studies that included 788 individuals of African ancestry, and the effects were found to be independent of APOE2 and C130R (APOE4) status (Radwan et al., 2014; Pirim et al., 2019). Of note, Pirim et al. reported the variant was tightly linked to APOE intronic variant c.43+349G>A, which also showed association with lower LDL-C levels (Pirim et al., 2019). Data on the linkage between this variant and other nearby variants, across several populations, can be found in the GWAS catalog (click on “Linkage Disequilibrium” tab in the “Available data” section). In addition, an association between R163C and an unknown plasma metabolite, a potential isomer of retinol, was reported in participants of the Jackson Heart Study, a cohort of Black individuals from Jackson, Mississippi (Tahir et al., 2022).

Biological effect

From a neurological perspective, the observation that R163C is associated with AD risk only when paired with APOE4 suggests it is a loss-of-function mutation, lacking a biochemical property that normally ameliorates the risk caused by APOE4 (Le Guen et al., 2023).

In the periphery, the in vivo behavior of this variant, located in the receptor-binding region of ApoE, has been reported to be similar to that of ApoE2, showing reduced efficiency at clearing lipoprotein remnant particles from circulation compared with ApoE3 (Stalenhoef et al., 1986). In vitro experiments using cells or isolated proteins, however, suggest distinct impairments in cell-surface binding. R163C’s affinity for receptors that bind low-density lipoprotein (LDLR) was reduced compared with ApoE3, but greater than that of ApoE2 (Rall et al., 1982, Bea et al., 2023).

On the other hand, R163C’s binding to heparin sulfate proteoglycans was decreased by 65 percent compared with ApoE3, while that of ApoE2 was reduced by only 30 percent (Ji et al., 1994; see also supplement 1 in Le Guen et al., 2023). This effect is consistent with observations indicating that R163 is critical for heparin binding (Libeu et al., 2001, Dong et al., 2001). Also of note, in a cell-free binding assay, R163C’s interaction with very low-density lipoprotein receptors (VLDLR) was substantially weaker than that of wildtype ApoE3 (Ruiz et al., 2005).

In addition, the R163C substitution which results in a change in charge has been predicted to abolish R163’s interaction with Q59 and thus weaken the interaction between ApoE’s N- and C-terminal domains (Chen et al., 2011, Zhou et al., 2018). This alteration could disrupt the way that lipid binding to the C-terminus normally facilitates receptor binding. Moreover, a study using FRET and computational simulations to study monomeric ApoE4 predicted interactions with E27 and E45 when the C-terminal domain is undocked from the N-terminal helix bundle, a form suspected to enable lipid binding (Stuchell-Brereton et al., 2023).

R163 may also play a role in the formation of ApoE dimers which adopt different conformations in an isoform-dependent manner (Nemergut et al., 2023). Interestingly, a metabolite of the AD drug candidate ALZ-801 was observed to interact with several amino acids involved in dimerization, including R163, possibly decreasing the stability of ApoE4 V-shaped dimers (note, however, that the R163C substitution is found mostly or always on an ApoE3 backbone).

In silico analyses using Polyphen2 and SIFT algorithms predicted the variant to be deleterious, and structural analysis predicted impaired LDLR binding (Wintjens et al., 2016). This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, May 2022). Moreover, a study analyzing whole-genome and whole-exome sequencing data from 138,632 individuals, identified R163C as one of six APOE variants likely to have functional consequences and clinical relevance given their high prevalence in at least one population and their classification by five algorithms (SIFT, Polyphen2, MutationAssessor, PROVEAN, and DANN) as deleterious with high confidence (Zhou et al., 2018).

Based on guidelines from the American College of Medical Genetics and Genomics (ACMG) (Richards et al., 2015), this variant was classified as Likely Pathogenic (Mariano et al., 2020).

Note on nomenclature:

Some papers include ApoE2 in the name of this variant because both proteins migrate to the same isoelectric position, while others include APOE3, or ε3, because R163C is co-inherited with APOE3.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

1. In People with African Ancestry, ApoE3 Variant Ups Alzheimer's Risk 9 Mar 2023

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE E31K
3. APOE C130R (ApoE4)
4. APOE c.43+349G>A (rs61357706)

Therapeutics Citations

1. ALZ-801

Paper Citations

1. Le Guen Y, Raulin AC, Logue MW, Sherva R, Belloy ME, Eger SJ, Chen A, Kennedy G, Kuchenbecker L, O'Leary JP, Zhang R, Merritt VC, Panizzon MS, Hauger RL, Gaziano JM, Bu G, Thornton TA, Farrer LA, Napolioni V, He Z, Greicius MD. Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease. JAMA. 2023 Feb 21;329(7):551-560. PubMed.
2. Kunkle BW, Schmidt M, Klein HU, Naj AC, Hamilton-Nelson KL, Larson EB, Evans DA, De Jager PL, Crane PK, Buxbaum JD, Ertekin-Taner N, Barnes LL, Fallin MD, Manly JJ, Go RC, Obisesan TO, Kamboh MI, Bennett DA, Hall KS, Goate AM, Foroud TM, Martin ER, Wang LS, Byrd GS, Farrer LA, Haines JL, Schellenberg GD, Mayeux R, Pericak-Vance MA, Reitz C, Writing Group for the Alzheimer’s Disease Genetics Consortium (ADGC), Graff-Radford NR, Martinez I, Ayodele T, Logue MW, Cantwell LB, Jean-Francois M, Kuzma AB, Adams LD, Vance JM, Cuccaro ML, Chung J, Mez J, Lunetta KL, Jun GR, Lopez OL, Hendrie HC, Reiman EM, Kowall NW, Leverenz JB, Small SA, Levey AI, Golde TE, Saykin AJ, Starks TD, Albert MS, Hyman BT, Petersen RC, Sano M, Wisniewski T, Vassar R, Kaye JA, Henderson VW, DeCarli C, LaFerla FM, Brewer JB, Miller BL, Swerdlow RH, Van Eldik LJ, Paulson HL, Trojanowski JQ, Chui HC, Rosenberg RN, Craft S, Grabowski TJ, Asthana S, Morris JC, Strittmatter SM, Kukull WA. Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis. JAMA Neurol. 2021 Jan 1;78(1):102-113. PubMed.
3. Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease. Mol Neurodegener. 2014 Mar 10;9:11. PubMed.
4. Hopkins PN, Brinton EA, Nanjee MN. Hyperlipoproteinemia type 3: the forgotten phenotype. Curr Atheroscler Rep. 2014 Sep;16(9):440. PubMed.
5. Koopal C, Marais AD, Westerink J, Visseren FL. Autosomal dominant familial dysbetalipoproteinemia: A pathophysiological framework and practical approach to diagnosis and therapy. J Clin Lipidol. 2017 Jan - Feb;11(1):12-23.e1. Epub 2016 Oct 13 PubMed.
6. Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C, Cenarro A. Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol. 2023 Jun;43(6):1066-1077. Epub 2023 Apr 13 PubMed.
7. Rall SC Jr, Weisgraber KH, Innerarity TL, Mahley RW. Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4696-700. PubMed.
8. Emi M, Wu LL, Robertson MA, Myers RL, Hegele RA, Williams RR, White R, Lalouel JM. Genotyping and sequence analysis of apolipoprotein E isoforms. Genomics. 1988 Nov;3(4):373-9. PubMed.
9. de Villiers WJ, van der Westhuyzen DR, Coetzee GA, Henderson HE, Marais AD. The apolipoprotein E2 (Arg145Cys) mutation causes autosomal dominant type III hyperlipoproteinemia with incomplete penetrance. Arterioscler Thromb Vasc Biol. 1997 May;17(5):865-72. PubMed.
10. Abou Ziki MD, Strulovici-Barel Y, Hackett NR, Rodriguez-Flores JL, Mezey JG, Salit J, Radisch S, Hollmann C, Chouchane L, Malek J, Zirie MA, Jayyuosi A, Gotto AM Jr, Crystal RG. Prevalence of the apolipoprotein E Arg145Cys dyslipidemia at-risk polymorphism in African-derived populations. Am J Cardiol. 2014 Jan 15;113(2):302-8. Epub 2013 Oct 3 PubMed.
11. Wintjens R, Bozon D, Belabbas K, MBou F, Girardet JP, Tounian P, Jolly M, Boccara F, Cohen A, Karsenty A, Dubern B, Carel JC, Azar-Kolakez A, Feillet F, Labarthe F, Gorsky AM, Horovitz A, Tamarindi C, Kieffer P, Lienhardt A, Lascols O, Di Filippo M, Dufernez F. Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. J Lipid Res. 2016 Mar;57(3):482-91. Epub 2016 Jan 22 PubMed.
12. Sinnott BP, Mazzone T. Tuberous xanthomas associated with olanzapine therapy and hypertriglyceridemia in the setting of a rare apolipoprotein E mutation. Endocr Pract. 2006 Mar-Apr;12(2):183-7. PubMed.
13. Abou Khalil Y, Marmontel O, Ferrières J, Paillard F, Yelnik C, Carreau V, Charrière S, Bruckert E, Gallo A, Giral P, Philippi A, Bluteau O, Boileau C, Abifadel M, Di-Filippo M, Carrié A, Rabès JP, Varret M. APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int J Mol Sci. 2022 May 21;23(10) PubMed.
14. Lohse P, Mann WA, Stein EA, Brewer HB Jr. Apolipoprotein E-4Philadelphia (Glu13----Lys,Arg145----Cys). Homozygosity for two rare point mutations in the apolipoprotein E gene combined with severe type III hyperlipoproteinemia. J Biol Chem. 1991 Jun 5;266(16):10479-84. PubMed.
15. Lohse P, Rader DJ, Brewer HB Jr. Heterozygosity for apolipoprotein E-4Philadelphia(Glu13----Lys, Arg145----Cys) is associated with incomplete dominance of type III hyperlipoproteinemia. J Biol Chem. 1992 Jul 5;267(19):13642-6. PubMed.
16. Pirim D, Radwan ZH, Wang X, Niemsiri V, Hokanson JE, Hamman RF, Feingold E, Bunker CH, Demirci FY, Kamboh MI. Apolipoprotein E-C1-C4-C2 gene cluster region and inter-individual variation in plasma lipoprotein levels: a comprehensive genetic association study in two ethnic groups. PLoS One. 2019;14(3):e0214060. Epub 2019 Mar 26 PubMed.
18. Hoffmann TJ, Theusch E, Haldar T, Ranatunga DK, Jorgenson E, Medina MW, Kvale MN, Kwok PY, Schaefer C, Krauss RM, Iribarren C, Risch N. A large electronic-health-record-based genome-wide study of serum lipids. Nat Genet. 2018 Mar;50(3):401-413. Epub 2018 Mar 5 PubMed.
19. Wojcik GL, Graff M, Nishimura KK, Tao R, Haessler J, Gignoux CR, Highland HM, Patel YM, Sorokin EP, Avery CL, Belbin GM, Bien SA, Cheng I, Cullina S, Hodonsky CJ, Hu Y, Huckins LM, Jeff J, Justice AE, Kocarnik JM, Lim U, Lin BM, Lu Y, Nelson SC, Park SL, Poisner H, Preuss MH, Richard MA, Schurmann C, Setiawan VW, Sockell A, Vahi K, Verbanck M, Vishnu A, Walker RW, Young KL, Zubair N, Acuña-Alonso V, Ambite JL, Barnes KC, Boerwinkle E, Bottinger EP, Bustamante CD, Caberto C, Canizales-Quinteros S, Conomos MP, Deelman E, Do R, Doheny K, Fernández-Rhodes L, Fornage M, Hailu B, Heiss G, Henn BM, Hindorff LA, Jackson RD, Laurie CA, Laurie CC, Li Y, Lin DY, Moreno-Estrada A, Nadkarni G, Norman PJ, Pooler LC, Reiner AP, Romm J, Sabatti C, Sandoval K, Sheng X, Stahl EA, Stram DO, Thornton TA, Wassel CL, Wilkens LR, Winkler CA, Yoneyama S, Buyske S, Haiman CA, Kooperberg C, Le Marchand L, Loos RJ, Matise TC, North KE, Peters U, Kenny EE, Carlson CS. Genetic analyses of diverse populations improves discovery for complex traits. Nature. 2019 Jun;570(7762):514-518. Epub 2019 Jun 19 PubMed.
20. Hu Y, Graff M, Haessler J, Buyske S, Bien SA, Tao R, Highland HM, Nishimura KK, Zubair N, Lu Y, Verbanck M, Hilliard AT, Klarin D, Damrauer SM, Ho YL, VA Million Veteran Program, Wilson PW, Chang KM, Tsao PS, Cho K, O'Donnell CJ, Assimes TL, Petty LE, Below JE, Dikilitas O, Schaid DJ, Kosel ML, Kullo IJ, Rasmussen-Torvik LJ, Jarvik GP, Feng Q, Wei WQ, Larson EB, Mentch FD, Almoguera B, Sleiman PM, Raffield LM, Correa A, Martin LW, Daviglus M, Matise TC, Ambite JL, Carlson CS, Do R, Loos RJ, Wilkens LR, Le Marchand L, Haiman C, Stram DO, Hindorff LA, North KE, Kooperberg C, Cheng I, Peters U. Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study. PLoS Genet. 2020 Mar;16(3):e1008684. Epub 2020 Mar 30 PubMed.
21. Radwan ZH, Wang X, Waqar F, Pirim D, Niemsiri V, Hokanson JE, Hamman RF, Bunker CH, Barmada MM, Demirci FY, Kamboh MI. Comprehensive evaluation of the association of APOE genetic variation with plasma lipoprotein traits in U.S. whites and African blacks. PLoS One. 2014;9(12):e114618. Epub 2014 Dec 12 PubMed.
22. Tahir UA, Katz DH, Avila-Pachecho J, Bick AG, Pampana A, Robbins JM, Yu Z, Chen ZZ, Benson MD, Cruz DE, Ngo D, Deng S, Shi X, Zheng S, Eisman AS, Farrell L, Hall ME, Correa A, Tracy RP, Durda P, Taylor KD, Liu Y, Johnson WC, Guo X, Yao J, Chen YI, Manichaikul AW, Ruberg FL, Blaner WS, Jain D, NHLBI Trans-Omics for Precision Medicine 1 Consortium, Bouchard C, Sarzynski MA, Rich SS, Rotter JI, Wang TJ, Wilson JG, Clish CB, Natarajan P, Gerszten RE. Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals. Nat Commun. 2022 Aug 22;13(1):4923. PubMed.
23. Stalenhoef AF, Malloy MJ, Kane JP, Havel RJ. Metabolism of apolipoproteins B-48 and B-100 of triglyceride-rich lipoproteins in patients with familial dysbetalipoproteinemia. J Clin Invest. 1986 Sep;78(3):722-8. PubMed.
24. Ji ZS, Fazio S, Mahley RW. Variable heparan sulfate proteoglycan binding of apolipoprotein E variants may modulate the expression of type III hyperlipoproteinemia. J Biol Chem. 1994 May 6;269(18):13421-8. PubMed.
25. Libeu CP, Lund-Katz S, Phillips MC, Wehrli S, Hernáiz MJ, Capila I, Linhardt RJ, Raffaï RL, Newhouse YM, Zhou F, Weisgraber KH. New insights into the heparan sulfate proteoglycan-binding activity of apolipoprotein E. J Biol Chem. 2001 Oct 19;276(42):39138-44. Epub 2001 Aug 10 PubMed.
26. Dong J, Peters-Libeu CA, Weisgraber KH, Segelke BW, Rupp B, Capila I, Hernáiz MJ, LeBrun LA, Linhardt RJ. Interaction of the N-terminal domain of apolipoprotein E4 with heparin. Biochemistry. 2001 Mar 6;40(9):2826-34. PubMed.
27. Ruiz J, Kouiavskaia D, Migliorini M, Robinson S, Saenko EL, Gorlatova N, Li D, Lawrence D, Hyman BT, Weisgraber KH, Strickland DK. The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor. J Lipid Res. 2005 Aug;46(8):1721-31. Epub 2005 May 1 PubMed.
28. Chen J, Li Q, Wang J. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14813-8. Epub 2011 Aug 22 PubMed.
29. Zhou Y, Mägi R, Milani L, Lauschke VM. Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk. J Lipid Res. 2018 Oct;59(10):1987-2000. Epub 2018 Aug 3 PubMed.
30. Stuchell-Brereton MD, Zimmerman MI, Miller JJ, Mallimadugula UL, Incicco JJ, Roy D, Smith LG, Cubuk J, Baban B, DeKoster GT, Frieden C, Bowman GR, Soranno A. Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2215371120. Epub 2023 Feb 7 PubMed.
31. Nemergut M, Marques SM, Uhrik L, Vanova T, Nezvedova M, Gadara DC, Jha D, Tulis J, Novakova V, Planas-Iglesias J, Kunka A, Legrand A, Hribkova H, Pospisilova V, Sedmik J, Raska J, Prokop Z, Damborsky J, Bohaciakova D, Spacil Z, Hernychova L, Bednar D, Marek M. Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate. Mol Neurodegener. 2023 Jun 6;18(1):38. PubMed.
32. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.
33. Mariano C, Alves AC, Medeiros AM, Chora JR, Antunes M, Futema M, Humphries SE, Bourbon M. The familial hypercholesterolaemia phenotype: Monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes. Clin Genet. 2020 Mar;97(3):457-466. PubMed.

External Citations

1. GWAS catalog

Further Reading