APOE-TOMM40 in the Pharmacogenomics of Dementia
Abstract
Polymorphic variants present in the APOE-TOMM40 region (19q13.2) are implicated in Alzheimer’s disease (AD) and have been shown to modify disease risk, age at onset of symptoms, and the therapeutic response to conventional drugs. We have investigated the structure of the APOE-TOMM40 region and the influence of APOE and TOMM40 poly T variants (rs10524523) in the therapeutic response to a multifactorial treatment in 920 Spanish patients with AD. The frequencies of TOMM40 poly T genotypes were: 18.37% S/S, 7.83% S/L, 38.80% S/VL, 1.52% L/L, 7.17% L/VL, and 26.31% VL/VL. The most frequent APOE-TOMM40 associations were as follows: 82% APOE-3/3 with S/S, 63% with S/VL, and 40% with VL/VL; 90% APOE-3/4 with S/L, 57% with L/VL, and 43% with VL/VL; and 100% APOE-4/4 with L/L. Globally, the response rate was about 59%, with no difference between females and males. APOE-4 carriers were found to be the worst responders (45-56%) whereas APOE-3/3 carriers were the best responders (70%) for a transient period of cognitive improvement (<12 a="" ad.="" among="" and="" apoe-tomm40="" best="" by="" carriers="" conventional="" exert="" followed="" genotype="" harboring="" in="" influence="" l="" m="" on="" p="" patients="" poly="" powerful="" responders="" response="" s="" specific="" t="" the="" therapeutic="" therefore="" those="" to="" tomm40="" treatments="" variants="" vl="" were="" worst="">
Keywords
Alzheimer’s disease; APOE; Multifactorial treatment; Pharmacogenomics; Therapeutic response rate; TOMM40
Abbreviations
A2BP1: Ataxin-2 Binding Protein 1; ABAT: 4-aminobutyrate aminotransferase; ABCA7: ATP-binding cassette, sub-family A (ABC1), member 7; ABCB1: ATP-binding cassette, sub-family B (MDR/TAP), member 1; ABCs: ATPbinding cassette family; ABO: ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase); ACE: Angiotensin I Converting Enzyme; AD: Alzheimer’s Disease; AGT: Angiotensinogen; APOC1: Apolipoprotein C-I; APOC2: Apolipoprotein C-II; APOC4: Apolipoprotein C-IV; APOE: Apolipoprotein E; APOs: Apolipoproteins; APP: Amyloid beta (A4) Precursor Protein; BIN1: Bridging Integrator 1; CD2AP: CD2-associated protein; CDH2: Cadherin 2, type 1; CLU: Clusterin; CNVs: Copy Number Variations; CR1: Complement Component (3b/4b) Receptor 1; CRMP1: Collapsin Response Mediator Protein 1; CRP: C-reactive protein; CVD: Cardiovascular Disease; CYP2D6: Cytochrome P450, family 2, subfamily D, polypeptide 6; CYPs: Cytochrome P450 family; DMRT1: Doublesex and mab-3 related transcription factor 1; EO-FAD: Earlyonset Familial Alzheimer’s Disease; EPHA5: EPH receptor A5; EPHA6: EPH receptor A6; ERMP1: Endoplasmic Reticulum metallopeptidase 1; GWAS: Genome-wide Association Studies; HMGCR: 3-hydroxy- 3-methylglutaryl-CoA reductase; ILs: Interleukins; L: Long; LOAD: Late Onset Alzheimer’s Disease; MAPT: Microtubule-associated protein tau; MS4A4E: Membrane-spanning 4-domains, subfamily A, member 4E ; MS4A6A: Membrane-spanning 4-domains, subfamily A, member 6A; MTHFR: Methylenetetrahydrofolate Reductase (NAD(P) H); NATs: N-acetyltransferase family; NFT: Neurofibrillary Tangles; NOS: Nitric Oxide Synthase; PICALM: Phosphatidylinositol binding clathrin assembly protein; PRNP: Prion protein; PSEN1: Presenilin 1; PSEN2: Presenilin 2; S: Short; SLCs: Solute Carrier Family; SNPs: Single-nucleotide Polymorphisms; TOMM40: Translocase of Outer Mitochondrial Membrane 40 homolog (yeast); UGTs: UDP glucuronosyltransferase family; VL: Very Long; VLDLR: Very Low Density Lipoprotein Receptor
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