TOMM40 rs10524523 Polymorphism's Role in Late-Onset Alzheimer's Disease and in Longevity

Article type: Research Article

Authors: Maruszak, Aleksandra^{a; *} | Pepłońska, Beata^a | Safranow, Krzysztof^b | Chodakowska-Żebrowska, Małgorzata^c | Barcikowska, Maria^a | Żekanowski, Cezary^a

Affiliations: [a] Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland | [b] Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin, Poland | [c] Neurology Clinic, Warsaw Central Clinic Hospital CSK MSWiA, Warszawa, Poland

Correspondence: [*] Correspondence to: Aleksandra Maruszak, Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland. Tel: +4822 6086485; Fax: +4822 6685532; E-mail: aleksandra.maruszak@gmail.com.

Abstract: Recently, it has been reported that TOMM40 variable-length poly-T sequence polymorphism (rs10524523) in combination with APOE alleles (E2, E3, E4) significantly influences late-onset Alzheimer's disease (LOAD) age of onset. In a group of 414 LOAD patients, 173 centenarians and 305 neurologically healthy individuals, we investigated the impact of TOMM40 poly-T tracts on LOAD incidence, age of onset, and longevity. TOMM40 allelic variants were classified into four categories: short (S; 14–16T), long a (La; 20–22T), long b (Lb; 26–30T), and very long (VL; 31–39T). Our results demonstrate that La and Lb share similar characteristics in affecting LOAD risk, thus for some analyses they were combined into L category. We observed significantly lower frequency of VL allele (p < 0.0001) and significantly higher frequency of L alleles in the LOAD patients compared to the control individuals (p < 0.0001). S/S, S/VL, and VL/VL genotypes and VL-E2, S-E3, VL-E3 haplotypes are significantly associated with lower LOAD risk. VL-E3 haplotype carriers significantly more frequently developed LOAD when they were ≥79 years old. Additionally, S/L genotype is associated with a significantly increased LOAD risk (p < 0.0001). We conclude that in the carriers of TOMM40-APOE haplotypes comprising E4 allele, the TOMM40 rs10524523 allele does not play substantial role in establishing LOAD risk. Nevertheless, TOMM40 L allele increases the risk when E4 is absent. Finally, L allele, as well as genotypes (S/L, V/L) and haplotypes (L-E3, L-E4) comprising L significantly reduce the likelihood of living up to 100 years.

Keywords: Alzheimer's disease, APOE, association study, haplotype, late-onset Alzheimer's disease, longevity, TOMM40

DOI: 10.3233/JAD-2011-110743

Journal: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 309-322, 2012