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

Aleksandra , Beata Krzysztof Małgorzata Chodakowska-Z˙ ebrowskac, Maria Barcikowskaa and Cezary Z˙ ekanowskia aDepartment of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland bDepartment of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin, Poland

bDepartment of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin, Poland cNeurology Clinic, Warsaw Central Clinic Hospital CSK MSWiA, Warszawa, Poland

Accepted 31 August 2011

Abstract. Recently, it has been reported that TOMM40 variable-length poly-T sequence polymorphism (rs10524523) in combi- nation 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

data available online: http://dx.doi.org/10.3233/JAD-2011-110743

INTRODUCTION

and its effect is dose-dependent [2, 3]. However, inher- itance of E4 is neither necessary nor sufficient for LOAD development.

The risk of developing late-onset Alzheimer’s dis- ease (LOAD) is in 60–80% attributable to genetic factors [1]. APOE4 (E4) allele of the APOE gene is the strongest acknowledged genetic risk factor for LOAD

Recently, it has been reported that a variable-length poly-T sequence polymorphism (rs10524523) in the gene encoding translocase of the outer mitochondrial membrane 40 homolog (TOM40) in combination with APOE alleles significantly influences LOAD age of onset (AOO) [4]. TOMM40 is adjacent to and in linkage disequilibrium with APOE on chromosome 19. TOM40 is a mitochondrial import channel protein

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