Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms

Abstract

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms.Neuromuscular Disorders, 23 (12 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractA polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in Alzheimer's disease and APOE-TOMM40genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer's disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-β and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90Caucasian s-IBM patients (55 males; age 69.1± 9.6). In carriers of APOE ε3/ε3 or ε3/ε4, genotypes with a very long (VL) poly-T repeat were under-represented in s-IBM compared to controls and were associated with a later age at symptom onset, suggesting that these genotypes may be protective.Our study is the first to suggest that polymorphisms in genes controlling mitochondrial function can influence susceptibility to s-IBM and have disease modifying effects. However, further studies in other s-IBM populations are needed to confirm these findings, as well as expression studies of different TOMM40 alleles in muscle tissue.

APOE-TOMM40 in the Pharmacogenomics of Dementia

“…Recent studies also suggest that the TOMM40 gene rs10524523 ("523") variable length poly T repeat polymorphism is associated to a certain extent with similar AD phenotypes as those reported for APOE, such as brain white matter changes [56,57] or different biomarkers [58][59][60][61]. In addition, the TOMM40 rs2075650 G allele may be a risk factor for the development of depression [62] and sporadic inclusion body myositis [63]. Different markers at the 19q13-q13.2 chromosomal region, including the rs2075650 and rs157590 (TOMM40), rs1064725 (APOC1), and rs429358 and rs7412 (APOE) SNPs also show association with primary progressive aphasia and the behavioural variant frontotemporal dementia [64].…”

African‐American TOMM40'523‐APOEhaplotypes are admixture of West African and Caucasian alleles

“…The relationship of other aggregating peptides, such as a-synuclein, may affect mitochondrial dynamics and select other specific neuronal cell types characteristic of other neurodegenerative diseases [35][36][37][38][39][40]. Clearly there is value in investigating the participation of other molecules, like synuclein and TDP-43 (transactive response DNA-binding protein 43, for mitochondrial interactions in neuronal cells specifically affected in other neuropathologically defined diseases [39,40]).…”

Sporadic inclusion body myositis: the genetic contributions to the pathogenesis

“…A polyT repeat, an intronic polymorphism (rs10524523), in the TOMM40 gene together with the APOE genotypes has been shown to influence disease susceptibility of AD [108]. It has been reported that carriers of the APOE ϵ3 allele with a very long (VL) polyT repeat alleles in TOMM40 had reduced risk of sIBM compared to controls, and this was also associated with a later age at onset of symptoms [56]. The rs10524523 may modulate expression levels of TOMM40 and/or APOE to influence disease susceptibility.…”