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

• Published in: Neuromuscular disorders : NMD 2013-12, Vol.23 (12), p.969-974
• Main Authors: Mastaglia, F.L, Rojana-udomsart, A, James, I, Needham, M, Day, T.J, Kiers, L, Corbett, J.A, Saunders, A.M, Lutz, M.W, Roses, A.D
• Format: Article
• Language: English
• Subjects: Age of Onset; Aged; APOE; Apolipoproteins E - genetics; Female; Gene Frequency; Genetic Predisposition to Disease - genetics; Genotype; Humans; Kaplan-Meier Estimate; Male; Membrane Transport Proteins - genetics; Middle Aged; Myositis, Inclusion Body - genetics; Myositis, Inclusion Body - mortality; Neurology; Polymorphism, Single Nucleotide - genetics; Sporadic IBM; Susceptibility; TOMM40; Trinucleotide Repeat Expansion - genetics
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2013.09.008

Abstract A 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-TOMM40 genotypes 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 90 Caucasian s-IBM patients (55 males; age 69.1 ± 9.6). In carriers of APOE ε 3/ ε 3 or ε 3 /ε 4, 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.