The effects of an intronic polymorphism in TOMM40 and APOE genotypes in sporadic inclusion body myositis

Qiang Gang,Simona Zanotti,Michael G Hanna,Jan De Bleecker,Marina Mora,Janice L Holton,Michela Ripolone,Richard J Barohn,Henry Houlden,Renato Mantegazza,Aziz Shaibani,Stefen Brady,Perry B Shieh,Estelle Healy,Edmar Zanoteli,Maurizio Moggio,Matt Parton,Mazen M Dimachkie,Raffaella Violano,Pedro Machado ,Boél De Paepe ,David Hilton‐Jones ,Conceição Bettencourt ,Zoë Fox

doi:10.1016/j.neurobiolaging.2014.12.039

Abstract

A previous study showed that, in carriers of the apolipoprotein E (APOE) genotype ε3/ε3 or ε3/ε4, the presence of a very long (VL) polyT repeat allele in “translocase of outer mitochondrial membrane 40” (TOMM40) was less frequent in patients with sporadic inclusion body myositis (sIBM) compared with controls and associated with a later age of sIBM symptom onset, suggesting a protective effect of this haplotype. To further investigate the influence of these genetic factors in sIBM, we analyzed a large sIBM cohort of 158 cases as part of an International sIBM Genetics Study. No significant association was found between APOE or TOMM40 genotypes and the risk of developing sIBM. We found that the presence of at least 1 VL polyT repeat allele in TOMM40 was significantly associated with about 4 years later onset of sIBM symptoms. The age of onset was delayed by 5 years when the patients were also carriers of the APOE genotype ε3/ε3. In addition, males were likely to have a later age of onset than females. Therefore, the TOMM40 VL polyT repeat, although not influencing disease susceptibility, has a disease-modifying effect on sIBM, which can be enhanced by the APOE genotype ε3/ε3.

Highlights

A previous study showed that, in carriers of the apolipoprotein E (APOE) genotype ε3/ε3 or ε3/ε4, the presence of a very long (VL) polyT repeat allele in “translocase of outer mitochondrial membrane 40” (TOMM40) was less frequent in patients with sporadic inclusion body myositis compared with controls and associated with a later age of sIBM symptom onset, suggesting a protective effect of this haplotype
We found that APOE ε3-TOMM40 VL allele carriers had an even later age of onset of sIBM by 4.9 years in average
Similar results were found when the analysis was restricted to Caucasians

Summary

Introduction

A previous study showed that, in carriers of the apolipoprotein E (APOE) genotype ε3/ε3 or ε3/ε4, the presence of a very long (VL) polyT repeat allele in “translocase of outer mitochondrial membrane 40” (TOMM40) was less frequent in patients with sporadic inclusion body myositis (sIBM) compared with controls and associated with a later age of sIBM symptom onset, suggesting a protective effect of this haplotype. That study reported that among carriers of the APOE genotype ε3/ε3 or ε3/ε4, carriage of a very long (VL) polyT repeats in the intron 6 of TOMM40 (rs10527454) was less frequent in sIBM compared with controls and was associated with a later age of onset of sIBM symptoms (Mastaglia et al, 2013). To further investigate the previously reported association between APOE-TOMM40 and sIBM, we genotyped APOE and the polyT repeat polymorphism in TOMM40 in a large sIBM cohort of 158 affected cases from the International IBM Genetics Consortium and investigated their association with disease risk and the age of onset of sIBM

Methods

Results

Conclusion