A TOMM40/APOE allele encoding APOE‐E3 predicts high likelihood of late‐onset Alzheimer’s disease in autopsy cases
Abstract Background The APOE‐ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE‐ε4 are at variance. Methods We investigated associations of A...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-08-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.1317 |
| _version_ | 1827345675384258560 |
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| author | Selma M. Soyal Markus Kwik Ognian Kalev Stefan Lenz Greta Zara Peter Strasser Wolfgang Patsch Serge Weis |
| author_facet | Selma M. Soyal Markus Kwik Ognian Kalev Stefan Lenz Greta Zara Peter Strasser Wolfgang Patsch Serge Weis |
| author_sort | Selma M. Soyal |
| collection | DOAJ |
| description | Abstract Background The APOE‐ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE‐ε4 are at variance. Methods We investigated associations of AD with haplotypes defined by three TOMM40 and two APOE single nucleotide polymorphisms in 73 and 71 autopsy cases with intermediate and high likelihood of AD (defined by BRAAK stages <V and V‐VI), respectively, and in 150 controls without major neurodegenerative diseases. Results We observed eight haplotypes with a frequency >0.02. The two haplotypes encoding APOE‐E4 showed strong associations with AD that did not differ between intermediate and high likelihood AD. In contrast, a TOMM40 haplotype encoding APOE‐E3 was identified as risk haplotype of high‐ (p = .0186), but not intermediate likelihood AD (p = .7530). Furthermore, the variant allele of rs2075650 located in intron 2 of TOMM40, increased the risk of high‐, but not intermediate likelihood AD on the APOE‐ε3/ε3 background (p = .0230). Conclusion The striking association of TOMM40 only with high likelihood AD may explain some contrasting results for TOMM40 in clinical studies and may reflect an association with more advanced disease and/or suggest a role of TOMM40 in the pathogenesis of neurofibrillary tangles. |
| first_indexed | 2024-03-07T23:15:58Z |
| format | Article |
| id | doaj.art-690badd416d14b2bba64e236ff88dc80 |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-07T23:15:58Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-690badd416d14b2bba64e236ff88dc802024-02-21T11:08:50ZengWileyMolecular Genetics & Genomic Medicine2324-92692020-08-0188n/an/a10.1002/mgg3.1317A TOMM40/APOE allele encoding APOE‐E3 predicts high likelihood of late‐onset Alzheimer’s disease in autopsy casesSelma M. Soyal0Markus Kwik1Ognian Kalev2Stefan Lenz3Greta Zara4Peter Strasser5Wolfgang Patsch6Serge Weis7Institute of Pharmacology and Toxicology Paracelsus Medical University Salzburg AustriaInstitute of Pharmacology and Toxicology Paracelsus Medical University Salzburg AustriaDivision of Neuropathology Neuromed Campus, Kepler University Hospital Linz AustriaDivision of Neuropathology Neuromed Campus, Kepler University Hospital Linz AustriaInstitute of Pharmacology and Toxicology Paracelsus Medical University Salzburg AustriaInstitute of Laboratory Medicine Paracelsus Medical University Salzburg AustriaInstitute of Pharmacology and Toxicology Paracelsus Medical University Salzburg AustriaDivision of Neuropathology Neuromed Campus, Kepler University Hospital Linz AustriaAbstract Background The APOE‐ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE‐ε4 are at variance. Methods We investigated associations of AD with haplotypes defined by three TOMM40 and two APOE single nucleotide polymorphisms in 73 and 71 autopsy cases with intermediate and high likelihood of AD (defined by BRAAK stages <V and V‐VI), respectively, and in 150 controls without major neurodegenerative diseases. Results We observed eight haplotypes with a frequency >0.02. The two haplotypes encoding APOE‐E4 showed strong associations with AD that did not differ between intermediate and high likelihood AD. In contrast, a TOMM40 haplotype encoding APOE‐E3 was identified as risk haplotype of high‐ (p = .0186), but not intermediate likelihood AD (p = .7530). Furthermore, the variant allele of rs2075650 located in intron 2 of TOMM40, increased the risk of high‐, but not intermediate likelihood AD on the APOE‐ε3/ε3 background (p = .0230). Conclusion The striking association of TOMM40 only with high likelihood AD may explain some contrasting results for TOMM40 in clinical studies and may reflect an association with more advanced disease and/or suggest a role of TOMM40 in the pathogenesis of neurofibrillary tangles.https://doi.org/10.1002/mgg3.1317Alzheimer’ diseaseAPOEbeta‐amyloidgeneticshaplotypesneurofibrillary tangles |
| spellingShingle | Selma M. Soyal Markus Kwik Ognian Kalev Stefan Lenz Greta Zara Peter Strasser Wolfgang Patsch Serge Weis A TOMM40/APOE allele encoding APOE‐E3 predicts high likelihood of late‐onset Alzheimer’s disease in autopsy cases Molecular Genetics & Genomic Medicine Alzheimer’ disease APOE beta‐amyloid genetics haplotypes neurofibrillary tangles |
| title | A TOMM40/APOE allele encoding APOE‐E3 predicts high likelihood of late‐onset Alzheimer’s disease in autopsy cases |
| title_full | A TOMM40/APOE allele encoding APOE‐E3 predicts high likelihood of late‐onset Alzheimer’s disease in autopsy cases |
| title_fullStr | A TOMM40/APOE allele encoding APOE‐E3 predicts high likelihood of late‐onset Alzheimer’s disease in autopsy cases |
| title_full_unstemmed | A TOMM40/APOE allele encoding APOE‐E3 predicts high likelihood of late‐onset Alzheimer’s disease in autopsy cases |
| title_short | A TOMM40/APOE allele encoding APOE‐E3 predicts high likelihood of late‐onset Alzheimer’s disease in autopsy cases |
| title_sort | tomm40 apoe allele encoding apoe e3 predicts high likelihood of late onset alzheimer s disease in autopsy cases |
| topic | Alzheimer’ disease APOE beta‐amyloid genetics haplotypes neurofibrillary tangles |
| url | https://doi.org/10.1002/mgg3.1317 |
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