TOMM40 gene

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
Post Reply
75percent
Contributor
Contributor
Posts: 7
Joined: Sat Nov 27, 2021 2:09 pm

TOMM40 gene

Post by 75percent »

Hello, I came across an article (https://link.springer.com/article/10.10 ... 21-00814-5) that discusses, in part, modified risk of APOE4 depending on the TOMM40 gene.

"Roses et al. reported one polymorphism, rs10524523, located in intron 6 of TOMM40, defined by the length of its polyT tract, to be closely associated with the age at AD onset [42]. After that, surging amounts of evidence showing the interaction between TOMM40 and AD have been published, suggesting that the TOMM40/APOE alleles are better predictors of disease onset than APOE alone"

I am wondering if anyone knows how to determine the length of the polyT tract from microarray or whole genome sequencing results?
NF52
Support Team
Support Team
Posts: 2772
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

Re: TOMM40 gene

Post by NF52 »

75percent wrote: Sun Nov 13, 2022 2:50 pm Hello, I came across an article (https://link.springer.com/article/10.10 ... 21-00814-5) that discusses, in part, modified risk of APOE4 depending on the TOMM40 gene.

"Roses et al. reported one polymorphism, rs10524523, located in intron 6 of TOMM40, defined by the length of its polyT tract, to be closely associated with the age at AD onset [42]. After that, surging amounts of evidence showing the interaction between TOMM40 and AD have been published, suggesting that the TOMM40/APOE alleles are better predictors of disease onset than APOE alone"

I am wondering if anyone knows how to determine the length of the polyT tract from microarray or whole genome sequencing results?
Hi "75percent",

You posed an interesting question. TOMM40 appears to have several variants involved with mitochondrial function. The one mentioned in your post, rs10524523, appears to have an S risk variant, an L protective variant and a possibly neutral V variant. Note that these letters are not the ones used in 23&me and other gene descriptions of A/T or G/C, and my 23& me report does not report on rs10524523 ,which later scientists apparently refer to as TOMM40 "523".

The article by Roses et al that was quoted in 2022 was actually written in 2010, and may be out of date per this 2021 article in the respected journal Nature: TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease
previous literature has indicated that the predictive value of TOMM40 ‘523’ in late-onset AD primarily applies to carriers of APOE ε3.
. This 2012 article appears to say the same thing, in studying a very large UK cohort followed of decades:
A polymorphic variant of TOMM40 (rs10524523) was included to differentiate between the effects of the APOE E3 and E4 allelic variants. Cognitive performance on the domains of verbal memory, abstract reasoning and verbal fluency was assessed at mean age 79 years (n=501), and again at mean ages of 83 (n=284) and 87 (n=187). Using linear mixed models adjusted for demographic variables, vascular risk factors and IQ at age 11 years, possession of the APOE E4 allele was associated with a higher relative rate of cognitive decline over the subsequent 8 years [i.e. from 79-87] for verbal memory and abstract reasoning. Individuals with the long allelic variant of TOMM40, which is linked to APOE E4, showed similar results.
Two things seem important:
1. In the large population group, the risk of ApoE 4 for a decline in verbal memory and reasoning was ONLY seen when comparing the 83-87 year olds with ApoE 4 and ApoE 3.
2. People with the variant of TOMM40 showed declines "similar" to those with ApoE4. That's not very clearly written, but seems to show that ApoE 4 and TOMM40 is no worse than ApoE 4, and that ApoE3 with TOMM 40 is more like ApoE 4.

But just to make it confusing, here's a study of another SNP for TOMM40 which MAY have an effect ONLY in women with ApoE4:
While APOE4 was linked to a reduced hippocampal volume (HV) in a number of studies, the impact of rs2075650...(in TOMM40) ...may have independent effects on HV or interact with APOE4. We studied associations of rs2075650 (G allele, risk factor for AD), rs429358 (C allele, proxy for APOE4)...among 10,738 women and 9,775 men aged 60-75, from UK Biobank. The studied associations didn’t reach statistical significance in men. Our results suggest that rs2075650(G) and rs429358(C) may contribute synergistically to a reduction in hippocampus volume, in females only, and support the role of interactions between genetic risk factors for AD in sex differences in preclinical biomarkers of AD pathology.
Hippocampal Volume Is Smaller In Female Double Carriers Of Two Strongest AD Genetic Risk Factors

I have one copy of rs2075650(G) and am ApoE 4/4 and since I am 70, cannot do anything about my genes at this point, but can make lifestyle choices to keep my healthy brain working. I leave the deep dives into individual genes to the PhDs--we are all more than our genes!
4/4 and still an optimist!
75percent
Contributor
Contributor
Posts: 7
Joined: Sat Nov 27, 2021 2:09 pm

Re: TOMM40 gene

Post by 75percent »

Thank you for the detailed reply NF52. Yes, you appear correct about the effects of the variants - although I still am curious how the variant can be determined from either 23andme or WGS data. Learning about how different genes can influence AD risk is fascinating (and terrifying), and I am definitely guilty of trying to find any mitigating genetic influence, but there appears to be so much left to figure out.
adriana268
Contributor
Contributor
Posts: 10
Joined: Sat Apr 10, 2021 12:31 pm

Re: TOMM40 gene

Post by adriana268 »

Hi ! how did you find your Tomm40 status? I couldn't find it in any of the reports
User avatar
floramaria
Support Team
Support Team
Posts: 1423
Joined: Tue Jul 04, 2017 11:22 am
Location: Northern New Mexico

Re: TOMM40 gene

Post by floramaria »

75percent wrote: Tue Nov 22, 2022 10:54 pm Thank you for the detailed reply NF52. Yes, you appear correct about the effects of the variants - although I still am curious how the variant can be determined from either 23andme or WGS data. Learning about how different genes can influence AD risk is fascinating (and terrifying), and I am definitely guilty of trying to find any mitigating genetic influence, but there appears to be so much left to figure out.
NF52 wrote: Wed Nov 16, 2022 6:35 pm You posed an interesting question.
adriana268 wrote: Sun Jan 08, 2023 10:09 am Hi ! how did you find your Tomm40 status? I couldn't find it in any of the reports
HI 75percent and NF52, Just want to be sure you see Adriana's question in case either of you can answer it. I don't have a clue. :roll:
Functional Medicine Certified Health Coach
IFM/ Bredesen Training in Reversing Cognitive Decline (March 2017)
ReCODE 2.0 Health Coach with Apollo Health
mike
Senior Contributor
Senior Contributor
Posts: 851
Joined: Fri Mar 09, 2018 4:55 pm
Location: CA - Sonoma County

Re: TOMM40 gene

Post by mike »

adriana268 wrote: Sun Jan 08, 2023 10:09 am Hi ! how did you find your Tomm40 status? I couldn't find it in any of the reports
You need to "Browse Raw Data" on the dropdown next to your name. Search for rs2075650.
Sonoma Mike
4/4
Max100
Contributor
Contributor
Posts: 17
Joined: Wed Aug 31, 2022 8:19 am

Re: TOMM40 gene

Post by Max100 »

With respect to rs10524523 or TOMM “523” it appears that 3/3 carriers are most affected by this SNP? There’s more variation with S, L, VL etc? If you check Roses’ chart from 2010 in his “discovery” study, there are A and B categories. “A” is the higher LOAD probability group and “B” less likely. 97% of 4/4 and 76% of 3/4 fall in group A. 3/3 is almost evenly split. This might imply that 3% of 4/4 and 24% of 3/4 could be at reduced risk based on the lifetime risk numbers. 3/3 risk could be very deterministic on which “clade” they fell into according at least to this initial study. There seems to very strong linkage disequilibrium between APOE and TOMM 523 which might reduce the importance? Is my understanding of this correct? Thanks in advance for any feedback!

https://www.ncbi.nlm.nih.gov/core/lw/2. ... 0969f2.jpg
Post Reply