Otherindependent cross-checkabstract checked I-EGG-115 standard review
Genetic study: TMAO may be a marker, not a cause, of heart disease
Assessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: A Bidirectional Mendelian Randomization Analysis.
Overview
Jia J et al.. Diabetes 2019 · PMID 31167879 · DOI 10.2337/db19-0153
Genetically higher TMAO was not linked to heart attack or stroke; kidney disease raised TMAO.
Does the study support the specific claim? No · Methodological quality: moderate
Plain-language summary
Study explained simply
- What did the researchers want to find out?
Test the causal direction between TMAO and disease.
- How was the study done?
Mendelian randomization.
- How many people, animals or samples were studied?
GWAS consortia.
- What was actually found?
No causal effect of TMAO on CVD; diseases raise TMAO.
- How large was the observed effect?
Not significant for CVD outcomes.
- What do the results mean in everyday life?
High TMAO may reflect kidney or metabolic disease rather than cause heart attacks.
- What are the study's limitations?
MR assumptions.
- What does it say about Elawady's specific claim?
Undermines the causal chain.
- Do the results apply to Germany and Europe?
Moderate.
- What can explicitly not be concluded from this study?
It cannot fully exclude a small causal effect.
Scientific in-depth review
1. Full reference
- Authors
- Jia J et al.
- Journal
- Diabetes
- Year
- 2019
- Identifier
- PMID 31167879 DOI 10.2337/db19-0153
- Verification
- verified – PubMed efetch 2026-10-26; Crossref works API 2026-10-26
- Retracted
- no
- Corrections
- none
- Extent checked
- abstract only
- Conflicts of interest and funding
not stated in abstract
2. Research question
Are TMAO and its precursors causally related to cardiometabolic diseases, or the reverse?
3. Study design and population
- Study design
- Other – Bidirectional two-sample Mendelian randomization
- Population
GWAS summary data (European-ancestry consortia; details not in abstract)
- Country
International consortia
- Period
not stated in abstract
- Sample size
Not stated in abstract
- Inclusion and exclusion criteria
not detailed in abstract
4. Methods and endpoints
- Exposure / intervention
Genetically predicted TMAO, carnitine, choline, betaine
- Comparator
Per unit genetic change
- Endpoints
T2DM, CAD, MI, stroke, AF, CKD
- Statistical methods
MR with Bonferroni correction
5. Actual results
- Results
Genetically predicted higher TMAO and carnitine were not associated with T2DM, AF, CAD, MI, stroke or CKD after Bonferroni correction. T2DM (0.130 +/- 0.036) and CKD (0.483 +/- 0.168) were causally associated with higher TMAO.
- Absolute risks
not reported
- Authors' conclusion
T2DM and kidney disease increase TMAO levels; observational evidence for cardiovascular diseases may be due to confounding or reverse causality.
6. Strengths
- Genetic instruments reduce confounding
- Bidirectional design
7. Weaknesses
- Weak instruments for metabolites possible
- Power for some outcomes unclear
8. Risk of bias
- Orienting tool
- none applicable
- Type of assessment
- simplified assessment (abstract only)
- Full formal assessment
- no
- Overall risk of bias
- some concerns
- Rationale
MR assumptions (pleiotropy, instrument strength) not fully verifiable from abstract.
9. Assessment of the statistical interpretation
Null MR for CVD plus positive reverse-direction MR supports TMAO as a marker rather than cause.
10. Relevance to the specific claim
Weakens the causal step 'TMAO causes cardiovascular events' on which the archive's argument depends.
11. Independent contrary findings
Animal data show proatherogenic effects of TMAO.
12. Transferability to Germany and Europe
Mostly European-ancestry data.
13. Overall methodological judgement
Important limiting evidence on causality.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | moderate |
| Risk of bias | some concerns |
| Precision of results | moderate |
| Directness | indirect |
| Reproducibility | unknown |
| Consistency with the overall evidence | unknown |
| Regional transferability | moderate |
| Adequacy of the interpretation (by the archive) | not applicable |
14. Open questions
Larger MR with stronger instruments.
15. Linked fact checks
- Egg-yolk phosphatidylcholine is converted by gut bacteria into TMAO, and therefore eggs raise the risk of major cardiovascular events (about 2.5-fold). – Studies contradicting or limiting the claim