Lp(a) Has Specific Effects on Coronary Artery Disease Independent of LDL-C: A Mendelian Randomization Study
Authors' conclusion
Increasing Lp(a) exposure had direct, independent causal effects on coronary artery disease and HbA1c only; very low Lp(a) exposure is suggested to not be causally associated with type 2 diabetes. The optimal European and African ancestry threshold to stratify cardiovascular risk is comparable, and below 125/105 nmol/L in current U.S./European medical professional society guidelines.
Study context
- Population
- Adults in the UK Biobankadults, 55% female
- Participants
- 425,677 adults
- Comparison
- Genetically estimated Lp(a) exposure across 1,456 phenotypes spanning 18 classes
- Outcome
- Phenotypes associated with Lp(a)
Methodological detailsNetwork deconvolution Mendelian randomization, 4 ancestry-specific polygenic risk scores, false discovery rate multiple testing correction
- Network deconvolution Mendelian randomization
- 4 ancestry-specific polygenic risk scores
- False discovery rate multiple testing correction
Performance
As reported in the abstract
Phenotypes significantly associated
80
Classes
7
Further findings
Direct causal effects of higher Lp(a) exposure, independent of low-density lipoprotein cholesterol
| OR (95% CI) | ||
|---|---|---|
| Higher Lp(a) exposureCoronary artery disease · only these two direct causal effects | 1.36 (1.21–1.54) | |
| 0.512Odds ratio (log scale) |
Very low Lp(a) exposure and type 2 diabetes / HbA1c
| OR (95% CI) | ||
|---|---|---|
| Very low Lp(a) exposureType 2 diabetes; not associated | 0.92 (0.64–1.31) | |
| 0.512Odds ratio (log scale) |
| Outcome | European ancestry | African ancestry | β (95% CI) |
|---|---|---|---|
| Direct causal effects of higher Lp(a) exposure, independent of low-density lipoprotein cholesterolHigher Lp(a) exposure · HbA1c · only these two direct causal effects | 0.099 (0.051–0.15) | ||
| Very low Lp(a) exposure and type 2 diabetes / HbA1cVery low Lp(a) exposure · HbA1c; not associated | −0.016 (−0.062 to 0.030) | ||
| Lp(a) threshold optimally discriminating myocardial infarction risk | (77th percentile) 86 nmol/L | (59th percentile) 93 nmol/L |
Original publication
Lp(a) Has Specific Effects on Coronary Artery Disease Independent of LDL-C: A Mendelian Randomization Study. JACC Adv. Published 25 March 2026. doi:10.
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