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Lp(a) Has Specific Effects on Coronary Artery Disease Independent of LDL-C: A Mendelian Randomization Study

Moa P Lee1, Sarah H Koenigsberg1, Mohammad Y Anwar1

  • 1Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.

JACC. Advances
|March 27, 2026
PubMed

Insights

Lipoprotein(a) (Lp(a)) causally impacts coronary artery disease and HbA1c, but not type 2 diabetes. Optimal Lp(a) thresholds for cardiovascular risk stratification vary by ancestry.

Area of Science:

  • Genetics and Cardiovascular Disease Research
  • Metabolic Disease Research
  • Biomarker Discovery

Background:

  • Mendelian randomization studies indicate a causal link between lipoprotein(a) (Lp(a)) and atherosclerotic cardiovascular disease.
  • The noncardiovascular effects of Lp(a), such as its impact on diabetes risk, remain under-investigated.

Purpose of the Study:

  • To estimate the direct causal phenotypic effects of lipoprotein(a) (Lp(a)) exposure.
  • To assess the association between the LPA null allele rs41272114 and type 2 diabetes.
  • To determine ancestry-specific Lp(a) thresholds for risk stratification.

Main Methods:

  • A noninterventional phenome-wide association study in the UK Biobank (n=425,677).
  • Utilized 1,456 phenotypes across 18 classes, 4 ancestry-specific polygenic risk scores, and false discovery rate correction.
  • Employed network deconvolution Mendelian randomization to differentiate direct from indirect causal effects, controlling for confounding factors.

Main Results:

  • Lipoprotein(a) (Lp(a)) showed significant associations with 80 phenotypes across 7 classes.
  • Higher Lp(a) had direct causal effects on coronary artery disease (OR: 1.36) and HbA1c (β=0.099), independent of LDL-C.
  • Very low Lp(a) was not causally linked to type 2 diabetes or HbA1c; optimal thresholds for myocardial infarction risk varied by ancestry.

Conclusions:

  • Elevated lipoprotein(a) (Lp(a)) exposure demonstrates direct, independent causal effects on coronary artery disease and HbA1c.
  • Very low Lp(a) exposure is not causally associated with type 2 diabetes.
  • Optimal European and African ancestry thresholds for cardiovascular risk stratification are comparable and below current guideline recommendations.
Abstract

Keywords:
Mendelian randomizationatherosclerotic cardiovascular diseaselipoprotein(a)phenome-wide association studytype 2 diabetes

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