Lipoprotein(a) and atrial fibrillation: Meta-analysis of observational and mendelian randomization studies shows no clinically meaningful association.

BACKGROUND

Elevated lipoprotein(a) [Lp(a)] is an established risk factor for atherosclerotic cardiovascular disease, but its relationship with atrial fibrillation (AF) remains uncertain. We conducted a meta-analysis of observational studies and Mendelian randomization (MR) analyses to clarify whether Lp(a) is associated with AF.

OBJECTIVE

To clarify the relationship between Lp(a) and AF.

METHODS

We systematically pooled 16 observational studies analyzing odds ratios (ORs) and hazard ratios (HRs) for AF across higher vs lower Lp(a) exposure, as defined within each study, in 2 separate random-effects models. In parallel, we pooled 7 MR studies that used genetic instruments for Lp(a) to estimate the causal effect on AF. Subgroup analyses were performed by ancestry (European and East Asian).

RESULTS

Observational studies showed no association between Lp(a) and AF (OR 0.980 [0.901, 1.070], P = 0.581; HR 1.058 [0.998, 1.110], P = 0.057). Stratification by ancestry showed no association either (European, OR 1.079 [0.759, 1.533], P = 0.673; East Asian, OR 0.978 [0.896, 1.068], P = 0.621). In MR studies accounting for sample overlap, we observed no association between Lp(a) and AF (OR 0.976 [0.940, 1.013], P = 0.208). All MR studies pooled with substantial sample overlap showed statistically significant but very small positive effects (OR 1.023 [1.002, 1.044], P < 0.001).

CONCLUSION

Lp(a) is not associated with AF in observational or MR meta-analysis. MR analyses do not demonstrate a significant association when restricted to independent datasets, indicating that any true causal relationship is unlikely to be clinically meaningful.