Genetics
Bidirectional Mendelian randomisation confirms Lp(a) causally raises chronic kidney disease risk, not the reverse (Ren Fail 2024)
Original title: Causal effect of lipoprotein(a) level on chronic kidney disease of European ancestry: a two-sample Mendelian randomization study
Using eight single-nucleotide polymorphisms as instrumental variables for Lp(a) and summary data from the CKDGen consortium genome-wide association study, this two-sample Mendelian randomisation study tested the causal relationship between Lp(a) and chronic kidney disease (CKD) of European ancestry in both directions. Fixed-effect inverse-variance weighted analysis found genetically predicted Lp(a) significantly increased CKD risk (odds ratio 1.039, 95% CI 1.009-1.069, p = 0.010), with no evidence of pleiotropy on MR-Egger testing and consistent results across sensitivity analyses (simple median, weighted median, maximum likelihood). In the reverse direction, random-effects analysis found no causal effect of CKD on Lp(a) levels (odds ratio 1.154, 95% CI 0.845-1.576, p = 0.367). The findings support a one-way causal path from elevated Lp(a) to CKD risk, not the reverse, strengthening the case for Lp(a) as a genuine, modifiable contributor to kidney disease rather than merely a marker of it.
Original abstract
Introduction: Chronic kidney disease is a growing health issue, and the options of prevention and therapy remain limited. Although a number of observational studies have linked higher Lp(a) [lipoprotein(a)] levels to the kidney impairment, the causal relationship remains to be determined. The purpose of this study was to assess the causal association between Lp(a) levels and CKD.
Methods: We selected eight single-nucleotide polymorphisms (SNPs) significantly associated with Lp(a) levels as instrumental variables. Genome-wide association study (GWAS) from CKDGen consortium yielded the summary data information for CKD. We designed the bidirectional two-sample Mendelian randomization (MR) analyses. The estimates were computed using inverse-variance weighted (IVW), simple median, weighted median, and maximum likelihood. MR-Egger regression was used to detect pleiotropy.
Results: Fixed-effect IVW analysis indicated that genetically predicted Lp(a) levels were associated with CKD significantly (odds ratio, 1.039; 95% CI, 1.009-1.069; p = 0.010). The SNPs showed no pleiotropy according to result of MR-Egger test. Results from sensitivity analyses were consistent. In the inverse MR analysis, random-effect IVW method showed CKD had no causal effect on the elevated Lp(a) (odds ratio, 1.154; 95% CI, 0.845-1.576; p = 0.367).
Conclusion: In this bidirectional two-sample MR analysis, the causal deteriorating effects of genetically predicted plasma Lp(a) levels on the risk of CKD were identified. On the contrary, there is no evidence to support a causal effect of CKD on Lp(a) levels.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.