The causal association between lipid-lowering drug targets and albuminuria risk: A drug-target Mendelian randomization study.

BACKGROUND

Lipid-lowering therapies may attenuate kidney disease progression; however, whether specific lipid-lowering drug targets exert causal effects on albuminuria, which is an early marker of kidney injury, remains unclear.

OBJECTIVE

To assess whether lipid-lowering drugs causally influence albuminuria risk and explore potential mediating pathways.

METHODS

We conducted drug-target Mendelian randomization (MR) for 4 targets (lipoprotein lipase [LPL], peroxisome proliferator-activated receptor alpha [PPARA], 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR], proprotein convertase subtilisin/kexin type 9 [PCSK9]) using 2 complementary approaches. Summary data-based MR (SMR) leveraged cis-expression quantitative trait loci to proxy target-gene expression, whereas cis-MR used lipid-associated cis variants to proxy target perturbation. Albuminuria summary statistics were obtained from CKDGen (cases: urinary albumin-to-creatinine ratio [UACR] >30 mg/g; controls: UACR <10 mg/g). Colocalization and 2-step MR evaluated shared genetic signals and potential mediation.

RESULTS

SMR suggested that higher LPL expression was associated with lower albuminuria risk (odds ratio [OR], 0.987; 95% CI, 0.979-0.995; P = 9.68 × 10-4). In cis-MR, a genetically predicted 1 mmol/L triglyceride (TG) decrease attributable to LPL was associated with reduced albuminuria risk (OR, 0.880; 95% CI, 0.832-0.931; P = 8.04 × 10-6). No significant effects were observed for LDL-C-lowering targets (HMGCR, PCSK9) or PPARA. Colocalization supported a possible shared signal between whole-blood LPL expression and albuminuria (posterior probability for hypothesis 4 = 0.657). Two-step MR suggested partial mediation via type 2 diabetes (mediated proportion 11.88%; 95% CI, 5.32%-18.45%), atrial fibrillation (4.49%; 95% CI, 1.25%-7.72%), and visceral adipose tissue (4.69%; 95% CI, 1.27%-8.11%).

CONCLUSION

Our genetic study suggests that genetically proxied LPL activation is associated with lower albuminuria risk, consistent with TG lowering and partial mediation through cardiometabolic pathways.