Association of ANGPTL3, ANGPTL4, and DOCK7 polymorphisms with lipid traits and long-term clinical outcomes in patients undergoing PCI
Y Cao, Q Sun, J Zhang, Z Ma, J Li, D Gu, J Yuan, Y SongAbstract
Background
Despite advances in PCI and lipid-lowering therapy, substantial residual cardiovascular risk persists in coronary artery disease (CAD) patients even after achieving LDL-C targets. Remnant cholesterol (RC) from triglyceride-rich lipoproteins is an independent causal driver of this risk. ANGPTL3 and ANGPTL4 regulate lipoprotein lipase and triglyceride catabolism, with loss-of-function variants linked to reduced atherosclerotic risk. DOCK7, co-localised with ANGPTL3 on chromosome 1p31, influences plasma triglyceride levels. The prognostic significance of ANGPTL3 (rs12563308), DOCK7 (rs2131925), and ANGPTL4 (rs1044250, rs7255436) polymorphisms and their haplotype structure in post-PCI populations remain poorly defined.
Purpose
We evaluated associations of these four SNPs and their haplotypes with long-term cardiovascular outcomes and lipid profiles in post-PCI patients, quantified the RC-mediated proportion of genotype-outcome pathways, and examined gene-environment interactions.
Methods
This prospective cohort enrolled 4,304 PCI-treated CAD patients. The primary endpoint was MACCE (composite of all-cause death, MI, revascularisation, and ischaemic stroke, time-to-first-event). Secondary endpoints were all-cause death, cardiac death, MI, stroke, and revascularisation assessed individually. Multivariable Cox regression under four genetic models assessed endpoint associations. Gene-environment interactions were FDR-adjusted using the Benjamini-Hochberg method.
Results
ANGPTL3 rs12563308 minor allele carriage significantly reduced MACCE risk (dominant: HR 0.790, 95% CI 0.656–0.952, P=0.013). ANGPTL4 rs1044250 and rs7255436 heterozygosity reduced cardiac death by ~60% (HR 0.398, 95% CI 0.209–0.756, P=0.005) and ~58% (HR 0.415, 95% CI 0.239–0.720, P=0.002). DOCK7 rs2131925 was associated with lower triglycerides (P=0.007), reduced MI risk (HR 0.747, 95% CI 0.601–0.930, P=0.009), and was the only variant independently associated with lower log-transformed RC (beta=−0.054, P=0.023). Strong linkage disequilibrium existed between ANGPTL3 rs12563308 and DOCK7 rs2131925 (D'=0.992, r²=0.162); their C-G haplotype was associated with reduced MACCE (OR 0.741, 95% CI 0.598–0.919, P=0.006). RC statistically mediated 4.3% of the DOCK7-MI protective association. DOCK7 rs2131925 interacted significantly with hypertension on MACCE (P~adj~=0.001) and on TC, RC, and ApoB (all P~adj~<0.05) after FDR correction.
Conclusion
ANGPTL3, ANGPTL4, and DOCK7 variants and their C-G haplotype are independently associated with long-term cardiovascular outcomes after PCI. RC accounts for a statistically significant but small proportion of DOCK7's MI-protective effect. The DOCK7-hypertension interaction on both MACCE and lipid traits indicates that this variant's effect is modified by blood pressure phenotype, the mechanism of this interaction warrant dedicated investigation.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.