Association between Human Blood Proteome and the Risk of Myocardial Infarction

TL;DR

This study identifies blood proteins linked to heart attack risk and evaluates their potential as safe drug targets.

Contribution

The study uses Mendelian randomization to identify causal proteins and assess their side effects for heart attack prevention.

Findings

Elevated CT-1, SELENOS, and NAGAT are linked to increased heart attack risk.

KIR2DS2 and VPS29 are associated with reduced heart attack risk and favorable side effect profiles.

KIR2DS2 shows promise as a safe drug target for preventing heart attacks.

Abstract

The objective of this study is to estimate the causal
relationship between plasma proteins and myocardial infarction (MI) through
Mendelian randomization (MR), predict potential target-mediated side effects
associated with protein interventions, and ensure a comprehensive assessment of
clinical safety.

From 3 proteome genome-wide association
studies (GWASs) involving 9775 European participants, 331 unique blood proteins
were screened and chosed. The summary data related to MI were derived from a GWAS
meta-analysis, incorporating approximately 61,000 cases and 577,000 controls. The
assessment of associations between blood proteins and MI was conducted through MR
analyses. A phenome-wide MR (Phe-MR) analysis was subsequently employed to
determine the potential on-target side effects of protein interventions.

Causal mediators for MI were identified, encompassing
cardiotrophin-1 (CT-1) (odds ratio [OR] per SD increase: 1.16; 95% confidence
interval [CI]: 1.13–1.18; p = 1.29 ×
10-31),
Selenoprotein S (SELENOS) (OR: 1.16; 95% CI: 1.13–1.20; p = 4.73
×
10-24), killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2)
(OR: 0.93; 95% CI: 0.90–0.96; p = 1.08 ×
10-5), vacuolar
protein sorting-associated protein 29 (VPS29) (OR: 0.92; 95% CI: 0.90–0.94;
p = 8.05 ×
10-13), and histo-blood group ABO system
transferase (NAGAT) (OR: 1.05; 95% CI: 1.03–1.07; p = 1.41 ×
10-5). In the Phe-MR analysis, memory loss risk was mediated by CT-1, VPS29
exhibited favorable effects on the risk of 5 diseases, and KIR2DS2 showed no
predicted detrimental side effects.

Elevated genetic
predictions of KIR2DS2 and VPS29 appear to be linked to a reduced risk of MI,
whereas an increased risk is associated with CT-1, SELENOS, and NAGAT. The
characterization of side effect profiles aids in the prioritization of drug
targets. Notably, KIR2DS2 emerges as a potentially promising target for
preventing and treating MI, devoid of predicted detrimental side effects.

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