# 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.

## Key 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.