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Proteome-wide genetic analyses identify ASGR1 as a potential biomarker linking smoking with ischemic heart disease
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Key result
Higher genetically predicted ASGR1 linked to ~25% greater IHD risk per SD, partially explaining smoking's effects.
- HR 1.25
- 95% CI 1.20-1.29
- P=1.68 x 10^-28
Why the study?
The biological mechanisms linking tobacco smoking with increased risk of ischemic heart disease remain incompletely understood.
Do genetically predicted smoking exposures alter circulating protein levels that causally mediate the risk of ischemic heart disease?
Population
European-ancestry populations
Comparison
Genetically predicted smoking exposures vs non-exposure
Design
Mendelian randomization and proteome-wide genetic analyses
Authors
Discussion
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
AAnonymousReviewer
“The central claim of the paper is that ASGR1 mediates the effect of smoking on IHD. It should be noted, however, that the association between ASGR1 variants and IHD risk is already well-established in the literature, with the expected mechanism being through LDL-cholesterol lowering. The novelty of this paper rests mainly on Stage 1: the use of MR to establish that smoking causally increases ASGR1 levels.”
AAnonymousReviewer
“This is an impressive paper which uses Mendelian randomisation and proteomics analysis to identify circulating proteins causally affected by smoking, smoking related proteins causally related to cardiometabolic diseases, and the proportion of the effect of smoking on these diseases mediated by the identified proteins. The findings in relation to the effects of smoking on ASGR1, and ASGR1 on ischaemic heart disease are internally consistent and convincing.”
AAnonymousReviewer
“The study has great clinical merit. The authors used plasma proteomics for large UK biobank cohort and identified 108 significant targets associated with strong smoking status, predicting a number of chronic diseases, e.g. ischemic heart disease, T2DM, COPD, ischemic stroke and lung cancer. ASGR1 was the top target.”
Implication
ASGR1 may mediate a modest fraction of smoking-related IHD risk; leaves open its value as a therapeutic target.
Key Points
- To characterize smoking-associated circulating protein profiles and determine causal biomarkers mediating tobacco's harmful effects on ischemic heart disease.
- Conducted a four-stage proteome-wide Mendelian randomization study evaluating 2,922 circulating plasma proteins using genetic instruments for smoking initiation, lifetime smoking index, and cigarettes smoked per day in European-ancestry populations.
- Assessed causal links with smoking-related diseases using two-step Mendelian randomization, Bayesian colocalization, negative-control analyses in never-smokers, and multivariable Mendelian randomization adjusting for body mass index and type 2 diabetes.
- Genetically predicted smoking exposures were significantly associated with levels of 93 of 2,922 circulating proteins, including higher levels of asialoglycoprotein receptor 1 (ASGR1).
- The positive association between ASGR1 and ischemic heart disease was supported by colocalization (posterior probability of hypothesis 4 = 0.91) and explained 6.35% (95% confidence interval 2.61–10.09%, P = 8.77 × 10−4) of smoking's effect on ischemic heart disease.
- Genetically predicted ASGR1 levels correlated inversely with over 100 plasma proteins, which all share rs55714927 (a cis-pQTL for ASGR1) as a trans-pQTL.
Study Design
Type
Observational
Randomization
Mendelian randomization
Multicenter
Yes
Structured PICO
Do genetically predicted smoking exposures alter circulating protein levels that causally mediate the risk of ischemic heart disease?
P
Population
Large-scale Mendelian randomization study of European-ancestry populations utilizing genetic and proteomic data to identify biomarkers linking smoking with ischemic heart disease.
E
Exposure
Genetically predicted smoking exposures (smoking initiation, lifetime smoking index, and cigarettes per day)
C
Comparator
Genetically predicted lower or no smoking exposure
O
Outcome
Circulating plasma protein levels (2,922 proteins) and their causal association with smoking-related diseases (specifically ischemic heart disease)surrogate
Main Result
Hazard Ratio: 1.25 (95% CI 1.2–1.29)
p-value: p=1.68 x 10^-28
Proteome-wide Mendelian randomization identifies ASGR1 as a potentially causal biomarker that partially mediates the effect of smoking on ischemic heart disease and hyperlipidemia.
Limitations
- Only one protein-disease association demonstrated convincing evidence of colocalization, suggesting others may be confounded by linkage disequilibrium.
- ASGR1 is a pleiotropic cardiovascular mediator rather than a uniquely smoking-dependent biomarker.
- Conditional F-statistics for smoking initiation declined below conventional thresholds when adjusting for BMI, raising the possibility of weak instrument bias.
- Univariable analyses did not replicate the smoking-ASGR1 association in the deCODE cohort.
Cite This Study
Tinworth et al. (2026) conducted an observational in Ischemic heart disease and smoking. Genetically predicted smoking exposure and ASGR1 levels vs. Lower genetic liability / never-smokers was evaluated on Incident ischemic heart disease per standard deviation higher ASGR1 abundance (HR 1.25, 95% CI 1.20-1.29, p=1.68 x 10^-28). Genetically predicted ASGR1 levels were positively associated with ischemic heart disease and estimated to explain 6.35% of smoking's effects on the disease.
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