Tobacco smoking influences 93 circulating blood proteins, one of which—ASGR1—appears to partially mediate smoking's effect on heart disease, according to a study published in *Nature Cardiovascular Research* by researchers analyzing data from the UK Biobank and other European cohorts. The investigation used Mendelian randomization, a genetic technique that reduces confounding, to identify proteins causally affected by smoking and trace their downstream effects on disease. Among the 93 proteins altered by smoking behavior, ASGR1 emerged as the sole biomarker showing robust genetic colocalization with ischemic heart disease, suggesting it plays a causal role rather than merely associating through shared genetic architecture.
The research team tested genetic instruments for three smoking measures—smoking initiation, lifetime smoking index, and cigarettes per day—against 2,922 plasma proteins from 34,557 UK Biobank participants. After filtering for statistical rigor and ruling out reverse causation, 93 unique proteins met all criteria: 59 were linked to smoking initiation, 57 to the lifetime smoking index, and seven to cigarettes per day. Of these, 15 proteins showed associations with five major smoking-related diseases—ischemic heart disease, type 2 diabetes, chronic obstructive pulmonary disease, ischemic stroke, and lung cancer. Higher genetically predicted ASGR1 levels correlated with increased heart disease risk, and this association held up across independent cohorts from ARIC, deCODE, and Fenland studies. Observational data reinforced the genetic findings: current smokers in the UK Biobank had ASGR1 levels elevated by 0.44 standard deviations compared to never-smokers, with dose-response relationships evident across cigarettes per day, smoking duration, and pack-years. Each standard deviation increase in ASGR1 abundance corresponded to a 25% higher risk of incident heart disease over follow-up.
The authors found that ASGR1 mediated an estimated 6.35% of smoking's effect on ischemic heart disease, and the protein also appeared to partially drive smoking's associations with nine cardiometabolic traits, including hyperlipidemia (30.36% mediated), triglycerides (8.89%), and glycated hemoglobin (11.92%). The study identified a broad network of 101 additional proteins whose circulating levels were inversely associated with ASGR1, several of which—particularly GAS6 and CDCP1—emerged as potential mediators of ASGR1's downstream effects on liver enzymes and metabolic markers. The lead genetic variant for ASGR1 also colocalized with two splicing sites in liver tissue, suggesting smoking may alter ASGR1 levels through changes in gene transcript splicing rather than protein secretion alone.
Smoking's proteomic footprint extends well beyond cardiovascular pathways, the report notes. Functional enrichment analyses linked the 93 smoking-related proteins to biological processes including macrophage activation, cytokine–cytokine receptor interactions, and regulation of responses to external stimuli—processes that likely reflect oxidative stress, endothelial damage, and immune-mediated inflammation underlying smoking-related disease. Ten proteins showed brain-enriched expression, supporting evidence that smoking directly affects brain structure and function, while 20 were actively secreted into plasma. The findings highlight ASGR1's role in lipid metabolism: the protein regulates cholesterol efflux and promotes lipogenesis through signaling pathways independent of PCSK9, consistent with prior genetic studies linking ASGR1 loss-of-function variants to substantial reductions in heart disease. However, the multivariable analyses revealed complexity—adjustment for body mass index strengthened the smoking–ASGR1 association while attenuating the BMI–ASGR1 link to near zero, suggesting genetic instruments for smoking and BMI capture overlapping pathways that can obscure direct effects in simple models.
The report positions ASGR1 as a plausible therapeutic target but cautions that its network effects and potential hepatic risks require careful evaluation. Early-phase clinical trials targeting ASGR1, including the monoclonal antibody AMG-529, have shown acceptable safety profiles, though clinical development remains sparse. The genetically defined protein network, particularly GAS6's role in mediating ASGR1's effects on liver enzymes and metabolic markers, represents a promising research avenue for evaluating whether cardiovascular benefits of ASGR1 modulation outweigh potential liver-related harms. The authors emphasize that ASGR1 shouldn't be interpreted as a smoking-specific biomarker—it's influenced by type 2 diabetes and other factors—but the convergent genetic, observational, and mechanistic evidence supports smoking exposure as one contributor to ASGR1 regulation and a pathway linking tobacco use to heart disease risk.