Genetic predisposition to coffee consumption and the association with the early risk of atherosclerosis

The cardiovascular effects of coffee consumption remain debated, particularly regarding early-stage subclinical atherosclerosis. This study investigated the association between coffee intake, genetic predisposition, and the risk of subclinical coronary and carotid atherosclerosis in 24,835 participants from the Swedish CArdioPulmonary bioImage Study (SCAPIS). Coffee intake was assessed via self-reported questionnaires. Atherosclerosis was assessed via segment involvement score (SIS), coronary artery calcium score (CACS) and carotid plaque. Observational analysis showed no significant association between coffee consumption and SIS, CACS, or carotid plaques. However, both one-sample and two-sample (SCAPIS and UK Biobank) Mendelian randomization (MR) analyses showed an association between genetic predisposition to higher coffee consumption and increased SIS. Stratification analyses further explored differences in genetic associations across varying coffee consumption levels. Among individuals consuming coffee more than twice daily, two coffee consumption-associated single nucleotide polymorphisms (SNPs) in AHR and CYP1A1/CYP1A2 were correlated with SIS. Integrative metabolomics and proteomics analyses identified lipid-related metabolites (triglycerides, phospholipids, free cholesterol) and inflammation-related proteins (DLK1, IL1RL2, CCL17) associated with the genetic proxy of coffee consumption. These findings suggest that genetically influenced coffee consumption may be associated with coronary atherosclerosis risk in frequent coffee drinkers, although the underlying biological basis remains to be clarified.