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Background Long-term heavy coffee consumption may adversely affect individuals’ cardiovascular disease (CVD) risk. As hyperlipidemia is a well-established contributor to CVD, we investigated the association between habitual coffee intake and plasma lipid profile. Methods We used data from up to 362,571 UK Biobank participants to examine associations between coffee intake and plasma lipid profiles, including LDL-C, HDL-C, total-C, triglycerides, ApoA1 and ApoB. Inverse variance weighted mendelian randomization (MR) was used to interrogate the causal nature of coffee-lipid associations, complemented by pleiotropy-robust methods, including MR-median, MR-Mode, MR-PRESSO and MR-Egger. Results We observed positive dose-dependent associations between self-reported coffee intake and plasma concentration of LDL-C, ApoB and total-C, with the highest lipid levels seen among participants drinking &amp;gt;6 cups/day (Plinear trend≤1.97E-57 for all). Genetic instrument for coffee intake was robustly associated with self-reported intake in the UK Biobank (F-statistic = 416). One cup increase in genetically instrumented intake was associated with 0.07 mmol/L (95%CI 0.03 to 0.12), 0.02 g/L (95%CI 0.01 to 0.03), and 0.09 mmol/L (95%CI 0.04 to 0.14) increase in LDL-C, ApoB, and total-C, respectively. Pleiotropy-robust methods provided largely consistent results albeit with greater imprecision when using MR-Egger. Conclusions Our phenotypic and genetic analysis consistently suggests that long-term heavy coffee consumption can lead to unfavourable lipid profile, which could potentially increase individuals’ risk for CVD. Individuals with elevated cholesterol may need to reduce their daily coffee intake. Key messages Our study provides evidence that long-term heavy coffee consumption can lead to unfavourable lipid profile.

861Mendelian randomization on habitual coffee intake and plasma lipid profile: evidence from UK Biobank