**1. Introduction**

While coffee consumption has increased globally, the research on biological function and effects of coffee intake remain controversial [1]. A meta-analysis of randomized controlled trials stated that coffee intake changed blood lipid profiles, including increase of cholesterol and triglyceride (TG) [2], which are clinical indicators for cardiovascular disease risk. On the contrary, other meta-analysis on observational and interventional studies suggested that high coffee consumption was associated with reduced risks of cardiovascular disease and mortality [3–5].

Genetic variation has been suggested as one of the main reasons why individuals respond differently to coffee intake [6]. Focused studies have been conducted on the ADORA locus and its genetic variants because their expression is antagonized by caffeine and, in turn, play a role in transmitting the effects of coffee intake throughout the body [7].

Studies investigating the association between coffee intake and the ADORA gene family have focused on neuronal effects such as habitual coffee intake [8], arousal [9], sleep disorders [10], and anxiety [11], or on blood pressure [6]. The *ADORA* gene family, composed of *ADORA1*, *ADORA2A*, *ADORA2B*, and *ADORA3*, are differently expressed in a tissue-specific manner and show unique

properties in regulating multiple physiological statuses [7]. A recent review highlighted that the *ADORA* gene members are modulators of lipid availability [12]. The physiological role of the ADORAs has been reported to be associated with lipid-related diseases, including cardiovascular disease [13], coronary blood flow [14], chronic heart failure [15], atherosclerosis, and dyslipidemia [16].

While the association of the *ADORA* gene family between coffee intake and multiple lipid-related diseases have been investigated in several studies, we hypothesized that the discrepancies in the findings of coffee intake with regard to dyslipidemia might be explained by genetic variants, which henceforth motivated this study.
