**1. Introduction**

Coronary heart disease, also known as ischemic heart disease (IHD) or coronary artery disease (CAD) is the top cause of global mortality [1,2]. It remains the second leading cause of death in Taiwan [3]. The global coronary heart disease (CHD) mortality is projected to grow from 7.594 million in 2016 to about 9.245 million in 2030 [4].

A complex interplay of numerous genetic and lifestyle factors influence the onset of CHD [5–7]. Genotypes are nonmodifiable factors, so they cannot be confounded by other factors. As such, they are

capable of playing direct causal roles in disease development [8,9]. Identification of genetic variants associated with diseases and the underlying pathophysiological mechanisms is an important step in the development of potential drug targets [8].

Genetic predisposition accounts for about 30%–60% of CHD [10,11]. Despite this, most underlying genes and molecular pathways are yet to be fully explored and therefore a significant portion of CHD heritability is not clearly understood [2]. For instance, SNPs account for just a minute fraction (approximately 10–15%) of CHD heritability [1,2,5,12,13]. The *TRIB1* is among the top genes having genome-wide significant single nucleotide polymorphisms (SNPs) for CHD [14]. It is located on chromosome 8q24 and is greatly involved in cholesterol metabolism and atherosclerosis process [15]. One of its variants, rs17321515, has been associated with variations in plasma lipid levels and CHD [14,16–18].

Coffee is a popular beverage that is widely consumed in the world [19]. In Taiwan, coffee consumption has grown rapidly in recent years. So far, the local coffee industry has expanded significantly [20]. Several studies have investigated the effects of coffee consumption on CHD. However, results have been controversial. For instance, in one of the studies, excessive consumption was significantly associated with a moderate increase in the risk of CHD [21]. However, in another study, CHD risk was higher among moderate than for excessive coffee consumers [22]. Cardioprotective effects of coffee may stem from its richness in bioactive compounds like polyphenols that possess hypocholesterolemic, antihypertensive, anti-inflammatory, and antioxidant properties [23,24]. The antioxidant content in coffee was found to be higher than that in tea, vegetables, and fruits [25].

It is well known that interactions between genes and the environment influence disease outcomes [26]. So far, there is substantial information on genetic variation and dietary patterns (including but not limited to coffee consumption) and the risk of CHD. Results from a previous study indicated that a variant in the *cytochrome P450 1A2 gene (CYP1A2)* modifies the association between caffeinated coffee consumption and the risk of myocardial infection [27]. Nevertheless, pinpointing a specific polymorphic variant is challenging considering that individual differences may exist in response to coffee or caffeine. To our knowledge, no prior study has discussed specific genotypes that can modify the association between coffee intake and the risk of CHD in Taiwan. In light of this, we determined the interaction between coffee consumption and the *TRIB1* rs17321515 variant on CHD.

#### **2. Materials and Methods**
