Abstract Background The relations of alcohol consumption and gene expression remain to be elucidated. Materials and Methods We examined cross-sectional associations between alcohol consumption and whole blood derived gene expression levels and between alcohol-associated genes and obesity, hypertension, and diabetes in 5531 Framingham Heart Study (FHS) participants. Results We identified 25 alcohol-associated genes. We further showed cross-sectional associations of 16 alcohol-associated genes with obesity, nine genes with hypertension, and eight genes with diabetes at P < 0.002. For example, we observed decreased expression of PROK2 (β = −0.0018; 95%CI: −0.0021, −0.0007; P = 6.5e − 5) and PAX5 (β = −0.0014; 95%CI: −0.0021, −0.0007; P = 6.5e − 5) per 1 g/day increase in alcohol consumption. Consistent with our previous observation on the inverse association of alcohol consumption with obesity and positive association of alcohol consumption with hypertension, we found that PROK2 was positively associated with obesity (OR = 1.42; 95%CI: 1.17, 1.72; P = 4.5e − 4) and PAX5 was negatively associated with hypertension (OR = 0.73; 95%CI: 0.59, 0.89; P = 1.6e − 3). We also observed that alcohol consumption was positively associated with expression of ABCA13 (β = 0.0012; 95%CI: 0.0007, 0.0017; P = 1.3e − 6) and ABCA13 was positively associated with diabetes (OR = 2.57; 95%CI: 1.73, 3.84; P = 3.5e − 06); this finding, however, was inconsistent with our observation of an inverse association between alcohol consumption and diabetes. Conclusions We showed strong cross-sectional associations between alcohol consumption and expression levels of 25 genes in FHS participants. Nonetheless, complex relationships exist between alcohol-associated genes and CVD risk factors.