Epidemiologic observations related to the comorbid smoking and drinking risks further suggest that distinct epigenetic mechanisms are at play in alcohol use disorders as compared to smoking. In combination, smoking one pack per day and heavy drinking (over 80 grams per day) act synergistically to increase risk of esophageal cancer by up to 44 times [76]. This consistent epidemiologic finding suggests that smoking and drinking have distinct toxicological mechanisms by which risk of disease is conferred. Similarly, it has been demonstrated that while the risks of cancer and other diseases due to smoking are due not to nicotine but to the cumulative effects of the thousands of toxic compounds found in smoke, the risks due to alcohol appear to be directly related to alcohol concentration and dose, with increasing concentration of alcoholic beverages (hence, less exposure to other compounds), conferring increasing risk [74]. From an epigenetic perspective, these findings have led investigators to pursue focused investigations of both candidate genes and broader investigations using array-based platforms to elucidate the underlying mechanisms at play. Relatedly, potential epigenetic biomarkers for alcohol use disorders are likely to follow distinct patterns from those of smoking, as will be detailed below.
