Genome-wide significant associations with cigarettes per day (CPD) and risk for lung cancer and chronic obstructive pulmonary disease (COPD) were previously reported in a region of 19q13, including CYP2A6 (nicotine metabolism enzyme) and EGLN2 (hypoxia response). The associated single nucleotide polymorphisms (SNPs) were assumed to be proxies for functional variation in CYP2A6. Here, we demonstrate that when CYP2A6 and EGLN2 genotypes are analyzed together, the key EGLN2 variant, rs3733829, is not associated with nicotine metabolism independent of CYP2A6, but is nevertheless independently associated with CPD, and with breath carbon monoxide (CO), a phenotype associated with cigarette consumption and relevant to hypoxia. SNPs in EGLN2 are also associated with nicotine dependence and with smoking efficiency (CO/CPD). These results indicate a previously unappreciated novelmechanism behind genome-wide significant associations with cigarette consumption and disease risk unrelated to nicotine metabolism.