Objective— Genetic studies implicated upstream stimulatory factor 1 (USF1) in familial combined hyperlipidemia because the rs2073658 minor allele was associated with reduced risk of familial combined hyperlipidemia and related disorders. The molecular mechanisms whereby rs2073658 influences trait expression have remained elusive. Methods and Results— Plasma lipids, rs2073658 genotypes (N=372), and hepatic transcript levels (N=96) of USF1 and genes involved in hepatic lipoprotein production were determined in obese subjects. The rs2073658 minor allele was associated with reduced plasma triglycerides (TGs) ( P <0.001), hepatic USF1 ( P <0.01), and microsomal TG transfer protein transcript levels ( P <0.05). Functional studies in human hepatocellular carcinoma cells showed that rs2073658 is located in a forkhead box A2 (FOXA2) binding site and that major allele constructs displayed higher transcriptional activity than minor allele constructs. Knockdown of FOXA2 reduced the activity of major, but not minor allele constructs. Furthermore, an interaction between hepatic FOXA2 transcript levels and rs2073658 minor allele carrier status on hepatic USF1 transcript levels was observed in vivo ( P <0.05). USF1 activated the transcription of FOXA2 and FOXA2 strongly activated the transcription of microsomal TG transfer protein. Conclusion— A feed-forward loop comprising activation of USF1 transcription by FOXA2 and activation of FOXA2 transcription by USF1 , driving microsomal TG transfer protein expression, is modulated by rs2073658. Hence, rs2073658 likely influences hepatic TG secretion.