Objective—A common haplotype of the upstream transcription factor 1 gene (USF1) has been associated with decreased susceptibility to familial combined hyperlipidemia (FCHL) and, paradoxically, with increased risk of cardiovascular disease (CVD) and all-cause mortality.

Methods and Results—We assessed associations between USF1 tagSNPs, CVD risk factors, and aging-related phenotypes using data from 2 large population-based cohorts, Coronary Artery Risk Development in Young Adults (CARDIA) and the Cardiovascular Health Study (CHS), comprising younger and older adults, respectively. In CARDIA, each additional copy of the FCHL low-risk allele was associated with 2.4 mg/dL lower levels of LDL cholesterol (P=0.01) and decreased risk of subclinical atherosclerosis as assessed by coronary artery calcium (odds ratio 0.79; 95%CI 0.63 to 0.98). Whereas there was little association between USF1 genotype and metabolic or CVD traits in older adults from CHS, the USF1 low-risk dyslipidemia allele was associated with higher plasma C-reactive protein and interleukin (IL)-6 levels and with increased risk of mortality, particularly attributable to noncardiovascular causes.

Conclusions—There appears to be a complex and possibly age-dependent relationship between USF1 genotype, atherosclerosis phenotypes, and CVD risk. USF1 may influence mortality through pathways distinct from atherosclerosis. Alternatively, linkage disequilibrium with neighboring polymorphisms in other genes such as F11R may be responsible for the observed USF1 genotype–phenotype associations in older adults.