USF1 gene variants, cardiovascular risk, and mortality in European Americans: analysis of two US cohort studies.
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.


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.
Reiner
Alexander P
AP
Department of Epidemiology, Box 357236, University of Washington, Seattle, WA 98195, USA. apreiner@u.washington.edu
Carlson
Christopher S
CS
Jenny
Nancy S
NS
Durda
J Peter
JP
Siscovick
David S
DS
Nickerson
Deborah A
DA
Tracy
Russell P
RP
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D017536:Carotid Artery, Common / Q000473:pathology; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000150:complications / Q000235:genetics; D003331:Coronary Vessels / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000150:complications / Q000235:genetics; D007328:Insulin / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D015810:Linkage Disequilibrium; D008055:Lipids / Q000097:blood; D008297:Male; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014481:United States; D051720:Upstream Stimulatory Factors / Q000235:genetics*; D044465:White People / Q000235:genetics*
D001786:Blood Glucose; C508600:IL6 protein, human; D007328:Insulin; D015850:Interleukin-6; D008055:Lipids; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; D002097:C-Reactive Protein; D002118:Calcium