Upstream Transcription Factor 1 (USF1) allelic variants regulate lipoprotein metabolism in women and USF1 expression in atherosclerotic plaque.
Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT < CT < CC and rs1556259 AA < AG < GG as well as according to USF1 H3 (GCCCGG) copy number 0 < 1 < 2. Furthermore, the carriers of minor alleles of rs2516839 (C) and rs1556259 (G) of USF1 gene had decreased USF1 expression in atherosclerotic plaques (P = 0.028 and 0.08, respectively) as compared to non-carriers. The genetic variation in USF1 influence USF1 transcript expression in advanced atherosclerosis and regulates levels and metabolism of circulating apoB and apoB-containing lipoprotein particles in sex-dependent manner, but is not a major determinant of early markers of atherosclerosis.
Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and School of Medicine at the University of Tampere, Tampere.
Yue-Mei
YM
Fan
Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and School of Medicine at the University of Tampere, Tampere.
Jussi
J
Hernesniemi
1] Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and School of Medicine at the University of Tampere, Tampere [2] Divison of Vascular Surgery, Department of Surgery, Tampere University Hospital and University of Tampere, Finland.
Niku
N
Oksala
Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and School of Medicine at the University of Tampere, Tampere.
Mari
M
Levula
Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and School of Medicine at the University of Tampere, Tampere.
Emma
E
Raitoharju
Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and School of Medicine at the University of Tampere, Tampere.
Auni
A
Collings
Department of Pediatrics, University of Tampere and Tampere University Hospital, Tampere.
Nina
N
Hutri-Kähönen
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku.
Markus
M
Juonala
Department of Health and Functional Capacity, Population Research Laboratory, National Public Health Institute.
Jukka
J
Marniemi
Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and School of Medicine at the University of Tampere, Tampere.
Leo-Pekka
LP
Lyytikäinen
Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and School of Medicine at the University of Tampere, Tampere.
Ilkka
I
Seppälä
Heart Center, Department of Cardiac Surgery, Tampere University Hospital, Finland.
Ari
A
Mennander
Heart Center, Department of Cardiac Surgery, Tampere University Hospital, Finland.
Matti
M
Tarkka
1] Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland [2] NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Antti J
AJ
Kangas
1] Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland [2] NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Pasi
P
Soininen
Divison of Vascular Surgery, Department of Surgery, Tampere University Hospital and University of Tampere, Finland.
Juha Pekka
JP
Salenius
Institute of Epidemiology, Helmholtz Center Munich, Munich, 85764, Germany.
Norman
N
Klopp
Institute of Epidemiology, Helmholtz Center Munich, Munich, 85764, Germany.
Thomas
T
Illig
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital and University of Eastern Finland, Finland.
Tomi
T
Laitinen
1] Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland [2] NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland [3] Oulu University Hospital, Oulu, Finland [4] Computational Medicine, School of Social and Community Medicine & Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
Mika
M
Ala-Korpela
Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and School of Medicine at the University of Tampere, Tampere.
Reijo
R
Laaksonen
Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland.
Jorma
J
Viikari
Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere.
Mika
M
Kähönen
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Department of Clinical Physiology, University of Turku and Turku University Hospital, Turku, Finland.
Olli T
OT
Raitakari
Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and School of Medicine at the University of Tampere, Tampere.
Terho
T
Lehtimäki
D000328:Adult; D000483:Alleles; D001055:Apolipoproteins B / Q000097:blood; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D058226:Plaque, Atherosclerotic; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D012737:Sex Factors; D051720:Upstream Stimulatory Factors / Q000235:genetics*
D001055:Apolipoproteins B; D008078:Cholesterol, LDL; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors