Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1).
Familial combined hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol, triglycerides or both, is observed in about 20% of individuals with premature coronary heart disease. We previously identified a locus linked to FCHL on 1q21-q23 in Finnish families with the disease. This region has also been linked to FCHL in families from other populations as well as to type 2 diabetes mellitus. These clinical entities have several overlapping phenotypic features, raising the possibility that the same gene may underlie the obtained linkage results. Here, we show that the human gene encoding thioredoxin interacting protein (TXNIP) on 1q, which underlies combined hyperlipidemia in mice, is not associated with FCHL. We show that FCHL is linked and associated with the gene encoding upstream transcription factor 1 (USF1) in 60 extended families with FCHL, including 721 genotyped individuals (P = 0.00002), especially in males with high triglycerides (P = 0.0000009). Expression profiles in fat biopsy samples from individuals with FCHL seemed to differ depending on their carrier status for the associated USF1 haplotype. USF1 encodes a transcription factor known to regulate several genes of glucose and lipid metabolism.
Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California 90095-7088, USA. ppajukanta@mednet.ucla.edu
Päivi
P
Pajukanta
Heidi E
HE
Lilja
Janet S
JS
Sinsheimer
Rita M
RM
Cantor
Aldons J
AJ
Lusis
Massimiliano
M
Gentile
Xiaoqun Joyce
XJ
Duan
Aino
A
Soro-Paavonen
Jussi
J
Naukkarinen
Janna
J
Saarela
Markku
M
Laakso
Christian
C
Ehnholm
Marja-Riitta
MR
Taskinen
Leena
L
Peltonen
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002878:Chromosomes, Human, Pair 1; D004268:DNA-Binding Proteins / Q000235:genetics*; D017930:Genes, Reporter; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013879:Thioredoxins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D051720:Upstream Stimulatory Factors
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C486715:TXNIP protein, human; D014157:Transcription Factors; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; D013879:Thioredoxins