Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1)

Abstract

Familial combined hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol, triglycerides or both 1,2 , is observed in about 20% of individuals with premature coronary heart disease 1 . We previously identified a locus linked to FCHL on 1q21-q23 in Finnish families with the disease 3 . This region has also been linked to FCHL in families from other populations 4-6 as well as to type 2 diabetes mellitus 7-12 . 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 13 , 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 14-17 .To identify the gene on 1q21 associated with FCHL, we initially sequenced four functionally relevant regional candidates: TXNIP, USF1, retinoid X receptor gamma (RXRG) and apolipoprotein A-II (APOA2). In parallel, we carried out a functionally unbiased genetic analysis of 60 single-nucleotide polymorphisms (SNPs) in 26 genes in 42 families with FCHL, including the 31 families in the original linkage study 3 . We then genotyped the ten SNPs most likely to be relevant in the extended sample of 60 families of FCHL (Supplementary Table 1 online). Fifty SNPs were located in a 5.8-Mb region flanking the peak markers D1S104 and D1S1677 (Fig. 1). All the families that we studied included a proband with severe coronary heart disease and an abnormal lipid phenotype and an average of 5-6 members affected with FCHL.We sequenced the entire TXNIP gene and the 2,000-bp upstream DNA region in 60 FCHL probands. Of the 20 SNPs identified, none resulted in amino acid changes, and all were rare, with a maximal 7% allele frequency. We also did not observe the nonsense mutation causing hyperlipidemia in mice 13 . We genotyped the four most common SNPs in the 60 families with FCHL but found no evidence of association Table 2 for distances, SNP numbers and LD clusters of these SNPs). (c) The SNPs associated with triglyceride levels in men and (d) the SNPs associated with FCHL and triglycerides in all family members.

Glucose increases hepatic lipase expression in HepG2 liver cells through upregulation of upstream stimulatory factors 1 and 2

“…The associated dyslipidaemia (low HDL, high triacylglycerol, increased small dense LDL) may result from the increased transactivation by USFs, not only of HL, but also of other HDL-and triacylglycerol-related genes [26][27][28][29]31]. Increased USF1 transactivation of its target genes has been suggested to explain the development of the metabolic syndrome [35,39], the dyslipidaemia associated with FCHL [36,40] and the development of diabetic complications [32,34]. Metabolic syndrome, type 2 diabetes and FCHL have all been linked to the USF1 gene [35][36][37].…”

“…Increased USF1 transactivation of its target genes has been suggested to explain the development of the metabolic syndrome [35,39], the dyslipidaemia associated with FCHL [36,40] and the development of diabetic complications [32,34]. Metabolic syndrome, type 2 diabetes and FCHL have all been linked to the USF1 gene [35][36][37]. A number of risk alleles of USF1 have been identified, which all represent variants of the non-coding sequence [36,38,41].…”

“…Metabolic syndrome, type 2 diabetes and FCHL have all been linked to the USF1 gene [35][36][37]. A number of risk alleles of USF1 have been identified, which all represent variants of the non-coding sequence [36,38,41]. It is not clear how non-coding polymorphisms in USF1 may contribute to these metabolic disorders.…”

“…In liver as well as in other tissues, USFs play an important role in the regulation of genes by insulin [24][25][26] or glucose [30][31][32][33][34]. Interestingly, the USF1 gene on chromosome 1q21 has been linked with type 2 diabetes [35], FCHL [36,37] and both cardiovascular disease and all-cause mortality among women [38]. Allelic variants of USF1 may confer susceptibility to core features of the metabolic syndrome, such as glucose intolerance and dyslipidaemia [36,39,40].…”

“…It is unclear how they convey glucose or insulin responsiveness to susceptible target genes. In USF1 a number of polymorphisms have been reported [36,38,40], some of which are associated with unfavourable results in oral glucose and fat tolerance tests [41], increased adipocyte lipolysis [42] and decreased expression of USF target genes in fat biopsies [40]. In nonhepatic cells, glucose has been shown to increase nuclear expression of either USF1 or USF2 [31][32][33][34].…”