Variation in USF1 shows haplotype effects, gene : gene and gene : environment associations with glucose and lipid parameters in the European Atherosclerosis Research Study II

Abstract

Upstream stimulatory factor 1 (USF 1), is a transcription factor controlling expression of several genes involved in lipid and glucose homeostasis and co-localizes with familial combined hyperlipidemia (FCHL) and type 2 diabetes on chromosome 1q22-23. We sequenced USF1 in 24 UK FCHL probands, but found no rare or common cSNPs. Three common intronic single nucleotide ploymorphisms (SNP), 306A>G, 475C>T and 1748C>T, were identified and their association was examined with fasting and postprandial lipids and after an oral glucose tolerance test (OGTT) in the European Atherosclerosis Research Study II offspring study. There were no significant differences in allelic frequencies of the SNPs between cases and controls. Individually none of the SNPs showed significant associations with any parameter. In haplotype analysis, compared with other haplotypes, 475C/1748T showed significantly higher and 475T/1748T showed lower peak glucose (P=0.004 and 0.07, respectively) during the OGTT. There was significant case-control heterogeneity in the interaction of genotype with body mass index, on fasting low density lipoprotein with 306A>G and 1748C>T, and on borderline significance with fasting glucose with 475C>T (P=0.002, 0.0007 and 0.015, respectively). Furthermore, 475C>T showed interaction with both HSL-60C>G (case-control heterogeneity P=0.0002) on AUC TG and APOC3 -482C>T on plasma apoE levels (P=0.0012). Thus, in these healthy young men, variation in USF1 was the influencing feature of both glucose and lipid homeostasis showing case-control heterogeneity.

Genetic variants in the USF1 gene are associated with low-density lipoprotein cholesterol levels and incident type 2 diabetes mellitus in women: results from the MONICA/KORA Augsburg case–cohort study, 1984–2002

“…No significant associations between various USF1 polymorphisms or haplotypes, inferred from these SNPs and TC and HDL cholesterol concentrations, were found in our study, which again is in agreement with most published studies so far (18,24,26,27,29). In Dutch FCHL families, genetic variants within the USF1 gene were associated with TC (18,44).…”

“…In a Swedish male cohort, the minor allele of rs2073658 highly correlated with rs3737787 was associated with higher LDL cholesterol levels (28). By contrast, a population-based Korean study and the EARSII study found no association between LDL cholesterol and genetic variants within the USF1 gene, but there was indication of interaction between genetic variants in the USF1 gene and fasting LDL cholesterol (27,29).…”

Variation Within the Gene Encoding the Upstream Stimulatory Factor 1 Does Not Influence Susceptibility to Type 2 Diabetes in Samples From Populations With Replicated Evidence of Linkage to Chromosome 1q

“…In 800 young men from the European Atherosclerosis Research Study, Putt et al (26) tested three intronic USF1 SNPs (one of which, rs2073655, was in complete LD with the SNPs displaying the strongest FCHL association signal in Finns) reporting weak haplotypic associations with glucose levels during an oral glucose tolerance test. A recent study in Hong Kong Chinese reported associations of USF1 SNPs (including rs3737787) with type 2 diabetes and metabolic syndrome in one case-control analysis (using family cases showing 1q linkage), but these were not replicated in a second Chinese sample (27).…”

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

“…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.…”

“…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].…”