Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides

Abstract

Positive evidence has been reported for linkage and association between the upstream stimulatory factor 1 gene (USF1) and familial combined hyperlipidemia (FCHL). We genotyped the two most positive single-nucleotide polymorphisms (SNPs) (usf1s1: rs3737787 and usf1s2: rs2073658) from previous studies in a large family sample. This sample included 2,195 subjects in 87 Utah pedigrees ascertained for early death due to coronary heart disease (CHD), early strokes, or early onset hypertension. There were a total of 262 relative pairs in these families with FCHL. In the full family sample, FCHL was associated with usf1s1 (P = 0.02). Triglyceride and LDL cholesterol defined qualitatively or quantitatively were also associated with usf1s1 (P = 0.02-0.05). Results were strengthened for qualitative and quantitative triglyceride and LDL cholesterol when data from males only was analyzed, revealing associations for usf1s1 (P = 0.001-0.02), usf1s2 (P = 0.02-0.05) and the haplotype of these two SNPs (P = 0.01-0.04). The strongest results were in the subset of subjects from families ascertained for premature stroke or hypertension, rather than those ascertained for premature CHD. This study replicates the involvement of USF1 in FCHL and related lipid traits in a family sample not ascertained for FCHL.

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

“…The sex-specific differences, observed in the present analyses, are in accordance with several reports from the literature demonstrating sex-specific results for genetic variants within the USF1 gene and lipid markers (18,21,23), whereas in other studies, only men were analyzed (28,41). Also for the association between USF1 and cardiovascular disease and mortality, sex-specific results were found (42).…”

“…In some studies (18,(21)(22)(23)(24), genetic variants within the USF1 gene showed associations with serum triglycerides, whereas in two US cohort studies of cardiovascular disease risk (25), in French Caucasians (26), and in Korean adults (27), no associations with serum triglycerides were observed.…”

“…Therefore, eight SNPs within the USF1 gene and their haplotypes were investigated in the case-cohort study of the Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg (MONICA/-KORA) project. Because of sex-specific dissimilarities in the development of T2DM (30)(31)(32) and sex-specific results concerning USF1 polymorphisms and lipid parameters, there was a separate analysis for men and women (18,21,23).…”

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

“…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].…”

“…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].…”