The linkage and association of the gene encoding upstream stimulatory factor 1 with type 2 diabetes and metabolic syndrome in the Chinese population

Abstract

Aims/hypothesis: The transcription factor upstream stimulatory factor 1 (USF1) regulates the expression of genes involved in glucose and lipid metabolism and has been associated with familial combined hyperlipidaemia. USF1 is located on chromosome 1q22-23, a region with evidence for linkage to type 2 diabetes and various traits of the metabolic syndrome in Chinese and other populations. The aim of this study was to investigate the linkage and association of USF1 with type 2 diabetes and the metabolic syndrome in Chinese individuals. Materials and methods: We genotyped three haplotypetagging single nucleotide polymorphisms (SNPs) (rs3737787, rs2516841 and rs2516839) at USF1 in three samples of the Hong Kong Chinese population, including members of 179 families from the Hong Kong Family Diabetes Study, 1,383 hospital cases with type 2 diabetes and/or the metabolic syndrome and 454 normal control subjects. Results: We found significant association of individual polymorphisms and haplotypes with type 2 diabetes and/or metabolic syndrome-related traits in the family samples using either family-based or unrelated normal control subjects. However, these variants could not explain much of the evidence for linkage in this region. Moreover, they were not associated with type 2 diabetes and/or the metabolic syndrome in the hospital cases. Conclusions/interpretation: The results are consistent with the hypothesis that variation at USF1 contributes to the risk of type 2 diabetes and the metabolic syndrome in families with strong evidence for linkage in the chromosome 1q region. However, they provide little support for USF1 as the susceptibility locus that generates the observed evidence for linkage at 1q21-25 for type 2 diabetes and/or the metabolic syndrome, and USF1 does not appear to have a major contribution to these phenotypes in the general Chinese population.

Association of variants in genes involved in pancreatic β-cell development and function with type 2 diabetes in North Indians

“…Although studies in French population and in multi-ethnic groups did not show any association, 30,31 the common allele was associated with an increased risk for T2D in the Chinese population. 32 Similar to Chinese, polymorphisms and haplotypes in USF1 are associated with T2D in North Indians. Further investigations are required to ascertain the role of USF1 in T2D.…”

Associations of insulin-like growth factor binding protein-3 gene polymorphisms with IGF-I activity and lipid parameters in adolescents

“…31 In this respect, USF is one of the candidate genes for familial dyslipidemia 32 and type 2 diabetes. 33 Taken together, our findings point to a genetic influence on lipid metabolism through IGF-I activity, which may influence the future risk of cancers.…”

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].…”

“…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].…”