title: 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.
abstract: The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels. Phenotypic overlap between FCHL and type 2 diabetes makes USF1 a compelling positional candidate for the widely replicated type 2 diabetes linkage signal on chromosome 1q. We typed 22 variants in the F11R/USF1 region (1 per 3 kb), including those previously implicated in FCHL-susceptibility (or proxies thereof) in 3,726 samples preferentially enriched for 1q linkage. We also examined glucose- and lipid-related continuous traits in an overlapping set of 1,215 subjects of European descent. There was no convincing evidence for association with type 2 diabetes in any of seven case-control comparisons, individually or combined. Family-based association analyses in 832 Pima subjects were similarly negative. At rs3737787 (the variant most strongly associated with FCHL), the combined odds ratio, per copy of the rarer A-allele, was 1.10 (95% CI 0.97-1.24, P = 0.13). In 124 Utah subjects, rs3737787 was significantly associated (P = 0.002) with triglyceride levels, but direction of this association was opposite to previous reports, and there was no corroboration in three other samples. These data exclude USF1 as a major contributor to type 2 diabetes susceptibility and the basis for the chromosome 1q linkage. They reveal only limited evidence for replication of USF1 effects on continuous metabolic traits.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: Coleen M
authors.initials: CM
authors.lastname: Damcott
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Karim
authors.forename: N William
authors.initials: NW
authors.lastname: Rayner
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Groves
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
authors.forename: Terri C
authors.initials: TC
authors.lastname: Hale
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hunt
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.forename: Toni I
authors.initials: TI
authors.lastname: Pollin
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Wang
authors.forename: Pamela
authors.initials: P
authors.lastname: Whittaker
authors.forename: Kunsan
authors.initials: K
authors.lastname: Xiang
authors.forename: Xiang
authors.initials: X
authors.lastname: Kunsun
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.forename: Juliana C N
authors.initials: JC
authors.lastname: Chan
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Steven C
authors.initials: SC
authors.lastname: Elbein
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics; D007198:Indians, North American / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D051720:Upstream Stimulatory Factors / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D051720:Upstream Stimulatory Factors