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.
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.
Zeggini
Eleftheria
E
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
Damcott
Coleen M
CM
Hanson
Robert L
RL
Karim
Mohammad A
MA
Rayner
N William
NW
Groves
Christopher J
CJ
Baier
Leslie J
LJ
Hale
Terri C
TC
Hattersley
Andrew T
AT
Hitman
Graham A
GA
Hunt
Sarah E
SE
Knowler
William C
WC
Mitchell
Braxton D
BD
Ng
Maggie C Y
MC
O'Connell
Jeffrey R
JR
Pollin
Toni I
TI
Vaxillaire
Martine
M
Walker
Mark
M
Wang
Xiaoqin
X
Whittaker
Pamela
P
Xiang
Kunsan
K
Kunsun
Xiang
X
Jia
Weiping
W
Chan
Juliana C N
JC
Froguel
Philippe
P
Deloukas
Panos
P
Shuldiner
Alan R
AR
Elbein
Steven C
SC
McCarthy
Mark I
MI
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
D051720:Upstream Stimulatory Factors