Genetic variants in human sterol regulatory element binding protein-1c in syndromes of severe insulin resistance and type 2 diabetes.
The transcription factor sterol regulatory element binding protein (SREBP)-1c is intimately involved in the regulation of lipid and glucose metabolism. To investigate whether mutations in this gene might contribute to insulin resistance, we screened the exons encoding the aminoterminal transcriptional activation domain in a cohort of 85 unrelated human subjects with severe insulin resistance. Two missense mutations (P87L and P416A) were found in single affected patients but not in 47 control subjects. However, these variants were indistinguishable from the wild-type in their ability to bind DNA or to transactivate an SREBP-1 responsive promoter construct. We also identified a common intronic single nucleotide polymorphism (C/T) located between exon 18c and 19c. In a case-control study of 517 U.K. Caucasian case subjects and 517 age- and sex-matched control subjects, the T-allele at this locus was significantly associated with type 2 diabetes in men (odds ratio = 1.42 [1.11-1.82], P = 0.005) but not women. In a separate population-based study of 1,100 Caucasians, carriers of the T-allele showed significantly higher levels of total and LDL cholesterol (P < 0.05) compared with wild-type individuals. In summary, we have conducted the first study of the SREBP-1c gene as a candidate for human insulin resistance. Although the rare mutations identified were functionally silent in the assays used, we obtained some evidence, which requires conformation in other populations, that a common variant in the SREBP-1c gene might influence diabetes risk and plasma cholesterol level.
Department of Medicine and Clinical Biochemistry, University of Cambridge/Addenbrooke's Hospital, Cambridge, U.K.
Matthias
M
Laudes
Inês
I
Barroso
Jian'an
J
Luan
Maria A
MA
Soos
Giles
G
Yeo
Aline
A
Meirhaeghe
Lisa
L
Logie
Antonio
A
Vidal-Puig
Alan J
AJ
Schafer
Nick J
NJ
Wareham
Stephen
S
O'Rahilly
D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D007438:Introns; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D044465:White People / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D002784:Cholesterol