Effects of genetic variation in the human retinol binding protein-4 gene (RBP4) on insulin resistance and fat depot-specific mRNA expression.
OBJECTIVE
Serum retinol binding protein 4 (RBP4) is a new liver- and adipocyte-derived signal that may contribute to insulin resistance. Therefore, the RBP4 gene represents a plausible candidate gene involved in susceptibility to type 2 diabetes.


METHODS
In this study, the RBP4 gene was sequenced in DNA samples from 48 nonrelated Caucasian subjects. Five novel and three known single nucleotide polymorphisms (SNPs) were identified. Furthermore, five recently reported SNPs were genotyped in 90 subjects. Six SNPs, representative of their linkage disequilibrium groups, were then genotyped in 934 diabetic and 716 nondiabetic subjects.


RESULTS
A haplotype of six common SNPs (A-G-G-T-G-C) was significantly increased in 934 case subjects with type 2 diabetes compared with 537 healthy control subjects with normal glucose tolerance (P = 0.02; odds ratio 1.37 [95% CI 1.05-1.79]). Furthermore, in the cohort of 716 nondiabetic Caucasian subjects, carriers of the A-G-G-T-G-C haplotype had significantly higher mean fasting plasma insulin and 2-h plasma glucose than subjects without the haplotype. Two single SNPs (rs10882283 and rs10882273) were also associated with BMI, waist-to-hip ratio, and fasting plasma insulin, and several SNPs were associated with circulating free fatty acids (all adjusted P < 0.05). In addition, subjects carrying a previously reported diabetes-associated haplotype had significantly higher mRNA levels in visceral adipose tissue (adjusted P < 0.05) in a subgroup of nondiabetic subjects (n = 170) with measurements of RBP4 mRNA expression in visceral and subcutaneous fat depots.


CONCLUSIONS
Our data indicate a role of RBP4 genetic variation in susceptibility to type 2 diabetes and insulin resistance, possibly through an effect on RBP4 expression.
Kovacs
Peter
P
Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany.
Geyer
Michaela
M
Berndt
Janin
J
Klöting
Nora
N
Graham
Timothy E
TE
Böttcher
Yvonne
Y
Enigk
Beate
B
Tönjes
Anke
A
Schleinitz
Dorit
D
Schön
Michael R
MR
Kahn
Barbara B
BB
Blüher
Matthias
M
Stumvoll
Michael
M
D000273:Adipose Tissue / Q000502:physiology*; D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005858:Germany; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics*; D012016:Reference Values; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics*; D014158:Transcription, Genetic; D044465:White People / Q000235:genetics
C101326:RBP4 protein, human; D012333:RNA, Messenger; D054839:Retinol-Binding Proteins, Plasma