Effects of Genetic Variation in the Human Retinol Binding Protein-4 Gene (RBP4) on Insulin Resistance and Fat Depot Specific mRNA Expression

Abstract

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 mellitus (T2DM).

Research design and methods: In this study, the RBP4 was sequenced in DNA samples from 48 non-related Caucasian subjects. Five novel and 3 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 in 716 non-diabetic subjects.

Results: A haplotype of 6 common SNPs [A-G-G-T-G-C] was significantly increased in 934 cases with type 2 diabetes (T2DM) compared with 537 healthy controls with normal glucose tolerance (P=0.02; OR=1.37 [95% CI: 1.05-1.79]). Furthermore, in the cohort of 716 non-diabetic Caucasian subjects, carriers of the [A-G-G-T-G-C] had significantly higher mean fasting plasma insulin and 2-h plasma glucose compared with subjects without the haplotype. Two single SNPs (rs10882283 and rs10882273) were also associated with body mass index, waist-to-hip ratio and fasting plasma insulin and several SNPs 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 non-diabetic 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 T2DM and insulin resistance, possibly through an effect on RBP4 expression.