title: Identification of a regulatory SNP in the retinol binding protein 4 gene associated with type 2 diabetes in Mongolia.
abstract: Increased levels of retinol binding protein 4 (RBP4) in serum is associated with insulin resistance. To examine this further, the genomic region of RBP4 was genetically surveyed in Mongolian people, who as a group are suffering from a recent rapid increase in diabetes. The RBP4 gene was screened by DHPLC system, and the PCR fragments which showed heteroduplex peaks in multiple samples were followed by direct sequencing to identify common polymorphisms in 48 Mongolian diabetic samples. Identified single nucleotide polymorphisms (SNPs) were genotyped in 511 control and 281 type 2 diabetes samples. The functions of SNPs in the regulatory region were assessed by reporter gene assay and electrophoretic mobility shift assay. Possible association between functional SNPs and serum RBP4 levels or metabolic parameters was statistically assessed. Nine SNPs were identified in the RBP4 gene. A case-control study revealed that the rare alleles of four SNPs were associated with increased risk of diabetes, even after Bonferroni correction (-803, G > A, P = 0.0054; +5169, C > T, P = 0.0025; +6969, G > C, P = 0.0015; +7542, T > del, P = 0.0015). The -803 G > A SNP influenced the transcription efficiency in a hepatocarcinoma cell line as well as the binding efficiency of hepatocyte nuclear factor 1 alpha to the motif. In addition, the -803 A allele was associated with increased serum RBP4 levels in diabetic patients. We have identified a functional SNP in the RBP4 gene associated with type 2 diabetes in Mongolian people.
authors.affiliation: Division of Human Genetics, Center for Community Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan.
authors.forename: Lkhagvasuren
authors.initials: L
authors.lastname: Munkhtulga
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakayama
authors.forename: Nanami
authors.initials: N
authors.lastname: Utsumi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yanagisawa
authors.forename: Takaya
authors.initials: T
authors.lastname: Gotoh
authors.forename: Toshinori
authors.initials: T
authors.lastname: Omi
authors.forename: Maki
authors.initials: M
authors.lastname: Kumada
authors.forename: Batmunkh
authors.initials: B
authors.lastname: Erdenebulgan
authors.forename: Khadbaatar
authors.initials: K
authors.lastname: Zolzaya
authors.forename: Tserenkhuu
authors.initials: T
authors.lastname: Lkhagvasuren
authors.forename: Sadahiko
authors.initials: S
authors.lastname: Iwamoto
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005809:Genes, Regulator; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D008986:Mongolia; D020641:Polymorphism, Single Nucleotide; D012177:Retinol-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma; D012307:Risk Factors
chemical_list: C101326:RBP4 protein, human; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D004247:DNA