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Case-control analysis of SNPs in GLUT4, RBP4 and STRA6: association of SNPs in STRA6 with type 2 diabetes in a South Indian population.

ABSTRACT: BACKGROUND:The inverse relationship between GLUT4 and RBP4 expression is known to play a role in the pathogenesis of type 2 diabetes. Elevated levels of RBP4 were shown to cause insulin resistance in muscles and liver. Identification of STRA6 as a cell surface receptor for RBP4 provides further link in this axis and hence we analyzed SNPs in these three genes for association with type 2 diabetes in a South Indian population. METHODOLOGY/PRINCIPAL FINDINGS:Selected SNPs in the three genes were analyzed in a total of 2002 individuals belonging to Dravidian ethnicity, South India, by Tetra Primer ARMS PCR or RFLP PCR. Allele frequencies and genotype distribution were calculated in cases and controls and were analyzed for association by Chi-squared test and Logistic regression. Haplotype analysis was carried out for each gene by including all the markers in a single block. We observed a significant association of three SNPs, rs974456, rs736118, and rs4886578 in STRA6 with type 2 diabetes (P = 0.001, OR 0.79[0.69-0.91], P = 0.003, OR 0.81[0.71-0.93], and P = 0.001, OR 0.74[0.62-0.89] respectively). None of the SNPs in RBP4 and GLUT4 showed any association with type 2 diabetes. Haplotype analysis revealed that two common haplotypes H1 (111, P = 0.001, OR 1.23[1.08-1.40]) and H2 (222, P = 0.002 OR 0.73[0.59-0.89]) in STRA6, H6 (2121, P = 0.006, OR 1.69[1.51-2.48]) in RBP4 and H4 (2121, P = 0.01 OR 1.41[1.07-1.85]) in GLUT4 were associated with type 2 diabetes. CONCLUSION:SNPs in STRA6, gene coding the cell surface receptor for RBP4, were significantly associated with type 2 diabetes and further genetic and functional studies are required to understand and ascertain its role in the manifestation of type 2 diabetes.

SUBMITTER: Nair AK

PROVIDER: S-EPMC2897881 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Case-control analysis of SNPs in GLUT4, RBP4 and STRA6: association of SNPs in STRA6 with type 2 diabetes in a South Indian population.

Nair Anup Kumar AK Sugunan Divya D Kumar Harish H Anilkumar Gopalakrishnapillai G

PloS one 20100706 7

<h4>Background</h4>The inverse relationship between GLUT4 and RBP4 expression is known to play a role in the pathogenesis of type 2 diabetes. Elevated levels of RBP4 were shown to cause insulin resistance in muscles and liver. Identification of STRA6 as a cell surface receptor for RBP4 provides further link in this axis and hence we analyzed SNPs in these three genes for association with type 2 diabetes in a South Indian population.<h4>Methodology/principal findings</h4>Selected SNPs in the thre ...[more]

PMID: 20625434

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Project description:BackgroundsFat infiltration of skeletal muscle has been recognized as a common feature of many degenerative muscle disorders. Retinol binding protein 4 (RBP4) is an adipokine that has been demonstrated to be correlated with the presence and severity of sarcopenia in the elderly. However, the exact role and the underlying mechanism of RBP4 in muscle atrophy remains unclear.MethodsDenervation-induced muscle atrophy model was constructed in wild-type and RBP4 knockout mice. To modify the expression of RBP4, mice were received intramuscular injection of retinol-free RBP4 (apo-RBP4), retinol-bound RBP4 (holo-RBP4) or oral gavage of RBP4 inhibitor A1120. Holo-RBP4-stimulated C2C12 myotubes were treated with siRNAs or specific inhibitors targeting signalling receptor and transporter of retinol 6 (STRA6)/Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) pathway. Fat accumulation, myofibre cross-sectional area, myotube diameter and the expression of muscle atrophy markers and myogenesis markers were analysed.ResultsThe expression levels of RBP4 in skeletal muscles were significantly up-regulated more than 2-fold from 7 days and sustained for 28 days after denervation. Immunofluorescence analysis indicated that increased RBP4 was localized in the infiltrated fatty region in denervated skeletal muscles. Knockout of RBP4 alleviated denervation-induced fatty infiltration and muscle atrophy together with decreased expression of atrophy marker Atrogin-1 and MuRF1 as well as increased expression of myogenesis regulators MyoD and MyoG. By contrast, injection of retinol-bound holo-RBP4 aggregated denervation-induced ectopic fat accumulation and muscle atrophy. Consistently, holo-RBP4 stimulation also had a dose-dependent effect on the reduction of C2C12 myotube diameter and myofibre cross-sectional area, as well as on the increase of Atrogin-1and MuRF1 expression and decrease of MyoD and MyoG expression. Mechanistically, holo-RBP4 treatment increased the expression of its membrane receptor STRA6 (>3-fold) and promoted the phosphorylation of downstream JAK2 and STAT3. Inhibition of STRA6/JAK2/STAT3 pathway either by specific siRNAs or inhibitors could decrease the expression of Atrogin-1 and MuRF1 (>50%) and decrease the expression of MyoD and MyoG (>3-fold) in holo-RBP4-treated C2C12 myotube. RBP4 specific pharmacological antagonist A1120 significantly inhibited the activation of STRA6/JAK2/STAT3 pathway, ameliorated ectopic fat infiltration and protected against denervation-induced muscle atrophy (30% increased myofibre cross-sectional area) in mice.ConclusionsIn conclusion, our data reveal that RBP4 promotes fat infiltration and muscle atrophy through a STRA6-dependent and JAK2/STAT3 pathway-mediated mechanism in denervated skeletal muscle. Our results suggest that lowering RBP4 levels might serve as a promising therapeutic approach for prevention and treatment of muscle atrophy.

Project description:BackgroundGlucose-dependent insulinotropic polypeptide (GIP) is one of the incretins, which plays a crucial role in the secretion of insulin upon food stimulus and in the regulation of postprandial glucose level. It also exerts an effect on the synthesis and secretion of lipoprotein lipase, from adipocytes, important for lipid metabolism. The aim of our study was to do a case-control association analysis of common variants in GIP in association with type 2 diabetes and related biochemical parameters.MethodA total of 2000 subjects which includes 1000 (584M/416F) cases with type 2 diabetes and 1000 (470M/530F) normoglycemic control subjects belonging to Dravidian ethnicity from South India were recruited to assess the effect of single nucleotide polymorphisms (SNPs) in GIP (rs2291725, rs2291726, rs937301) on type 2 diabetes in a case-control manner. The SNPs were genotyped by using tetra primer amplification refractory mutation system-PCR (ARMS PCR). For statistical analysis, our study population was divided into sub-groups based on gender (male and female). Association analysis was carried out using chi-squared test and the comparison of biochemical parameters among the three genotypes were performed using analysis of covariance (ANCOVA).ResultInitial analysis revealed that, out of the total three SNPs selected for the present study, two SNPs namely rs2291726 and rs937301 were in complete linkage disequilibrium (LD) with each other. Therefore, only two SNPs, rs2291725 and rs2291726, were genotyped for the association studies. No significant difference in the allele frequency and genotype distribution of any of the SNPs in GIP were observed between cases and controls (P > 0.05). Analysis of biochemical parameters among the three genotypes showed a significant association of total cholesterol (P = 0.042) and low density lipoprotein (LDL) with the G allele of the SNP rs2291726 in GIP (P = 0.004), but this was observed only in the case of female subjects. However this association does not remain significant after correction for multiple testing by Bonferroni's inequality method.ConclusionNo statistically significant association was observed between any of the SNPs analysed and type 2 diabetes in our population. But the analysis of biochemical parameters indicates that the G allele in rs2291726 may be a putative risk allele for increased LDL cholesterol and further studies in other population needs to be carried out for ascertaining its role in cholesterol metabolism and subsequent cardiovascular risk.

Dataset Information

Case-control analysis of SNPs in GLUT4, RBP4 and STRA6: association of SNPs in STRA6 with type 2 diabetes in a South Indian population.

Publications

Case-control analysis of SNPs in GLUT4, RBP4 and STRA6: association of SNPs in STRA6 with type 2 diabetes in a South Indian population.

Similar Datasets

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