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

BackgroundThe 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 FindingsSelected 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.ConclusionSNPs 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.

RBP4: a controversial adipokine

“…Two haplotypes (SNP (risk allele): rs3758538(A), rs3758539(G), rs10882283(G), c248C44TOC(T), rs12265684(G), rs10882273(C); and rs3758539(G), 390COG(G), 406TOC(T), rs36014035(G), rs12265684(G), rs34571439(T), rs12766992(G), rs10882273(C)) are significantly increased in Caucasians with T2D when compared with healthy controls (33,48). Four SNPs in Mongolian population (SNP (risk allele): rs3758539(A), rs7094671(T), rs12265684(C), and 7542TOdel(del)) and a haplotype in South Indian population (rs3758538(C), rs3758539(T), rs36014035(G), and rs34571439(T)) have also been determined that are associated with T2D (31,49). Haplotype (SNP (risk allele)) rs3758538(A), rs3758539(G), rs10882283(G), c248C44TOC(T), rs12265684(G), rs10882273(C)) is also associated with higher mean fasting plasma insulin and 2 h plasma glucose in OGTT in non-diabetic Caucasians (33).…”

Contrasting effects of type 2 and type 1 diabetes on plasma RBP4 levels: The significance of transthyretin

“…However, till date, no information is available on the expression of STRA6 (RBP4 receptor) under these conditions. In a recent study, a G[A single-nucleotide polymorphism in STRA6 was found to be significantly associated with elevated risk of development of T2D in a South Indian cohort (27). This mutation is predicted to alter the trafficking and cell surface expression of this protein, thus suggesting a critical role of STRA6 in the development of insulin resistance.…”

Association of <i>GLUT4</i> gene variants with HbA1c level in Japanese men

“…Recently, two independent studies in south Indian population revealed that SNP haplotypes of GLUT4 gene marginally associate with T2D [12,13]. Therefore, in this study, we retrieved two SNPs, rs5418 and rs2654185, from the south Indian studies and determined their association with T2D prospective trait of HbA1c in a Japanese population.…”