Evaluation of Sox2 genetic effect on the development of type 2 diabetes Harvest F. Gu a, ⁎, Tianwei Gu a , Claes-Göran Östenson a , Lars Kärvestedt b , Kerstin Brismar a a Rolf Luft Center for Diabetes Research, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Se-171 76 Sweden b Stockholm Sjukhem, Stockholm, Sweden abstract article info Article history: Accepted 10 July 2011 Available online 26 July 2011 Received by A.J. van Wijnen Keywords: Sox2 gene Single nucleotide polymorphism Type 2 diabetes Sox2 is a transcription factor, which plays an important role in the induction of pluripotent stem cells from somatic cells. The Sox2 gene is located in chromosome 3q26.33 and resides in a linkage region of diabetes. In the present study, we attempted to evaluate the genetic effect of Sox2 in the development of type 2 diabetes (T2D). A total of 1598 Swedish subjects of T2D, pre-diabetes and non-diabetic control subjects were enrolled in the present study. Genotyping experiments for allelic discrimination of SNP rs11915160 were performed with TaqMan allelic discrimination. Sox2 mRNA expression levels in pancreatic islets of T2D patients (n = 16) and control subjects (n = 8) were detected by using real time RT-PCR. Among the non-diabetic control subjects with and without family history of diabetes (FHD, i.e. at least one first degree relative with diabetes or at least two second degree relatives with diabetes), the A allele frequency in Sox2 rs11915160 were 12.3% and 12.9%. This allele frequency was increased to 13.4% in T2D patients with FHD selected from SDPP and 17.9% in the patients with FHD from Kronan study, while the patients without FHD had the allele frequency at 12.4%. The difference of mRNA expression levels of the Sox2 gene in pancreatic islets between T2D patients and controls was not statistically significant. The present study thus suggests that Sox2 is unlikely to exert the genetic effect on the development of T2D. © 2011 Elsevier B.V. All rights reserved. 1. Introduction Evidence from stem cell research has demonstrated that four transcription factors, including Oct3/4, Sox2, Klf4 and c-Myc, play an important role in induction of pluripotent stem cells from somatic cells (Yu et al., 2007; Takahashi et al., 2007; Masui et al., 2007; Stadtfeld et al., 2008). Of these four transcription factors, Sox2 (sex determining region Y-box 2) is a member of the SRY-related HMG-box (SOX) family of transcription factors. The Sox2 gene is located in chromosome 3q26.33 and resides in the linkage region of type 1 diabetes (T1D), type 2 diabetes (T2D) and diabetic nephropathy (DN) (Moczulski et al., 1998; Francke et al., 2001). Moreover, the Sox2 gene is found to be expressed in the adult human pancreas (Zhou et al., 2008). We thus hypothesized that Sox2 may have a genetic impact in the development of T1D, T2D and DN. To test our hypothesis, we began with selection and validation of single nucleotide polymorphisms (SNPs) in the Sox2 gene. This gene consists of one exon with 5′- and 3′-untranslated regions (UTRs). In 3’- UTR of the gene, there is a Tag SNP rs11915160, which represents polymorphic with minor allele frequency (MAF) N 5% in European Caucasians but b 3% in Han Chinese and Japanese populations (http:// www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=11915160). We then carried out a genetic association study in DN using well- characterized T1D subjects, which are European descents and selected from Genetics of Kidney Diseases in Diabetes (GoKinD) study. Data indicated that this Sox2 polymorphism was associated with DN and end- stage renal disease (ESRD) in female T1D patients (Gu et al., 2009). Furthermore, the Sox2, MCF2L2 (MCF.2 cell line derived transforming sequence-like 2) and ADIPOQ (adiponectin) genes are located the same chromosomal region of 3q26–27. We found that Sox2 together with MCF2L2 and ADIPOQ polymorphisms had accumulated genetic effects on DN, which may explain the linkage to DN in chromosome 3q (Zhang et al., 2010). However, the question whether Sox2 has genetic effect in the development of T2D is still unanswered. In the present study, we have performed a genetic association study of the Sox2 gene in a total of 1598 Swedish subjects of T2D, pre-diabetes including impaired glucose tolerance and/or impaired fasting glucose and non-diabetic controls. We have also detected Sox2 mRNA expression levels in pancreatic islets of 24 Swedish subjects with and without T2D. Data may provide useful information for evaluation of Sox2 genetic effect on the development of T2D. Gene 486 (2011) 94–96 Abbreviations: DN, diabetic nephropathy; ESRD, end-stage renal disease; FHD, family history of diabetes; GoKinD, Genetics of Kidney Diseases in Diabetes; MAF, minor allele frequency; SDPP, Stockholm Diabetes Prevention Program; SNP, single nucleotide polymorphism; Sox2, sex determining region Y-box 2; T1D, type 1 diabetes; T2D, type 2 diabetes; UTR, untranslated region. ⁎ Corresponding author at: Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, M1:03 Karolinska Institutet, Stockholm, Se-171 76, Sweden. Tel.: +46 8 51779515; fax: +46 8 51773658. E-mail address: harvest.gu@ki.se (H.F. Gu). 0378-1119/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.gene.2011.07.014 Contents lists available at ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene