Expression analyses of the genes harbored by the type 2 diabetes and pediatric BMI associated locus on 10q23

BMC Medical Genetics

Struan FA Grant¹  Ali Rahim Aziz²  Sandra Deliard²  Jianhua Zhao² 

[1] Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, USA;Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, USA

关键词: Genomics;    Expression;    Pediatrics;    Obesity;   

Others  :  1177793
DOI  :  10.1186/1471-2350-13-89

 received in 2012-03-15, accepted in 2012-09-22,  发布年份 2012

【 摘 要 】

Background

There is evidence that one of the key type 2 diabetes (T2D) loci identified by GWAS exerts its influence early on in life through its impact on pediatric BMI. This locus on 10q23 harbors three genes, encoding hematopoietically expressed homeobox (HHEX), insulin-degrading enzyme (IDE) and kinesin family member 11 (KIF11), respectively.

Methods

We analyzed the impact of adipogeneis on the mRNA and protein expression levels of these genes in the human adipocyte Simpson-Golabi-Behmel syndrome (SGBS) cell line in order to investigate which could be the culprit gene(s) in this region of linkage disequilibrium.

Results

Following activation of differentiation with a PPARγ ligand, we observed ~20% decrease in IDE, ~40% decrease in HHEX and in excess of 80% decrease in KIF11 mRNA levels when comparing the adipocyte and pre-adipocyte states. We also observed decreases in KIF11 and IDE protein levels, but conversely we observed a dramatic increase in HHEX protein levels. Subsequent time course experiments revealed some marked changes in expression as early as three hours after activation of differentiation.

Conclusion

Our data suggest that the expression of all three genes at this locus are impacted during SGBS adipogenesis and provides insights in to the possible mechanisms of how the genes at this 10q23 locus could influence both adipocyte differentiation and susceptibility to T2D through insulin resistance.

【 授权许可】

   
2012 Zhao et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S, et al.: A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007, 445(7130):881-885.
• [2]Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007, 447(7145):661-678.
• [3]Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, et al.: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007, 316(5829):1331-1336.
• [4]Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM, et al.: Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007, 316(5829):1336-1341.
• [5]Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, et al.: A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007, 316(5829):1341-1345.
• [6]Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, et al.: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007, 316(5826):889-894.
• [7]Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, et al.: Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006, 38(3):320-323.
• [8]Zhao J, Bradfield JP, Zhang H, Annaiah K, Wang K, Kim CE, Glessner JT, Frackelton EC, Otieno FG, Doran J, et al.: Examination of all type 2 diabetes GWAS loci reveals HHEX-IDE as a locus influencing pediatric BMI. Diabetes 2010, 59(3):751-755.
• [9]Winkler C, Bonifacio E, Grallert H, Henneberger L, Illig T, Ziegler AG: BMI at age 8 years is influenced by the type 2 diabetes susceptibility genes HHEX-IDE and CDKAL1. Diabetes 2010, 59(8):2063-2067.
• [10]Fischer-Posovszky P, Kukulus V, Tews D, Unterkircher T, Debatin KM, Fulda S, Wabitsch M: Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner. Am J Clin Nutr 2010, 92(1):5-15.
• [11]Li Y, Lazar MA: Differential gene regulation by PPARgamma agonist and constitutively active PPARgamma2. Mol Endocrinol 2002, 16(5):1040-1048.
• [12]Wabitsch M, Brenner RE, Melzner I, Braun M, Moller P, Heinze E, Debatin KM, Hauner H: Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. Int J Obes Relat Metab Disord 2001, 25(1):8-15.
• [13]Fischer-Posovszky P, Newell FS, Wabitsch M, Tornqvist HE: Human SGBS cells - a unique tool for studies of human fat cell biology. Obes Facts 2008, 1(4):184-189.
• [14]Morton RE, Evans TA: Modification of the bicinchoninic acid protein assay to eliminate lipid interference in determining lipoprotein protein content. Anal Biochem 1992, 204(2):332-334.
• [15]Schupp M, Curtin JC, Kim RJ, Billin AN, Lazar MA: A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity. Mol Pharmacol 2007, 71(5):1251-1257.
• [16]Wilson-Fritch L, Nicoloro S, Chouinard M, Lazar MA, Chui PC, Leszyk J, Straubhaar J, Czech MP, Corvera S: Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J Clin Invest 2004, 114(9):1281-1289.
• [17]Lahnalampi M, Heinaniemi M, Sinkkonen L, Wabitsch M, Carlberg C: Time-resolved expression profiling of the nuclear receptor superfamily in human adipogenesis. PLoS One 2010, 5(9):e12991.
• [18]Blangy A, Lane HA, d'Herin P, Harper M, Kress M, Nigg EA: Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 1995, 83(7):1159-1169.
• [19]Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S: Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003, 100(7):4162-4167.