Assessment of Relationship between Fyn-related Kinase Gene Polymorphisms and Overweight/Obesity in Korean Population

  • Jung, Mi-Young (Kohwang Medical Research Institute, Kyung Hee University) ;
  • Kim, Bum-Shik (Kohwang Medical Research Institute, Kyung Hee University) ;
  • Kim, Youn-Jung (Kohwang Medical Research Institute, Kyung Hee University) ;
  • Koh, In-Song (Department of Physiology, College of Medicine, Han Yang University) ;
  • Chung, Joo-Ho (Kohwang Medical Research Institute, Kyung Hee University)
  • Published : 2008.04.30

Abstract

The fyn-related kinase (FRK) belongs to the tyrosine kinase family of protein kinases. Recent studies have shown that Frk affects pancreatic beta cell number during embryogenesis and promotes beta cell cytotoxic signals in response to streptozotocin. To investigate the genetic association between FRK polymorphisms and the risk of obesity in Korean population, single nucleotide polymorphisms (SNPs) in the FRK gene region were selected and analyzed. The body mass index (BMI) was calculated, and biochemical data (systolic blood pressure, diastolic blood pressure, hemoglobin A1C, triglyceride, total cholesterol, high density lipoprotein, and low density lipoprotein) of blood sample from each subject were also measured. One hundred fifty five healthy control and 204 overweight/obesity subjects were recruited. Genotype frequencies of six SNPs [rs6568920 (+8391G>A), rs3756772 (+56780A>G), rs3798234 (+75687C>T), rs9384970 (+68506G>A), rs1933739 (+72978G>A), and rs9400883 (+75809A>G)] in the FRK gene were determined by Affymetrix Targeted Genotyping Chip data. According to the classification of Korean Society for the Study of Obesity, control (BMI 18 to < 23) and overweight/obesity (BMI$\geq$23) subjects were recruited. For the analysis of genetic data, EM algorithm, SNPStats, Haploview, HapAnalyzer, SNPAnalyzer, and Helixtree programs were used. Multiple logistic regression analysis (codominant, dominant, and recessive models) was performed. Age and gender as covariates were adjusted. For biochemical data, Student's t test was used. The mean value of BMI in the control and overweigh/obesity groups was 21.1${\pm}$1.2 (mean${\pm}$SD) and 25.6${\pm}$2.0, respectively. All biochemical data of the overweight/obesity group were statistically significance, compared with the control group. Among six SNPs, two linkage disequilibrium (LD) blocks were discovered. One block consisted of rs1933739 and rs9400883, and the other comprised rs3756772 and rs3798234. One SNP (rs9384970, +68506G>A) showed an association with overweight/obesity in the codominant model (p=0.03). Interestingly, the AA genotype distribution in the overweight/obesity group (n=7, 3.5%) was higher than those in the control group (n=1, 0.6%), which is not found in either Japanese or Chinese subjects. Therefore, the AA genotype of rs9384970 may be a risk factor for development of obesity in Korean population. The results suggest that FRK may be associated with overweight/obesity in Korean population.

Keywords

References

  1. Akerblom B, Anneren C, Welsh M. A role of FRK in regulation of embryonal pancreatic beta cell formation. Mol Cell Endocrinol 270: 73-78, 2007 https://doi.org/10.1016/j.mce.2007.02.009
  2. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15: 539-553, 1998 https://doi.org/10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S
  3. Annerén C. Dual role of the tyrosine kinase GTK and the adaptor protein SHB in beta-cell growth: enhanced beta-cell replication after 60% pancreatectomy and increased sensitivity to streptozotocin. J Endocrinol 172: 145-153, 2002 https://doi.org/10.1677/joe.0.1720145
  4. Annerén C, Welsh M. Increased cytokine-induced cytotoxicity of pancreatic islet cells from transgenic mice expressing the Src-like tyrosine kinase GTK. Mol Med 7: 301-310, 2001
  5. Annerén C, Welsh M, Jansson L. Glucose intolerance and reduced islet blood flow in transgenic mice expressing the FRK tyrosine kinase under the control of the rat insulin promoter. Am J Physiol Endocrinol Metab 292: E1183-1190, 2007 https://doi.org/10.1152/ajpendo.00168.2006
  6. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263-265, 2005 https://doi.org/10.1093/bioinformatics/bth457
  7. Bell GI, Polonsky KS. Diabetes mellitus and genetically programmed defects in beta-cell function. Nature 414: 788-791, 2001 https://doi.org/10.1038/414788a
  8. Burton BT, Foster WR, Hirsch J, Van Itallie TB. Health implications of obesity: an NIH Consensus Development Conference. Int J Obes 9: 155-170, 1985
  9. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39: 175-191, 2007 https://doi.org/10.3758/BF03193146
  10. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960-1994. Int J Obes Relat Metab Disord 22: 39-47, 1998 https://doi.org/10.1038/sj.ijo.0800541
  11. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D. The structure of haplotype blocks in the human genome. Science 296: 2225-2229, 2002 https://doi.org/10.1126/science.1069424
  12. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 67: 968-977, 1983 https://doi.org/10.1161/01.CIR.67.5.968
  13. Jung HY, Park JS, Park YJ, Kim YJ, Kim K, Koh I. HapAnalyzer: minimum Haplotype analysis system for association studies. Genomics Inform 2: 107-109, 2004
  14. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 46: 3-19, 2003 https://doi.org/10.1007/s00125-003-1190-9
  15. Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, 1991-1998. JAMA 282: 1519-1522, 1999 https://doi.org/10.1001/jama.282.16.1519
  16. Nakano Y, Akahane A, Tanaka H, Ueno M, Kunugi H, Nanko S. Analysis of the fyn kinase gene in Alzheimer's disease and schizophrenia. No To Shinkei 56: 153-156, 2004
  17. Rybakowski JK, Borkowska A, Skibinska M, Hauser J. Polymorphisms of the Fyn kinase gene and a performance on the Wisconsin Card Sorting Test in schizophrenia. Psychiatr Genet 17: 201-204, 2007 https://doi.org/10.1097/YPG.0b013e3280991219
  18. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics 22: 1928-1929, 2006 https://doi.org/10.1093/bioinformatics/btl268
  19. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68: 978-989, 2001 https://doi.org/10.1086/319501
  20. Thuveson M, Albrecht D, Zürcher G, Andres AC, Ziemiecki A. iyk, a novel intracellular protein tyrosine kinase differentially expressed in the mouse mammary gland and intestine. Biochem Biophys Res Commun 209: 582-589, 1995 https://doi.org/10.1006/bbrc.1995.1540