Gas6 gene rs8191974 and Ap3s2 gene rs2028299 are associated with type 2 diabetes in the northern Chinese Han population
Previous studies in other countries have shown that single nucleotide polymorphisms (SNPs) in the growth arrest-specific gene 6 (Gas6; rs8191974) and adapter- related protein complex 3 subunit sigma-2 (Ap3s2; rs2028299) were associated with an increasedrisk for type 2 diabetes mellitus (T2DM). However, the association of these loci with T2DM has not been examined in Chinese populations. We performed a replication study to investigate the association of these susceptibility loci with T2DM in the Chinese population. We genotyped 1968 Chinese participants (996 with T2DM and 972controls) for rs8191974 in Gas6 and rs2028299 near Ap3s2, and examined their association with T2DM using a logistic regression analysis. We also analyzed the correlation of genotypes and clinical phenotypes. The distribution of the T allele of SNP rs8191974 in the Gas6 gene was significantly different between T2DM cases and controls when compared with the C allele (P<0.05, OR: 0.80，95% CI: 0.69–0.94). The occurrence of the CT genotype and the dominant model was also significantly less frequent in the T2DM cases vs. controls when compared with the CC genotype (CT vs. CC: P<0.05, OR: 0.75, 95% CI:0.62–0.90; TT+CT vs. CC: P<0.05, OR:0.75, 95% CI:0.63–0.90). In SNP rs2028299, the allele C showed no statistically significant differencein distribution between the control and T2DM groups when compared with allele A. However, in male populations, the dominant model was statistically more frequent when compared with genotype AA (CC+CA vs. AA: P<0.05, OR:1.29, 95% CI:1.02–1.64), and in obesity-stratified analysis, we also observed a significant difference in the distribution of the dominant model between the T2DM cases and controls in subjects with BMI≥24 kg/ m2 and BMI<28kg/m2 (CC+CA vs. AA: P<0.05, OR: 6.33, 95% CI:4.17–9.61). In conclusion, our study shows that SNPsrs8191974 and rs2028299 are significantly associated with T2DM in the Chinese population.
Whiting DR, Guariguata L, Weil C, Shaw J (2011) IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 94: 311–321. doi: http://dx.doi.org/10.1016/j. diabres.2011.10.029
Bellido-Martin L, de Frutos PG (2008) Vitamin K-dependent actions of Gas6. Vitam Horm 78: 185–209. http://dx.doi.org/10.1016/ S0083-6729(07)00009-X
Hafizi S, Dahlback B (2006) Gas6 protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily. FEBS J 273: 5231–5244. doi: http://dx.doi.org/10.1111/j.1742- 4658.2006.05529.x
Bellosta P, Zhang Q, Goff SP, Basilico C (1997) Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation. Oncogene 15: 2387–2397. http://dx.doi. org/10.1038/sj.onc.1201419
Nagata K, Ohashi K, Nakano T, Arita H, Zong C, Hanafusa H et al. (1996) Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J BiolChem 271: 30022–30027. http://dx.doi.org/10.1074/ jbc.271.47.30022
Collett G, Wood A, Alexander MY, Varnum BC, Boot-Handford RP, Ohanian V et al. (2003) Receptor tyrosine kinase Axlmodulates the osteogenic differentiation of pericytes. Circ Res 92: 1123–1129. http://dx.doi.org/10.1161/01.RES.0000074881.56564.46
Godowski PJ, Mark MR, Chen J, Sadick MD, Raab H, Hammonds RG (1995) Reevaluation of the roles of protein S and Gas6 as ligands for the receptor tyrosine kinase Rse/Tyro 3. Cell 82: 355–358. http://dx.doi.org/10.1016/0092-8674(95)90424-7
Lee CH, Chu NF, Shieh YS, Hung YJ (2012) The growtharrest-specific6 (Gas6) gene polymorphism c.834+7G>A is associated with type 2 diabetes. Diabetes Res Clin Pract 95: 201–206. http://dx.doi. org/10.1016/j.diabres.2011.09.013
Kooner JS, Saleheen D, Sim X, Sehmi J, Zhang W et al. (2011) Genome- wide association study in individuals of South Asian ancestry identifies six new type 2diabetes susceptibility loci. Nat Genet 43: 984–989. http://dx.doi.org/10.1038/ng.921
Fukuda H, Imamura M, Tanaka Y, Iwata M, Hirose H et al. (2012) A single nucleotide polymorphism within DUSP9 is associated with susceptibility to type 2 diabetes in a Japanese population. PLoS One 7: e46263. http://dx.doi.org/10.1371/journal.pone.0046263
Lyssenko V, Groop L, Prasad RB (2015) Genetics of type 2 diabetes: it matters from which parent we inherit the risk. Rev Diabet Stud 12: 233–242. http://dx.doi.org/10.1900/RDS.2015.12.233
Imamura M, Maeda S (2011) Genetics of type 2 diabetes: the GWAS and future perspectives. Endocr J 58: 723–739
Sladek R, Rocheleau G, Rung J, Dina C, Shen L et al. (2007) A genome- wide association study identifies novel risk loci for type 2 diabetes. Nature 445: 881–885. http://dx.doi.org/10.1038/nature05616
Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, et al. (2007) Replication of genome-wide association signal in U.K. samples reveals risk loci for type 2 diabetes. Science 316: 1336–1341. http://dx.doi.org/10.1126/science.1142364
Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42: 105–116. http://dx.doi.org/10.1038/ng.520
Nagai K, Arai H, Yanagita M, Matsubara T, Kanamori H, Nakano T, et al. (2003) Growth arrest-specific gene 6 is involved in glomerular hypertrophy in the early stage of diabetic nephropathy. J Biol Chem 278: 18229–18234. http://dx.doi.org/10.1074/jbc.M213266200
Cavet ME, Smolock EM, Ozturk OH, World C, Pang J, Konishi A, et al. (2008) Gas6-axl receptor signaling is regulated by glucose in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 28: 886–891. http://dx.doi.org/10.1161/ATVBAHA.108.162693
Augustine KA, Rossi RM, Van G, Housman J, Stark K, Danilenko D, et al. (1999) Non-insulin-dependent diabetes mellitus occurs in mice ectopically expressing the human Axl tyrosine kinase receptor. J Cell Physiol 181: 433–447. http://dx.doi.org/10.1002/(SICI)1097- 4652(199912)181:3<433::AID-JCP7>3.0.CO;2-Y
Hsieh CH, Chung RH, Lee WJ, Lin MW, Chuang LM, Quertermous T, Assimes T, Hung YJ, Yu YW (2015) Effect of common genetic variants of growth arrest-specific 6 gene on insulin resistance, obesity and type 2 diabetes in an Asian population. PLoS One 10: http:// dx.doi.org/10.1371/journal.pone.0135681
Sumoy L, Ramírez-Lorca R, Villar J, de Frutos PG, Sala N (2004) Human vitamin K-dependent GAS6: gene structure, allelic variation, and association with stroke. Hum Mutation 23: 506–512. http://dx. doi.org/10.1002/humu.20025
Muñoz X1, Obach V, Hurtado B, de Frutos PG, Chamorro A, Sala N (2007) Association of specific haplotypes of GAS6 gene with stroke. Thromb Haemost 98: 406–412. https://doi.org/10.1160/ TH06-12-0681
Acta Biochimica Polonica is an open access quarterly and publishes four issues a year. All contents are distributed under the Creative Commons Attribution-ShareAlike 4.0 International (CC BY-SA 4.0) license. Everybody may use the content following terms: Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made, ShareAlike — If you remix, transform, or build upon the material, you must distribute your contributions under the same license as the original. There are no additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
Copyright for all published papers © stays with the authors.
Copyright for the journal: © Polish Biochemical Society.