KCNJ11基因和WFS1基因多态性与2型糖尿病和肥胖的相关性研究
|
摘要
目的探讨KCNJ11基因与青岛地区汉族人群2型糖尿病和肥胖的相关性以及WFS1基因单核苷酸多态性与2型糖尿病的关系。
方法运用病例-对照研究,采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)技术,对青岛地区188例2型糖尿病病人和170例对照者的KCNJ11基因E23K和rs2285676位点多态性进行基因型分析,并对160例肥胖和117例对照者的KCNJ11基因E23K位点多态性进行基因型分析；应用PCR-RFLP技术分析209例2型糖尿病病人和211例对照者的WFS1基因R456H位点的多态性。
结果T2DM组KCNJ11基因E23K位点EE、EK、KK3种基因型频率分别是38.8%、44.7%和16.5%,对照组分别为34.1%、51.8%和14.1%；两组基因型频率分布比较,差异无显著性(x2=1.801,P>0.05)；K等位基因频率在病例组和对照组中分别为38.8%和40%,两组比较差异亦无显著性(x2=0.102,P>0.05)。T2DM组KCNJ11基因rs2285676位点CC、CT、TT3种基因型频率分别是22.3%、54.3%和23.4%,对照组分别为21.8%、48.2%和30%；T2DM组与对照组基因型频率分布比较,差异无显著性(x2=2.106,P>0.05)；T2DM组和对照组T等位基因频率分别为50.5%和54.1%,两组等位基因频率比较,差异无显著性(x2=0.920,P>0.05)。调整性别、年龄、WHR、BMI、TC和血压等因素,Logistic回归分析未发现KCNJ11基因与青岛地区汉族人2型糖尿病相关。
单因素非条件Logistic回归分析结果显示,与EE基因型比较,EK和KK基因型与肥胖均无相关性。调整年龄、性别、血糖和血脂等因素进行多因素非条件Logistic回归分析表明,与EE基因型比较,EK基因型与肥胖无关联,而KK基因型与肥胖存在相关性(OR=2.843,P<0.05)。
T2DM组WFS1基因多态性R456H位点GG、GA、AA3种基因型频率分别是74.6%、20.1%和5.3%,对照组分别为82%、15.2%和2.8%,两组基因型频率分布比较,差异无显著性(x2=3.691,P>0.05)；T2DM组G、A等位基因频率分别为84.7%和15.3%,对照组分别为89.6%和10.4%,两组G、A等位基因频率比较,差异有显著性(x2=4.472,P<0.05)。无论经单因素还是多因素非条件Logistic回归分析,均未发现R456H位点基因型与青岛地区汉族人2型糖尿病相关,而A等位基因与2型糖尿病具有相关性(OR=1.564,P<0.05)。
结论KCNJ11基因E23K位点KK基因型可能是青岛地区汉族人肥胖的危险因素。WFS1基因R456H位点A等位基因可能是青岛地区汉族人2型糖尿病的遗传危险因子。
Objective To explore the correlation of KCNJ11 gene polymorphisms with type 2 diabetes mellitus and obesity and to analyze the relationship between WFS1 gene polymorphism and type 2 diabetes mellitus in Han ethnic population in Qingdao area.
Methods Case-control designs was used and two single nucleotide polymorphisms (SNPs) E23K and rs2285676 in the KCNJ11 gene were genotyped in 188 type 2 diabetic patients and 170 control subjects and the E23K polymorphism in the KCNJ11 gene were genotyped in 160 obesity patients and 170 control subjects by a polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP); the WFS1 gene R456H polymorphism was analyzed using PCR-RFLP in 209 type 2 diabetic patients and 211 control subjects.
Results The frequencies of EE, EK and KK genotype were 38.8%,44.7% and 16.5%, respectively, in T2DM group, and 34.1%,51.8% and 14.1%, respectively, in control group. Frequency of KK genotype in T2DM group was higher than that for controls. The frequencies of K allele were 38.8% and 40% in T2DM group and control group, respectively. No significant difference in the distribution rate of genotype was found between T2DM group and control group (χ2=1.801, P>0.05), and no significant difference in the allelic frequencies existed between the two groups(χ2=0.102,P>0.05). The frequencies of CC, CT and TT genotype were 22.3%,54.3% and 23.4%, respectively, in T2DM group, and 21.8%,48.2% and 30%, respectively, in control group. The frequencies of T allele were 50.5% and 54.1% in T2DM group and control group, respectively. No significant differences in the distribution rate of genotype and allelic frequencies existed between the two groups (χ2= 2.106, P>0.05 vsχ2=0.920, P>0.05). After adjusting sex, age, WHR, BMI, TC and hypertension, multiple factors, unconditional Logistic regression analysis showed there was no relationship between type 2 diabetes and KCNJ11 gene.
After single factors unconditional Logistic regression analysis, no association was found between obesity and EK and KK genotype, compaired with EE genotype respectively. Compaired with EE genotype, EK genotype was not associated with obesity, but KK genotype was associated with obesity, after multiple factors unconditional Logistic regression analysis (OR=2.843, P<0.05)
The frequencies of GG, GA and AA genotype were 74.6%,20.1%and 5.3%, respectively, in T2DM group, and 82%,15.2% and 2.8%, respectively, in control group. Frequency of AA genotype in T2DM group was higher than that for controls. But there was no significant difference in the distribution rate of genotype between T2DM group and control group (χ2= 3.691, P>0.05). The frequencies of A allele were 15.3% and 10.4% in T2DM group and control group, respectively. The allelic frequencies showed significant difference between the two groups (χ2=4.472, P<0.05). Logistic regression analysis indicated that the WFS1 R456H genotype was not associated with type 2 diabetes. But there was a relationship between A allele and type 2 diabetes (OR= 1.564, P<0.05)
Conclusion The KK genotype of E23K in KCNJ11 is a risk factor of obesity in Han ethnic population in Qingdao area. The A allele of WFS1 R456H serves as a genetic risk factor of T2DM in Han ethnic population in Qingdao area.
方法运用病例-对照研究,采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)技术,对青岛地区188例2型糖尿病病人和170例对照者的KCNJ11基因E23K和rs2285676位点多态性进行基因型分析,并对160例肥胖和117例对照者的KCNJ11基因E23K位点多态性进行基因型分析；应用PCR-RFLP技术分析209例2型糖尿病病人和211例对照者的WFS1基因R456H位点的多态性。
结果T2DM组KCNJ11基因E23K位点EE、EK、KK3种基因型频率分别是38.8%、44.7%和16.5%,对照组分别为34.1%、51.8%和14.1%；两组基因型频率分布比较,差异无显著性(x2=1.801,P>0.05)；K等位基因频率在病例组和对照组中分别为38.8%和40%,两组比较差异亦无显著性(x2=0.102,P>0.05)。T2DM组KCNJ11基因rs2285676位点CC、CT、TT3种基因型频率分别是22.3%、54.3%和23.4%,对照组分别为21.8%、48.2%和30%；T2DM组与对照组基因型频率分布比较,差异无显著性(x2=2.106,P>0.05)；T2DM组和对照组T等位基因频率分别为50.5%和54.1%,两组等位基因频率比较,差异无显著性(x2=0.920,P>0.05)。调整性别、年龄、WHR、BMI、TC和血压等因素,Logistic回归分析未发现KCNJ11基因与青岛地区汉族人2型糖尿病相关。
单因素非条件Logistic回归分析结果显示,与EE基因型比较,EK和KK基因型与肥胖均无相关性。调整年龄、性别、血糖和血脂等因素进行多因素非条件Logistic回归分析表明,与EE基因型比较,EK基因型与肥胖无关联,而KK基因型与肥胖存在相关性(OR=2.843,P<0.05)。
T2DM组WFS1基因多态性R456H位点GG、GA、AA3种基因型频率分别是74.6%、20.1%和5.3%,对照组分别为82%、15.2%和2.8%,两组基因型频率分布比较,差异无显著性(x2=3.691,P>0.05)；T2DM组G、A等位基因频率分别为84.7%和15.3%,对照组分别为89.6%和10.4%,两组G、A等位基因频率比较,差异有显著性(x2=4.472,P<0.05)。无论经单因素还是多因素非条件Logistic回归分析,均未发现R456H位点基因型与青岛地区汉族人2型糖尿病相关,而A等位基因与2型糖尿病具有相关性(OR=1.564,P<0.05)。
结论KCNJ11基因E23K位点KK基因型可能是青岛地区汉族人肥胖的危险因素。WFS1基因R456H位点A等位基因可能是青岛地区汉族人2型糖尿病的遗传危险因子。
Objective To explore the correlation of KCNJ11 gene polymorphisms with type 2 diabetes mellitus and obesity and to analyze the relationship between WFS1 gene polymorphism and type 2 diabetes mellitus in Han ethnic population in Qingdao area.
Methods Case-control designs was used and two single nucleotide polymorphisms (SNPs) E23K and rs2285676 in the KCNJ11 gene were genotyped in 188 type 2 diabetic patients and 170 control subjects and the E23K polymorphism in the KCNJ11 gene were genotyped in 160 obesity patients and 170 control subjects by a polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP); the WFS1 gene R456H polymorphism was analyzed using PCR-RFLP in 209 type 2 diabetic patients and 211 control subjects.
Results The frequencies of EE, EK and KK genotype were 38.8%,44.7% and 16.5%, respectively, in T2DM group, and 34.1%,51.8% and 14.1%, respectively, in control group. Frequency of KK genotype in T2DM group was higher than that for controls. The frequencies of K allele were 38.8% and 40% in T2DM group and control group, respectively. No significant difference in the distribution rate of genotype was found between T2DM group and control group (χ2=1.801, P>0.05), and no significant difference in the allelic frequencies existed between the two groups(χ2=0.102,P>0.05). The frequencies of CC, CT and TT genotype were 22.3%,54.3% and 23.4%, respectively, in T2DM group, and 21.8%,48.2% and 30%, respectively, in control group. The frequencies of T allele were 50.5% and 54.1% in T2DM group and control group, respectively. No significant differences in the distribution rate of genotype and allelic frequencies existed between the two groups (χ2= 2.106, P>0.05 vsχ2=0.920, P>0.05). After adjusting sex, age, WHR, BMI, TC and hypertension, multiple factors, unconditional Logistic regression analysis showed there was no relationship between type 2 diabetes and KCNJ11 gene.
After single factors unconditional Logistic regression analysis, no association was found between obesity and EK and KK genotype, compaired with EE genotype respectively. Compaired with EE genotype, EK genotype was not associated with obesity, but KK genotype was associated with obesity, after multiple factors unconditional Logistic regression analysis (OR=2.843, P<0.05)
The frequencies of GG, GA and AA genotype were 74.6%,20.1%and 5.3%, respectively, in T2DM group, and 82%,15.2% and 2.8%, respectively, in control group. Frequency of AA genotype in T2DM group was higher than that for controls. But there was no significant difference in the distribution rate of genotype between T2DM group and control group (χ2= 3.691, P>0.05). The frequencies of A allele were 15.3% and 10.4% in T2DM group and control group, respectively. The allelic frequencies showed significant difference between the two groups (χ2=4.472, P<0.05). Logistic regression analysis indicated that the WFS1 R456H genotype was not associated with type 2 diabetes. But there was a relationship between A allele and type 2 diabetes (OR= 1.564, P<0.05)
Conclusion The KK genotype of E23K in KCNJ11 is a risk factor of obesity in Han ethnic population in Qingdao area. The A allele of WFS1 R456H serves as a genetic risk factor of T2DM in Han ethnic population in Qingdao area.
引文
[1]Kaprio J,Tuomilehto J, Koskenvuo M, et al. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin- dependent) diabetes mellitus in a population-based cohort of twins in Finland [J]. Diabetologia.1992,35:1060-1067.
[2]Newman B, Selby JV, King MC, et al. Concordance for type 2 diabetes mellitus in male twins [J]. Diabetologia.1987,30:763-768.
[3]Pijl M, Henneman L, Claassen L, et al. Family history of diabetes:exploring perceptions of people at risk in the Netherlands [J]. Prev Chronic Dis.2009,6(2):A54.
[4]Lander ES, Schork NJ. Genetic dissection of complex traits [J]. Science.1994,265:2037-2048.
[5]Parikh H, Groop L. Candidate genes for type 2 diabetes [J]. Rev Endocr Metab Disord.2004, 5(2):151-176.
[6]Horikawa Y, Oda N, Cox NJ, et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus [J]. Nat Genet.2000,26(2):163-175.
[7]Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes [J]. Nat Genet.2000,26(1): 76-80.
[8]Gloyn AL, Weedon MN, Owen KR, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes [J]. Diabetes.2003, 52(2):568-572.
[9]黄青阳,程孟荣,姬森林.2型糖尿病易感基因的连锁和关联研究[J].遗传学报.2006,33：573-589.
[10]BarrettTG, Bundey SE. Wolfram(DIDMOAD)syndrome[J]. Med. Genet.1997,34:838-841.
[11]Wolfram DJ, Wagener HP. Diabetes mellitus and simple optic atrophy among siblings:report of four cases [J]. Mayo Clin. Proc.1938,13:715-718.
[12]Inoue H, Tanizawa Y, Wasson J, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome) [J]. Nat Genet.1998,20(2): 143-148.
[13]Collier DA, Barrett TG, Curtis D, et al. Linkage of Wolfram syndrome to chromosome 4p16.1 and evidence for heterogeneity [J]. Am J Hum Genet.1996,59(4):855-863.
[14]Polymeropoulos MH, Swift RG, Swift M.Linkage of the gene for Wolfram syndrome to markers on the short arm of chromosome 4 [J]. Nat Genet.1994,8(1):95-97.
[15]Strom TM, Hortnagel K, Hofmann S, et al. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein [J]. Hum Mol Genet.1998,7(13):2021-2028.
[16]Osman AA, Saito M, Makepeace C, et al. Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium [J]. J Biol Chem. 2003,278(52):52755-52762.
[17]Fonseca SG, Fukuma M, Lipson KL, et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells [J]. J Biol Chem.2005,280(47):39609-39615.
[18]Yamada T, Ishihara H, Tamura A, et al.WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells [J]. Hum Mol Genet.2006,15(10):1600-1609.
[19]Ishihara H, Takeda S, Tamura A, et al.Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion. Hum Mol Genet. 2004,13(11):1159-1170.
[20]Hofmann S, Philbrook C, Gerbitz KD, et al. Wolfram syndrome:structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product [J]. Hum Mol Genet.2003, 12(16):2003-2012.
[21]Tirasophon W, Welihinda AA, Kaufman RJ. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Irelp) in mammalian cells [J]. Genes Dev.1998,12(12):1812-1824.
[22]Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 Mrna [J]. Nature.2002,415(6867):92-96.
[23]Hoeflich KP, Yeh WC, Yao Z, et al. Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1(ASK1)[J]. Oncogene.1999,18(42):5814-5820.
[24]Karasik A, O'Hara C, Srikanta S, et al. Genetically programmed selective islet beta-cell loss in diabetic subjects with Wolfram's syndrome [J]. Diabetes Care.1989,12(2):135-138.
[25]Yamaguchi S, Ishihara H, Tamura A, et al. Endoplasmic reticulum stress and N-glycosylation modulate expression of WFS1 protein [J]. Biochem Biophys Res Commun.2004,325(1): 250-256.
[26]Ueda K, Kawano J, Takeda K, et al. Endoplasmic reticulum stress induces Wfsl gene expression in pancreatic beta-cells via transcriptional activation [J]. Eur J Endocrinol.2005,153(1): 167-176.
[27]石慧,,曹丽华,袁栎等.WFS1在大鼠胰腺发育不同时期的表达[J].现代生物医学进展.2008,8(4)：605-607.
[28]Pahl HL. Signal transduction from the endoplasmic reticulum to the cell nucleus [J]. Physiol Rev. 1999,79(3):683-701.
[29]Pakula TM, Laxell M, Huuskonen A, et al.The effects of drugs inhibiting protein secretion in the filamentous fungus Trichoderma reesei. Evidence for down-regulation of genes that encode secreted proteins in the stressed cells [J]. J Biol Chem.2003,278(45):45011-45020.
[30]Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase [J]. Nature.1999,397(6716):271-274.
[31]Friedlander R, Jarosch E, Urban J, et al. A regulatory link between ER-associated protein degradation and the unfolded-protein response [J]. Nat Cell Biol.2000,2(7):379-384.
[32]Yoshida H, Matsui T, Hosokawa N, et al.A time-dependent phase shift in the mammalian unfolded protein response [J]. Dev Cell.2003,4(2):265-271.
[33]Puthalakath H, O'Reilly LA, Gunn P, et al. ER stress triggers apoptosis by activating BH3-only protein Bim [J]. Cell.2007,129(7):1337-1349.
[34]Harding HP, Zeng H, Zhang Y, et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival [J]. Mol Cell.2001, 7(6):1153-1163.
[35]Zhang P, McGrath B, Li S, et al.The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas [J]. Mol Cell Biol.2002,22(11):3864-3874.
[36]林志楠,罗红飞,都健等.胰岛素抵抗大鼠肝脏组织PERK和p-PERK的表达及意义[J].中国医科大学学报.2010,7：529-531
[37]Kaufman RJ, Scheuner D, Schroder M, et al. The unfolded protein response in nutrient sensing and differentiation [J]. Nat Rev Mol Cell Biol.2002,3(6):411-421.
[38]Kaufman RJ. Orchestrating the unfolded protein response in health and disease [J]. J Clin Invest. 2002,110(10):1389-1398.
[39]Scheuner D, Gromeier M, Davies MV, et al. The double-stranded RNA-activated protein kinase mediates viral-induced encephalitis [J]. Virology.2003,317(2):263-274.
[40]Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes:a review [J]. Diabetes.2002,51 (3):S455-S461.
[41]Marchetti P, Bugliani M, Lupi R, et al. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients [J]. Diabetologia.2007,50(12):2486-2494.
[42]Szegezdi E, Logue SE, Gorman AM, et al.Mediators of endoplasmic reticulum stress-induced apoptosis [J]. EMBO Rep.2006,7(9):880-885.
[43]Minton JA, Hattersley AT, Owen K, et al. Association studies of genetic variation in the WFS1 gene and type 2 diabetes in U.K. populations [J]. Diabetes.2002,51(4):1287-1290.
[44]Kawamoto T, Horikawa Y, Tanaka T, et al. Genetic variations in the WFS1 gene in Japanese with type 2 diabetes and bipolar disorder [J]. Mol Genet Metab.2004,82(3):238-245.
[45]Sandhu MS, Weedon MN, Fawcett KA, et al. Common variants in WFS1 confer risk of type 2 diabetes [J]. Nat Genet.2007,39(8):951-953.
[46]Inagaki N, Gonoi T, Clement JP 4th, et al. Reconstitution of IKATP:an inward rectifier subunit plus the sulfonylurea receptor [J]. Science.1995,270(5239):1166-1170.
[47]Ashcroft FM, Rorsman P. ATP-sensitive K channels:a link between B-cell metabolism and insulin secretion [J]. Biochem Soc Trans.1990,18(1):109-111.
[48]Misler S, Barnett DW, Gillis KD, et al. Electrophysiology of stimulus-secretion coupling in human B-cells [J]. Diabetes.1992,41(10):1221-1228.
[49]Proks P, Reimann F, Green N, et al. Sulfonylurea stimulation of insulin secretion [J]. Diabetes. 2002,51(3):S368-S376.
[50]Seino S, Miki T Physiological and pathophysiological roles of ATP-sensitive K+ channels [J]. Prog Biophys Mol Biol.2003,81(2):133-7612.
[51]Riedel MJ, Steckley DC, Light PE. Current status of the E23K Kir6.2 polymorphism: implications for type 2 diabetes. Human Genetics.2005,116:133-145.
[52]Noma A. ATP-regulated K+ channels in cardiac muscle [J]. Nature.1983,305(5930):147-148.
[53]Koster JC, Marshall BA, Ensor N, et al. Targeted oversctivity of β-cell KATP channels induces profound neonatal diabetes [J]. Cell.2000,100:645-654.
[54]Inoue H, Ferret J, Warren-Perry M, et al. Sequence variants in the pancreatic islet β-cell inwardly rectification and lack of role in Caucasian patients with NIDDM [J]. Diabetes.1997,46: 502-507.
[54]Sakura H, Wat N, Horton V, et al. Sequence variants in the human kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel:no association with NIDDM in white Caucasian subjects or evidence of abnormal function when expressed in vitro [J]. Diabetologia.1996,39:1233-1236.
[55]Inoue H, Ferrer J, Warren-perry M, et al. Sequence variants in the pancreatic islet beta-cell inwardly rectifying K+ channel Kir6.2 (Bir) gene:identification and lack of role in Caucasian patients with NIDDM [J]. Diabetes 1997,46:502-507.
[56]Hansen L, Eschwald SM, Hansen T, et al. Amion acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion the insulin sensitivity index and NIDDM [J]. Diabetes.1997,46:508-512.
[57]Yamada Y, Kuroe A, Li Q, et al. Genomic variation in pancreatic ion channel genes in Japanese type 2 diabetic patients [J]. Diabetes.2001.17:213-216.
[58]Yokoi N, KanamoriM, Horikawa Y, et al. Association studies of variants in the genes involved in pancreatic β-cell function in type 2 diabetes in Japanese subjects [J]. Diabetes.2006,55: 2379-2386.
[59]Hani EH, Boutin P, Durand E, et al. Mlssense mutations in the Pancreatic islet beta cellinwardly rectifying K- channelgene(KIR6.2/BIR):a meta-analysis suggests a role in the polygenic basis of Type 2 diabetes mellitus in Caucasians [J]. Diabetologia.1998,41:1511-1515.
[60]Nielsen EM, Hansen L, Carstensen B, et al. The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes [J]. Diabetes.2003,52: 573-577.
[61]Florez JC, BurttN, de Bakker PI, et al. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region [J]. Diabetes.2004,53:1360-1368.
[62]张险峰,杨明功,王长江等.Kir6.2基因多态性与2型糖尿病的相关研究[J].中华医学遗传学杂志.2001,18(6)：486-487.
[63]刘卓,张永伟,冯起平等.中国汉族人群2型糖尿病30个候选基因相关性分析[J].中国医学科学院学报.2006,28(2)：124-128.
[64]Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes [J]. Nat Genet.2000,26:76-80.
[65]Love-Gregory L, Wasson J, Lin J, et al. The E23K single nucleotide polymorphism in the islet ATP-sensitive potassium channel gene (Kir6.2) contributes as much to the risk of type 2 diabetes in Caucasians as the PPARgamma Pr1l2Ala variant [J]. Diabetologia.2003,46:136-137.
[66]Li H, Isomaa B, Taskinen MR, Groop L, et al. Consequences of a family history of type 1 and type 2 diabetes on the phenotype of patients with type 2 diabetes [J]. Diabetes Care.2000,23 (5): 589-594.
[67]Pannacciulli N, De Pergola G, Ciccone M, et al. Effect of family history of type 2 diabetes on the intima-media thickness of the common carotid artery in normal-weight, overweight, and obese glucose-tolerant young adults [J]. Diabetes Care.2003,26(4):1230-1234.
[68]Mohan V, Shanthirani CS, Deepa R. Glucose intolerance (diabetes and IGT) in a selected South Indian population with special reference to family history, obesity and lifestyle factors--the Chennai Urban Population Study (CUPS 14) [J]. J Assoc Physicians India.2003,51:771-777.
[69]Gokcel A, Ozsahin AK, Sezgin N, et al. High prevalence of diabetes in Adana, a southern province of Turkey [J]. Diabetes Care.2003,26(11):3031-3034.
[70]Pannacciulli N, Giorgino F, Martina RA, et al. Effect of family history of type 2 diabetes on white blood cell count in adult women [J]. Obes Res.2003,11(10):1232-1237.
[71]Sanchez SE, Zhang C, Qiu CF, et al. Family history of hypertension and diabetes in relation to preeclampsia risk in Peruvian women [J]. Gynecol Obstet Invest.2003,56(3):128-132.
[72]Purnell JQ, Dev RK, Steffes MW, et al. Relationship of family history of type 2 diabetes, hypoglycemia, and autoantibodies to weight gain and lipids with intensive and conventional therapy in the Diabetes Control and Complications Trial [J]. Diabetes.2003,52(10):2623-2629.
[73]Meyre D, Bouatia-Naji N, Tounian A, et al. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet.2005, 37(8):863-867.
[74]Love-Gregory LD, Wasson J, Ma J, et al.A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4 alpha gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an ashkenazi jewish population [J]. Diabetes.2004,53(4):1134-1140.
[2]Newman B, Selby JV, King MC, et al. Concordance for type 2 diabetes mellitus in male twins [J]. Diabetologia.1987,30:763-768.
[3]Pijl M, Henneman L, Claassen L, et al. Family history of diabetes:exploring perceptions of people at risk in the Netherlands [J]. Prev Chronic Dis.2009,6(2):A54.
[4]Lander ES, Schork NJ. Genetic dissection of complex traits [J]. Science.1994,265:2037-2048.
[5]Parikh H, Groop L. Candidate genes for type 2 diabetes [J]. Rev Endocr Metab Disord.2004, 5(2):151-176.
[6]Horikawa Y, Oda N, Cox NJ, et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus [J]. Nat Genet.2000,26(2):163-175.
[7]Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes [J]. Nat Genet.2000,26(1): 76-80.
[8]Gloyn AL, Weedon MN, Owen KR, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes [J]. Diabetes.2003, 52(2):568-572.
[9]黄青阳,程孟荣,姬森林.2型糖尿病易感基因的连锁和关联研究[J].遗传学报.2006,33：573-589.
[10]BarrettTG, Bundey SE. Wolfram(DIDMOAD)syndrome[J]. Med. Genet.1997,34:838-841.
[11]Wolfram DJ, Wagener HP. Diabetes mellitus and simple optic atrophy among siblings:report of four cases [J]. Mayo Clin. Proc.1938,13:715-718.
[12]Inoue H, Tanizawa Y, Wasson J, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome) [J]. Nat Genet.1998,20(2): 143-148.
[13]Collier DA, Barrett TG, Curtis D, et al. Linkage of Wolfram syndrome to chromosome 4p16.1 and evidence for heterogeneity [J]. Am J Hum Genet.1996,59(4):855-863.
[14]Polymeropoulos MH, Swift RG, Swift M.Linkage of the gene for Wolfram syndrome to markers on the short arm of chromosome 4 [J]. Nat Genet.1994,8(1):95-97.
[15]Strom TM, Hortnagel K, Hofmann S, et al. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein [J]. Hum Mol Genet.1998,7(13):2021-2028.
[16]Osman AA, Saito M, Makepeace C, et al. Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium [J]. J Biol Chem. 2003,278(52):52755-52762.
[17]Fonseca SG, Fukuma M, Lipson KL, et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells [J]. J Biol Chem.2005,280(47):39609-39615.
[18]Yamada T, Ishihara H, Tamura A, et al.WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells [J]. Hum Mol Genet.2006,15(10):1600-1609.
[19]Ishihara H, Takeda S, Tamura A, et al.Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion. Hum Mol Genet. 2004,13(11):1159-1170.
[20]Hofmann S, Philbrook C, Gerbitz KD, et al. Wolfram syndrome:structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product [J]. Hum Mol Genet.2003, 12(16):2003-2012.
[21]Tirasophon W, Welihinda AA, Kaufman RJ. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Irelp) in mammalian cells [J]. Genes Dev.1998,12(12):1812-1824.
[22]Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 Mrna [J]. Nature.2002,415(6867):92-96.
[23]Hoeflich KP, Yeh WC, Yao Z, et al. Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1(ASK1)[J]. Oncogene.1999,18(42):5814-5820.
[24]Karasik A, O'Hara C, Srikanta S, et al. Genetically programmed selective islet beta-cell loss in diabetic subjects with Wolfram's syndrome [J]. Diabetes Care.1989,12(2):135-138.
[25]Yamaguchi S, Ishihara H, Tamura A, et al. Endoplasmic reticulum stress and N-glycosylation modulate expression of WFS1 protein [J]. Biochem Biophys Res Commun.2004,325(1): 250-256.
[26]Ueda K, Kawano J, Takeda K, et al. Endoplasmic reticulum stress induces Wfsl gene expression in pancreatic beta-cells via transcriptional activation [J]. Eur J Endocrinol.2005,153(1): 167-176.
[27]石慧,,曹丽华,袁栎等.WFS1在大鼠胰腺发育不同时期的表达[J].现代生物医学进展.2008,8(4)：605-607.
[28]Pahl HL. Signal transduction from the endoplasmic reticulum to the cell nucleus [J]. Physiol Rev. 1999,79(3):683-701.
[29]Pakula TM, Laxell M, Huuskonen A, et al.The effects of drugs inhibiting protein secretion in the filamentous fungus Trichoderma reesei. Evidence for down-regulation of genes that encode secreted proteins in the stressed cells [J]. J Biol Chem.2003,278(45):45011-45020.
[30]Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase [J]. Nature.1999,397(6716):271-274.
[31]Friedlander R, Jarosch E, Urban J, et al. A regulatory link between ER-associated protein degradation and the unfolded-protein response [J]. Nat Cell Biol.2000,2(7):379-384.
[32]Yoshida H, Matsui T, Hosokawa N, et al.A time-dependent phase shift in the mammalian unfolded protein response [J]. Dev Cell.2003,4(2):265-271.
[33]Puthalakath H, O'Reilly LA, Gunn P, et al. ER stress triggers apoptosis by activating BH3-only protein Bim [J]. Cell.2007,129(7):1337-1349.
[34]Harding HP, Zeng H, Zhang Y, et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival [J]. Mol Cell.2001, 7(6):1153-1163.
[35]Zhang P, McGrath B, Li S, et al.The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas [J]. Mol Cell Biol.2002,22(11):3864-3874.
[36]林志楠,罗红飞,都健等.胰岛素抵抗大鼠肝脏组织PERK和p-PERK的表达及意义[J].中国医科大学学报.2010,7：529-531
[37]Kaufman RJ, Scheuner D, Schroder M, et al. The unfolded protein response in nutrient sensing and differentiation [J]. Nat Rev Mol Cell Biol.2002,3(6):411-421.
[38]Kaufman RJ. Orchestrating the unfolded protein response in health and disease [J]. J Clin Invest. 2002,110(10):1389-1398.
[39]Scheuner D, Gromeier M, Davies MV, et al. The double-stranded RNA-activated protein kinase mediates viral-induced encephalitis [J]. Virology.2003,317(2):263-274.
[40]Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes:a review [J]. Diabetes.2002,51 (3):S455-S461.
[41]Marchetti P, Bugliani M, Lupi R, et al. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients [J]. Diabetologia.2007,50(12):2486-2494.
[42]Szegezdi E, Logue SE, Gorman AM, et al.Mediators of endoplasmic reticulum stress-induced apoptosis [J]. EMBO Rep.2006,7(9):880-885.
[43]Minton JA, Hattersley AT, Owen K, et al. Association studies of genetic variation in the WFS1 gene and type 2 diabetes in U.K. populations [J]. Diabetes.2002,51(4):1287-1290.
[44]Kawamoto T, Horikawa Y, Tanaka T, et al. Genetic variations in the WFS1 gene in Japanese with type 2 diabetes and bipolar disorder [J]. Mol Genet Metab.2004,82(3):238-245.
[45]Sandhu MS, Weedon MN, Fawcett KA, et al. Common variants in WFS1 confer risk of type 2 diabetes [J]. Nat Genet.2007,39(8):951-953.
[46]Inagaki N, Gonoi T, Clement JP 4th, et al. Reconstitution of IKATP:an inward rectifier subunit plus the sulfonylurea receptor [J]. Science.1995,270(5239):1166-1170.
[47]Ashcroft FM, Rorsman P. ATP-sensitive K channels:a link between B-cell metabolism and insulin secretion [J]. Biochem Soc Trans.1990,18(1):109-111.
[48]Misler S, Barnett DW, Gillis KD, et al. Electrophysiology of stimulus-secretion coupling in human B-cells [J]. Diabetes.1992,41(10):1221-1228.
[49]Proks P, Reimann F, Green N, et al. Sulfonylurea stimulation of insulin secretion [J]. Diabetes. 2002,51(3):S368-S376.
[50]Seino S, Miki T Physiological and pathophysiological roles of ATP-sensitive K+ channels [J]. Prog Biophys Mol Biol.2003,81(2):133-7612.
[51]Riedel MJ, Steckley DC, Light PE. Current status of the E23K Kir6.2 polymorphism: implications for type 2 diabetes. Human Genetics.2005,116:133-145.
[52]Noma A. ATP-regulated K+ channels in cardiac muscle [J]. Nature.1983,305(5930):147-148.
[53]Koster JC, Marshall BA, Ensor N, et al. Targeted oversctivity of β-cell KATP channels induces profound neonatal diabetes [J]. Cell.2000,100:645-654.
[54]Inoue H, Ferret J, Warren-Perry M, et al. Sequence variants in the pancreatic islet β-cell inwardly rectification and lack of role in Caucasian patients with NIDDM [J]. Diabetes.1997,46: 502-507.
[54]Sakura H, Wat N, Horton V, et al. Sequence variants in the human kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel:no association with NIDDM in white Caucasian subjects or evidence of abnormal function when expressed in vitro [J]. Diabetologia.1996,39:1233-1236.
[55]Inoue H, Ferrer J, Warren-perry M, et al. Sequence variants in the pancreatic islet beta-cell inwardly rectifying K+ channel Kir6.2 (Bir) gene:identification and lack of role in Caucasian patients with NIDDM [J]. Diabetes 1997,46:502-507.
[56]Hansen L, Eschwald SM, Hansen T, et al. Amion acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion the insulin sensitivity index and NIDDM [J]. Diabetes.1997,46:508-512.
[57]Yamada Y, Kuroe A, Li Q, et al. Genomic variation in pancreatic ion channel genes in Japanese type 2 diabetic patients [J]. Diabetes.2001.17:213-216.
[58]Yokoi N, KanamoriM, Horikawa Y, et al. Association studies of variants in the genes involved in pancreatic β-cell function in type 2 diabetes in Japanese subjects [J]. Diabetes.2006,55: 2379-2386.
[59]Hani EH, Boutin P, Durand E, et al. Mlssense mutations in the Pancreatic islet beta cellinwardly rectifying K- channelgene(KIR6.2/BIR):a meta-analysis suggests a role in the polygenic basis of Type 2 diabetes mellitus in Caucasians [J]. Diabetologia.1998,41:1511-1515.
[60]Nielsen EM, Hansen L, Carstensen B, et al. The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes [J]. Diabetes.2003,52: 573-577.
[61]Florez JC, BurttN, de Bakker PI, et al. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region [J]. Diabetes.2004,53:1360-1368.
[62]张险峰,杨明功,王长江等.Kir6.2基因多态性与2型糖尿病的相关研究[J].中华医学遗传学杂志.2001,18(6)：486-487.
[63]刘卓,张永伟,冯起平等.中国汉族人群2型糖尿病30个候选基因相关性分析[J].中国医学科学院学报.2006,28(2)：124-128.
[64]Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes [J]. Nat Genet.2000,26:76-80.
[65]Love-Gregory L, Wasson J, Lin J, et al. The E23K single nucleotide polymorphism in the islet ATP-sensitive potassium channel gene (Kir6.2) contributes as much to the risk of type 2 diabetes in Caucasians as the PPARgamma Pr1l2Ala variant [J]. Diabetologia.2003,46:136-137.
[66]Li H, Isomaa B, Taskinen MR, Groop L, et al. Consequences of a family history of type 1 and type 2 diabetes on the phenotype of patients with type 2 diabetes [J]. Diabetes Care.2000,23 (5): 589-594.
[67]Pannacciulli N, De Pergola G, Ciccone M, et al. Effect of family history of type 2 diabetes on the intima-media thickness of the common carotid artery in normal-weight, overweight, and obese glucose-tolerant young adults [J]. Diabetes Care.2003,26(4):1230-1234.
[68]Mohan V, Shanthirani CS, Deepa R. Glucose intolerance (diabetes and IGT) in a selected South Indian population with special reference to family history, obesity and lifestyle factors--the Chennai Urban Population Study (CUPS 14) [J]. J Assoc Physicians India.2003,51:771-777.
[69]Gokcel A, Ozsahin AK, Sezgin N, et al. High prevalence of diabetes in Adana, a southern province of Turkey [J]. Diabetes Care.2003,26(11):3031-3034.
[70]Pannacciulli N, Giorgino F, Martina RA, et al. Effect of family history of type 2 diabetes on white blood cell count in adult women [J]. Obes Res.2003,11(10):1232-1237.
[71]Sanchez SE, Zhang C, Qiu CF, et al. Family history of hypertension and diabetes in relation to preeclampsia risk in Peruvian women [J]. Gynecol Obstet Invest.2003,56(3):128-132.
[72]Purnell JQ, Dev RK, Steffes MW, et al. Relationship of family history of type 2 diabetes, hypoglycemia, and autoantibodies to weight gain and lipids with intensive and conventional therapy in the Diabetes Control and Complications Trial [J]. Diabetes.2003,52(10):2623-2629.
[73]Meyre D, Bouatia-Naji N, Tounian A, et al. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet.2005, 37(8):863-867.
[74]Love-Gregory LD, Wasson J, Ma J, et al.A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4 alpha gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an ashkenazi jewish population [J]. Diabetes.2004,53(4):1134-1140.