葡萄糖激酶基因3个标签单核苷酸多态性位点与2型糖尿病的相关性研究

Study on relationship between glucokinase gene 3 tag single nucleotide polymorphism sites and type 2 diabetes

目的 探讨葡萄糖激酶（GCK）基因3个标签单核苷酸多态性（tagSNPs）位点rs2971672、rs2268573、rs2300587与2型糖尿病的关系。方法 选取2013年8月至2014年12月在中山大学附属中山医院住院的中国南方汉族2型糖尿病患者499例（2型糖尿病组）,同时选择同期在该院康体保健中心体检的汉族健康人499例作为对照组,对GCK基因的3个tagSNPs位点采用改良多重高温连接酶检测反应技术（iMLDR）进行基因分型,应用Hardy-Weinberg平衡规律检测标本代表性,采用χ2检验、Logistic回归分析比较2型糖尿病组和对照组基因型和等位基因频率的差异,并在加性、显性和隐性3种遗传模型下对各SNP位点进行相关性分析。应用Haploview软件构建GCK基因3个tagSNPs位点的单体型,分析是否存在连锁不平衡（LD）及不同的GCK单体型与2型糖尿病易感性的关系。结果 rs2268573、rs2300587的基因型（χ2=3.361、2.076,均P〉0.05）和等位基因频率（χ2=0.222、1.980,均P〉0.05）在2型糖尿病组和对照组之间差异均无统计学意义。rs2971672的基因型（χ2=6.896,P〈0.01）和等位基因分布（χ2=4.708,P〈0.05）在2型糖尿病组和对照组之间差异有统计学意义。在显性遗传模式下以及在加性遗传模式下,rs2971672的基因型分布在2型糖尿病组和对照组之间的差异有统计学意义（显性遗传模式下OR=1.74,95%CI：1.17~2.57,P〈0.01;加性遗传模式下OR=1.51,95%CI：1.06~2.14,P〈0.05）。GCK基因3个位点中的rs2971672和rs2300587有一个LD域,其中TC、TA、CA3种主要单体型,单体型TA和CA均降低个体患2型糖尿病的风险,OR值分别为0.81（95%CI：0.66~1.00,P〈0.05）和0.78（95%CI：0.62~0.98,P〈0.05）。结论 在汉族人群中,GCK基因区域的rs2971672位点与糖尿病遗传易感性密切相关,而rs2268573、rs2300587位点与糖尿病遗传易感性无明确相关性。rs2971672和rs2300587的LD域单体型TA和CA均降低个体患2型糖尿病的风险。

Objective To investigate the relationships between glucokinase（GCK） gene 3 tag single‐nucleotide polymorphisms （tagSNPs）sites rs2971672 ,rs2268573 and rs2300587 polymorphisms with type 2 diabetes （T2DM ） .Methods A total of 499 south‐ern Han inpatients with T2DM （T2DM group） in our hospital and contemporaneous 499 Han individuals undergoing the physical examination（control group） in the Health and Fitness Protection Center of our hospital from August 2013 to December 2014 were chosen .The GCK gene 3 tagSNPs sites in all subjects were genotyped by adopting the improved multiple ligase detection reaction （iMLDR） ,and the genotype and allele frequency between the T2DM group and healthy controls were compared by the chi‐square test ,logistic regression analysis ,moreover the tagSNPs sites were performed the correlation analysis under three genetic modes （dominant ,recessive and additive） .The Haploview software was used to construct the haplotype of GCK gene 3 tagSNPs and the linkage disequilibrium（LD） and relationship between various GCK haplotype and T2DM susceptibility was analyzed .Results The differences of rs2268573 and rs2300587 genotypes（χ2 =3 .361 ,2 .076 ,P＆gt;0 .05） and allele frequency（χ2 =0 .222 ,1 .980 ,P〉0 .05） between the T2DM group and the control group were not statistically significant .The difference of rs2971672 genotype（χ2 =6 .896 , P〈0 .01） and allele distribution（χ2 =4 .708 ,P〈0 .05） between the T2DM group and the control group was statistically signifi‐cant .Under the dominant genetic model and additive genetic model ,the genotype distribution of rs2971672 between the T2DM group and the control group was statistically significant（OR= 1 .74 ,95% CI：1 .17 -2 .57 ,P〈0 .01 ;OR=1 .51 ,95% CI：1 .06-2 .14 ,P〈0 .05） .Among 3 GCK gene sites ,rs2971672 and rs2300587 had the LD domain including 3 main haplotypes of TC ,TA and CA3 ,the TA and CA haplotypes all decreased the risk suffering from T2DM（OR=0 .81 ,95% CI：0 .66-1 .00 ,P〈0 .05 ;OR=0 .78 ,95% CI：0 .62-0 .98 ,P〈0 .05） .Conclusion In Han population ,GCK gene rs2971672 site is closely related with T2DM ge‐netic susceptibility ,while rs2268573 and rs2300587 sites have no obvious correlation with T2DM susceptibility .Haplotype TA and CA in rs2971672 and rs2300587 LD domain all reduce the individual risk suffering from T2DM .