中国汉族人群中IRE1α基因多态性与糖尿病前期风险的相关性研究

Genetic variability in IRE1α gene is associated with the risk of prediabetes in a Chinese Han population

目的研究中国汉族人群中IRE1α基因多态性是否参与糖尿病前期的发病风险。方法本研究选取临床资料完整且无亲缘关系的汉族受试者共1448人。其中经标准口服葡萄糖耐量试验证实为糖尿病前期的患者共828例;无糖尿病的对照组620名。应用质谱法(Mass Array技术)对IRE1α4个单体型标记的单核苷酸多态性(Haplotype-tagging SNPs)进行检测,观察人群的基因型分布,分析基因变异性与糖尿病前期风险的相关性。结果 (1)IRE1α的4个SNPs在观察人群中均存在多态性,各SNP基因型频率分布符合Hardy-Weinberg平衡检验。(2)SNP rs880069等位基因频率在正常人群和糖尿病前期组间存在统计学差异。显性遗传模式下,SNP rs880069次要等位基因A携带者糖尿病前期的风险较非携带者升高[OR=1.284,95%CI(1.041～1.583),P=0.020],校正年龄、性别和BMI后差异仍然显著(OR’=1.246,P’=0.048)。(3)在对糖尿病前期发生风险的影响上,rs880069与年龄存在交互作用(交互作用P=0.012)。(4)SNP rs196940次要等位基因A携带者发生糖尿病前期的风险较非携带者升高(OR=1.248,P=0.038),按年龄分层分析发现,这种糖尿病前期风险的差异性主要表现在65岁以下的人群[OR=1.447(1.091～1.923),P=0.010],校正了性别和BMI后[OR’=1.414(1.060～1.887),P’=0.018]。(5)rs880069和rs196940基因型组合分析发现,风险基因型组合AX/AX携带者与非携带者相比,糖尿病前期的风险显著增高[OR=1.259,95%CI(1.021～1.552),P=0.021]。(6)当以年龄≥65岁或BMI≥25kg/m2或携带rs196940或rs880069风险等位基因为糖尿病前期的风险因素进行累积风险分析时发现,携带风险因素越多者糖尿病前期的风险越高。携带1个风险因素的人群发生糖尿病前期的风险约为不携带上述任何风险因素人群的2倍(OR=1.785,P=0.046),携带全部4个风险因素的人群与不携带风险因素的人群相比,发生糖尿病前期的风险增加约4倍(OR=4.60,P=0.004)。结论中国汉族人群中IRE1α基因多态性与糖尿病前期的风险相关。

Objective To investigate the association between the genetic polymorphisms in IRE1α and the risks of prediabetes in a Chinese Han population. Method Of total 1448 subjects, 828 individuals were diagnosed as prediabetes, and 620 controls with negative family history of type 2 diabetes had normal glucose tolerance according to 75 g OGTT. Total 4 haplotype-tagging single nucleotide polymorphisms （SNPs） in IRE1α gene were selected to genotype all the subjects by mass spectrometry assay. The frequencies of genotypes and alleles at 4 SNPs were compared between the case and control groups byChi - square test. The difference in the risks for prediabetes among the groups with differentgenotypes was analyzed by logistic regression analysis. Results （1） The distributions of genotypic frequencies at 4 SNIPs were in accordance with Hardy-Weinberg＇ s law, being colony representative. （2） The frequencies of alleles at rs880069 between prediabetes and controls showed a statistical significance. The minor allele A at rs880069 locus was a risk allele for prediabetes, with the carriers of allele A at a higher risk as compared to non-carriers [OR=1. 284, 95 % CI （1. 041 - 1. 583）, P = 0. 020] in dominant inheritance mode. After adjusted for gender, age and BMI, the association was consistent （OR= 1. 246, P＇ =0. 048）. （3） Age as a continual variable was found to interact with rs880069 in relation to prediabetic risk （P for interaction =0. 012）. （4） At rs196940 locus, the carriers of genotype AX were at a higher risk than the non-carriers （OR= 1. 248, P= 0. 038）, which appeared mainly in the people younger than 65 years old （OR= 1. 447, P = 0. 010; adjusted OR = 1. 414, P＇ = 0. 018）. （5） The analysis for genotype combination showed that the carriers of 2 risk genotypes （AX/AX） had a higher risk of prediabetes as compared to non-carriers （OR=1. 259,P=0. 021）. （6） When age≥ 65yr or BMI≥25 kg/mz, or carrying the risk allele of SNP rs196940 or rs880069 was taken as a risk factor of prediabetes respectively, the cumulative risk analysis showed that the more factors the individuals carried, the higher risk they were at for prediabetes. The subjects who carried all the 4 risk factors had a risk about four times higher than those who didn＇t carry any of the factors （OR=4. 60,P=0. 004）. Conclusion The genetic variables in IRE1α gene may be associated with the risk of prediabetes in the Chinese Han population.