PGC-1α基因多态性与2型糖尿病的相关性

Association of PGC-let gene polymorphism with type 2 diabetes mellitus

目的了解华南汉族人群PGC-1α基因单核苷酸多态性与2型糖尿病的相关性。方法采集350例2型糖尿病患者和其父母以及366名正常糖耐量志愿者的血样，提取基因组DNA。应用PCR-限制性片段长度多态性（RFLP）和DNA直接测序技术鉴定PGC-1α基因多态性位点的基因型。应用病例-对照方法和基于家庭的单倍型相对危险度分析（HRR）和传递不平衡检验（TDT）方法分析相关多态性及其单倍型与2型糖尿病的相关性。结果（1）病例一对照研究显示Gly482Ser（G／A）多态性G、A等位基因在2型糖尿病组和正常糖耐量组分布频率分别为0．589、0．411和0．687、0．313（χ^2=15．076，P〈0．01）。Thr394Thr（G／A）、Thr528Thr（A／G）和Thr612Met（C／T）等位基因在两组间分布频率差异无统计学意义（均P〉0．05）。394A-482A-528A单倍型在两组间分布差异有统计学意义（χ^2=40．2，P〈0．05），且与2型糖尿病存在连锁不平衡（t=2．503，P〈0．05）。（2）基于家庭研究显示PGC-1α基因Gly482Ser变异的A等位基因由父母更多地向患者传递（χ^2=7．217，P=0．007，HRR=1．450），TDT—ETDT结果均显示482位点A等位基因由杂合子父母传递给患病子代的频率偏离0．5（均P〈0．05），单倍型TDT分析显示394A-482A-528A-612C，394A-482A-528A-612T，394A-482A-528G-612C和394A-482A-528G-612T单倍型分布频率显著偏离0．5（P〈0．05或P〈0．01）。结论Gly482Ser（G／A）变异与华南汉族2型糖尿病的易感性密切相关，Thr394Thr（G／A）变异可能辅助了这种作用。

Objective To investigate the association of PGC-1α gene single nucleotide polymorphisms （SNPs） with type 2 diabetes mellitus in Southern China Han population. Methods 350 patients with type 2 diabetes mellitus and their parents and 366 normal Han volunteers were recruited in the study. Their blood specimens were collected to extract the genomic DNA. Thr394Thr（ G/A）, Gly482Ser（ G/A ）, Thr528Thr（A/G） and Thr612Met （C/T） genotypes were identified by PCR-RFLP and DNA direct sequencing. The possible association was analyzed between diabetic patients with the specific cSNPs and their haplotypes by case-control and haplotype relative risk （HRR） and transmission disequilibrium test （TDT） methods. Results （ 1 ） The casecontrol study indicated that G and A allele frequencies of PGC-1α gene Gly482Ser variant were 0. 589, 0. 411 in type 2 diabetic group and 0. 687, 0. 313 in normal group respectively （ χ^2 = 15. 076, P 〈 0.01 ）. The allele frequencies of Thr394Thr, Thr528Thr, Thr612Met polymorphisms did not show significant difference between two groups respectively （all P 〉 0.05 ）. The distributions of Thr394Thr-Gly482Ser-Thr528Thr haplotypes in the diabetic group were significanly different from the controls （ χ^2 = 40.2, P 〈 0.05 ） and had a linkage disequilibrium with type 2 diabetes mellitus （ t = 2. 503, P 〈 0.05 ）. （ 2 ） The family-based studies showed that 482A allele was transmitted more significantly both via TDT and extended TDT from heterozygous parents to patients than expected respectively （ all P 〈 0.05 ）. HRR also supported that the 482A allele was more often transmitted to patients than predicted by chance （ χ^2 = 7. 217, P = 0. 007, HRR = 1. 450）. TDT analyses of haplotypes suggested that the frequencies of 394A-482A-528A-612C,394A-482A-528A-612T, 394A-482A-528G-612C and 394A-482A-528G- 612T haplotypes significantly deviated from 0.5 （ P 〈 0.05 or P 〈 0.01 ）. Condusion In Southern China Han population, type 2 diabetes mellitus is associated with the Gly482Ser variant of PGC-1α gene, and Thr394Thr （ G/ A） variant of PGC-1α gene appears to play an auxiliary role in this association.