Prudente S, Di Paola R, Pezzilli S, Garofolo M, Lamacchia O, Filardi T, Mannino G C, Mercuri L, Alberico F, Scarale M G, Sesti G, Morano S, Penno G, Cignarelli M, Copetti M, Trischitta V
Research Unit of Metabolic and Cardiovascular Diseases, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.
Research Unit of Diabetes and Endocrine Diseases, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.
Pharmacogenomics J. 2018 May 22;18(3):431-435. doi: 10.1038/tpj.2017.32. Epub 2017 Jul 11.
To investigate the role of IRS1 locus on failure to oral antidiabetes drugs (OADs) we genotyped single-nucleotide polymorphisms (SNPs), rs2943641, rs7578326 (tagging all SNPs genome-wide associated with type 2 diabetes (T2D) and related traits at this locus) and rs1801278 (that is, the loss-of-function IRS1 G972R amino acid substitution) in 2662 patients with T2D. Although no association with OAD failure was observed for rs2943641 and rs7578326 SNPs (odds ratio (OR): 1.04, 95% confidence interval (CI): 0.93-1.16 and OR: 0.97, 95% CI: 0.87-1.09 respectively), a significant association was observed for rs1801278 (OR: 1.34, 95% CI: 1.08-1.66). When meta-analyzed with previous published data, an allelic OR of 1.41 (1.15-1.72; P=0.001) was obtained, so that homozygous R972R individuals have >80% higher risk of failing to OADs as compared with their G972G counterparts. In all, though further studies are needed for confirming this finding, our present data point to IRS1 rs1801278 as a potential biomarker for pursuing the goal of stratified medicine in the field of antihyperglycemic treatment in T2D.
为研究胰岛素受体底物1（IRS1）基因座在口服抗糖尿病药物（OADs）治疗失败中的作用，我们对2662例2型糖尿病（T2D）患者的单核苷酸多态性（SNP）进行了基因分型，包括rs2943641、rs7578326（标记该基因座上所有与2型糖尿病（T2D）及相关性状全基因组关联的SNP）和rs1801278（即功能丧失的IRS1 G972R氨基酸替换）。尽管未观察到rs2943641和rs7578326 SNP与OAD治疗失败有关联（优势比（OR）：1.04，95%置信区间（CI）：0.93 - 1.16；OR：0.97，95% CI：0.87 - 1.09），但观察到rs1801278与OAD治疗失败存在显著关联（OR：1.34，95% CI：1.08 - 1.66）。当与先前发表的数据进行荟萃分析时，获得的等位基因OR为1.41（1.15 - 1.72；P = 0.001），因此与G972G纯合子个体相比，R972R纯合子个体OAD治疗失败的风险高出80%以上。总之，尽管需要进一步研究来证实这一发现，但我们目前的数据表明IRS1 rs1801278是T2D抗高血糖治疗领域中实现分层医学目标的潜在生物标志物。
