Variation in TCF7L2 influences therapeutic response to sulfonylureas -: A GoDARTs study
Variation in TCF7L2 influences therapeutic response to sulfonylureas -: A GoDARTs study
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DOI：
10.2337/db07-0440
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发表时间：
2007-08-01
期刊：
影响因子：
7.7
通讯作者：
Palmer, Colin N. A.
中科院分区：
文献类型：
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作者：
Pearson, Ewan R.;Donnelly, Louise A.;Palmer, Colin N. A.
磺脲类药物对2型糖尿病的反应在个体间有相当大的差异。转录因子7样2（TCF 7 L2）变异体已被确定与2型糖尿病风险密切相关，可能是由于P细胞功能降低。我们假设TCF 7 L2的变异会影响对磺脲类药物的反应，但不会影响二甲双胍。我们研究了TCF 7 L2 rs 12255372和rs7903146基因型对血糖反应的影响。研究设计和方法-DARTS/MEMO（糖尿病审计和研究泰赛德/药物监测单位）合作数据库包括处方，生物化学和临床表型的所有糖尿病患者泰赛德，苏格兰，从1992年。其中，TCF 7 L2基因型在4，469名2型糖尿病患者中确定，这些患者被招募到GoDARTS（糖尿病遗传学审计和研究泰赛德）。1997年和2006年7月。共确定了901例磺脲类药物使用者和945例二甲双胍使用者。使用逻辑回归，治疗失败定义为治疗开始后3-12个月内A1 C>7%。协变量包括TCF 7 L2基因型、BMI、性别、确诊年龄、药物依从性和药物剂量。A1 C预处理可用于一个亚组的患者（磺脲类药物n = 579;二甲双胍n = 755）。结果-风险等位基因携带者对磺脲类药物的反应较低，失败的比值比（OR）为1.95（95%CI 1.23-3.06; P = 0.005），比较rs 12255372 T/T与G/G。包括基线A1 C加强了这种关联（OR 2.16 [95% CI 1.21-3.86]，P = 0.009）。与rs7903146的相关性相似，但略弱。调整基线A1 C. Conclusion-TCF 7 L2变异体影响磺脲类药物的治疗反应，但不影响二甲双胍之间没有关联，二甲双胍的反应和单核苷酸多态性。这项研究表明，遗传变异可以改变2型糖尿病患者对治疗的反应。
Objective-There is considerable interindividual variation in sulfonylurea response in type 2 diabetes. Transcription factor 7-like 2 (TCF7L2) variants have been identified to be strongly associated with type 2 diabetes risk, probably due to decreased P-cell function. We hypothesized that variation in TCF7L2 would influence response to sulfonylureas but not metformin. We studied the effect of TCF7L2 rs12255372 and rs7903146 genotypes on glycemic response.Research design and methods-The DARTS/MEMO (Diabetes Audit and Research Tayside/Medicines Monitoring Unit) collaboration database includes prescribing, biochemistry, and clinical phenotype of all patients with diabetes within Tayside, Scotland, from 1992. Of these, the TCF7L2 genotype was determined in 4,469 patients with type 2 diabetes recruited to GoDARTS (Genetics of Diabetes Audit and Research Tayside) between. 1997 and July 2006. A total of 901 incident sulfonylurea users and 945 metformin users were identified. A logistic regression was used with treatment failure defined as an A1C >7% within 3-12 months after treatment initiation. Covariates included the TCF7L2 genotype, BMI, sex, age diagnosed, drug adherence, and drug dose. A1C pretreatment was available in a subset of patients (sulfonylurea n = 579; metformin n = 755).Results-Carriers of the risk allele were less likely to respond to sulfonylureas with an odds ratio (OR) for failure of 1.95 (95% CI 1.23-3.06; P = 0.005), comparing rs12255372 T/T vs. G/G. Including the baseline A1C strengthened this association (OR 2.16 [95% CI 1.21-3.86], P = 0.009). A similar, although slightly weaker, association was seen with rs7903146. No association was seen between metformin response and either single nucleotide polymorphism, after adjustment for baseline A1C.Conclusions-TCF7L2 variants influence therapeutic response to sulfonylureas but not metformin. This study establishes that genetic variation can alter response to therapy in type 2 diabetes.