The p53 codon 72 (Arg72Pro) polymorphism is associated with the degree of insulin resistance in type 2 diabetic subjects: a cross-sectional study
The p53 codon 72 (Arg72Pro) polymorphism is associated with the degree of insulin resistance in type 2 diabetic subjects: a cross-sectional study
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DOI：
10.1007/s00592-012-0450-x
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发表时间：
2013-06-01
影响因子：
3.8
通讯作者：
Franceschi, Claudio
中科院分区：
文献类型：
--
作者：
Bonfigli, Anna Rita;Sirolla, Cristina;Franceschi, Claudio
肿瘤抑制蛋白p53已被证明可以调节参与能量产生代谢途径和细胞凋亡的基因。TP 53密码子72（Arg 72 Pro）多态性与糖尿病的关系是近年来研究的一个新领域。本研究旨在探讨TP 53（rs 1042522）Arg 72 Pro多态性基因型及相关遗传模型与糖尿病和非糖尿病人群胰岛素抵抗及其代谢参数的相关性。我们检查了335例2型糖尿病患者（65.5 +/- A 8.4岁）和367例非糖尿病受试者（60.5 +/- A 11.7岁）。在由199名2型糖尿病患者（66.2 +/- A 8.5岁）和224名非糖尿病受试者（61.2 +/- A 12.7岁）组成的验证样本中验证了结果。在研究样本中，校正年龄、性别和BMI影响的协方差分析显示，基因型糖尿病对HOMA-IR评估的胰岛素抵抗有显著影响（p = 0.038）。该结果由空腹血浆胰岛素的变化介导（p = 0.027），因为没有检测到TP 53基因型糖尿病对空腹血浆葡萄糖的影响。特别是，在糖尿病受试者中，Pro/Pro基因型与Arg/Arg（p = 0.013）和Arg/Pro（p = 0.006）携带者的HOMA-IR值较低相关。糖尿病和非糖尿病Pro/Pro携带者之间的HOMA-IR无差异，隐性模型-糖尿病交互作用对空腹胰岛素和HOMA-IR的影响经年龄、性别和BMI校正后显著（分别为p = 0.007和p = 0.029）。线性回归分析，基于加性遗传模型的假设，调整了年龄，性别和BMI，强调了p53基因-糖尿病相互作用对空腹胰岛素（β = -1.27; p = 0.001）和HOMA-IR（β = -0.22; p = 0.006）的影响。空腹胰岛素和HOMA-IR的统计分析结果均在验证样本中得到证实。此外，逻辑回归模型证实，HOMA-IR水平对糖尿病的影响在研究和验证样本中均受到Pro/Pro基因型的调节（分别为OR = 0.29，p = 0.034，95% CI = 0.09-0.91，OR = 0.37，p = 0.035，95% CI = 0.15-0.93）。我们的研究结果表明，p53密码子72（Arg 72 Pro）多态性影响2型糖尿病患者的胰岛素抵抗独立的体重。
Tumor suppressor protein p53 has been demonstrated to regulate genes involved in energy generating metabolic pathways and apoptosis. To date, a new field of research is the involvement of TP53 codon 72 (Arg72Pro) polymorphism in the diabetic disease. The aim of this study was to evaluate whether the genotype and the related genetic models of Arg72Pro polymorphism of TP53 (rs1042522) are associated with insulin resistance and its metabolic parameters in diabetic and non-diabetic subjects. We examined 335 type 2 diabetic patients (65.5 +/- A 8.4 years) and 367 non-diabetic subjects (60.5 +/- A 11.7 years). The results were validated in a validation sample consisting of 199 type 2 diabetic (66.2 +/- A 8.5 years) and 224 non-diabetic subjects (61.2 +/- A 12.7 years). In the study sample, the analysis of covariance, adjusted for the effects of age, gender and BMI, showed a significant genotype-diabetes effect on insulin resistance evaluated by HOMA-IR (p = 0.038). This result was mediated by variations in fasting plasma insulin (p = 0.027), as no TP53 genotype-diabetes effects were detected for fasting plasma glucose. In particular, in the diabetic subjects, Pro/Pro genotype was associated with lower values of HOMA-IR with respect to Arg/Arg (p = 0.013) and Arg/Pro (p = 0.006) carriers. No difference in HOMA-IR between diabetic and non-diabetic Pro/Pro carriers was found. Significant recessive model-diabetes interaction effects on fasting insulin and HOMA-IR adjusted for age, sex and BMI were found (p = 0.007 and p = 0.029, respectively). Linear regression analyses, based on the assumption of an additive genetic model adjusted for age, sex and BMI, highlight p53 gene-diabetes interaction effects on fasting insulin (beta = -1.27; p = 0.001) and HOMA-IR (beta = -0.22; p = 0.006). The results of statistical analyses on fasting insulin and HOMA-IR were all confirmed in the validation sample. Furthermore, the logistic regression models confirmed that the effect of HOMA-IR levels on diabetes was moderated by Pro/Pro genotype in both study and validation samples (OR = 0.29, p = 0.034, 95 % CI = 0.09-0.91, OR = 0.37, p = 0.035, 95 % CI = 0.15-0.93, respectively). Our findings suggest that p53 codon 72 (Arg72Pro) polymorphism influences insulin resistance in type 2 diabetic patients independently of body mass.