title: The p53 codon 72 (Arg72Pro) polymorphism is associated with the degree of insulin resistance in type 2 diabetic subjects: a cross-sectional study.
abstract: 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 ± 8.4 years) and 367 non-diabetic subjects (60.5 ± 11.7 years). The results were validated in a validation sample consisting of 199 type 2 diabetic (66.2 ± 8.5 years) and 224 non-diabetic subjects (61.2 ± 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 (β = -1.27; p = 0.001) and HOMA-IR (β = -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.
authors.affiliation: Metabolic Diseases and Diabetology Unit, National Institute of Health and Science on Aging (INRCA), Via della Montagnola 81, 60131, Ancona, Italy. a.bonfigli@inrca.it
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Bonfigli
authors.forename: Cristina
authors.initials: C
authors.lastname: Sirolla
authors.forename: Roberto
authors.initials: R
authors.lastname: Testa
authors.forename: Michela
authors.initials: M
authors.lastname: Cucchi
authors.forename: Liana
authors.initials: L
authors.lastname: Spazzafumo
authors.forename: Stefano
authors.initials: S
authors.lastname: Salvioli
authors.forename: Antonio
authors.initials: A
authors.lastname: Ceriello
authors.forename: Fabiola
authors.initials: F
authors.lastname: Olivieri
authors.forename: Roberto
authors.initials: R
authors.lastname: Festa
authors.forename: Antonio Domenico
authors.initials: AD
authors.lastname: Procopio
authors.forename: Gabriele
authors.initials: G
authors.lastname: Brandoni
authors.forename: Massimo
authors.initials: M
authors.lastname: Boemi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Marra
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D003062:Codon / Q000235:genetics; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics; D005215:Fasting; D005260:Female; D005838:Genotype; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D003062:Codon; D008055:Lipids; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53