-
Pharmacological Research Sep 2018We herein conducted a systematic review and meta-analysis of published studies to estimate diagnostic accuracy of NUDT15 gene polymorphisms for detection of... (Meta-Analysis)
Meta-Analysis
We herein conducted a systematic review and meta-analysis of published studies to estimate diagnostic accuracy of NUDT15 gene polymorphisms for detection of thiopurine-induced leukopenia. Eligible studies were identified through a comprehensive search on PubMed, Web of Knowledge, Cochrane and OpenGrey datasets up to April 2018. The methodological quality of eligible studies was assessed using the QUADAS-2 criteria. The diagnostic odds ratio (DOR) was used as a single measure of diagnostic performance. Sixteen studies including a total of 3538 thiopurine-treated patients fulfilled inclusion criteria for the systematic review. Among these, 16 studies were available for the meta-analysis of rs116855232, 6 studies for rs186364861 and 5 studies for rs554405994 of NUDT15. A higher DOR was found for rs116855232 (8.44, 95% CI: 5.46-13.03), as compared to rs554405994 (4.336, 95% CI 2.924-6.429) or rs186364861 (2.742, 95% CI 1.453-5.175). Results of meta-regression analysis showed that incidence of leukopenia (relative DOR: 0.96; 95%CI: 0.93-1.00, p = 0.037) and leukopenia onset (late vs early leukopenia, relative DOR: 0.41, 95% CI 0.20-0.85, p = 0.0189) significantly influenced diagnostic accuracy of rs116855232. Subgroup analysis for rs186364861 and rs554405994 revealed a significant DOR for early-onset leukopenia (rs186364861: 4.04, 95% CI 1.78-9.20; rs554405994: 2.94, 95% CI 1.74-4.95), but not for late-onset leukopenia (rs186364861: 1.52, 95% CI 0.52-4.43; rs554405994: 2.02, 95% CI 0.93-4.40). The present meta-analysis points to rs116855232, rs554405994 and rs186364861 of NUDT15 as clinically relevant predictors of thiopurine-induced leukopenia. Nevertheless, prospective studies of genotype-guided dosing of thiopurines are warranted to prove clinical benefit and cost-effectiveness of pretreatment NUDT15 gene testing across different populations.
Topics: Antineoplastic Agents; Azathioprine; Humans; Leukopenia; Mercaptopurine; Polymorphism, Genetic; Pyrophosphatases; Thioguanine
PubMed: 30048756
DOI: 10.1016/j.phrs.2018.07.021 -
BioMed Research International 2014The protooncogene PCPH was recently identified as being the ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5). This protooncogene is converted into an oncogene... (Review)
Review
The protooncogene PCPH was recently identified as being the ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5). This protooncogene is converted into an oncogene by a single base pair deletion, resulting in frame change and producing a premature stop codon, leading to a mutated protein (mt-PCPH) with only 27 kDa, which is much smaller than the original 47 kDa protein. Overexpression of the PCPH as well as the mutated PCPH increases the cellular resistance to stress and apoptosis. This is intriguing considering that the active form, that is, the oncogene, is the mutated PCPH. Several studies analyzed the expression of NTPDase5/mt-PCPH in a wide range of tumor cells and evaluated its role and mechanisms in cancer and other pathogenic processes. The main point of this review is to integrate the findings and proposed theories about the role played by NTPDase5/mt-PCPH in cancer progression, considering that these proteins have been suggested as potential early diagnostic tools and therapy targets.
Topics: Apoptosis; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Neoplasm Staging; Neoplasms; Oncogene Proteins; Pyrophosphatases; Sequence Deletion
PubMed: 25045656
DOI: 10.1155/2014/123010 -
Diabetes Apr 2008Functional studies suggest that the nonsynonymous K121Q polymorphism in the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) may confer susceptibility to... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Functional studies suggest that the nonsynonymous K121Q polymorphism in the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) may confer susceptibility to insulin resistance; genetic evidence on its effect on type 2 diabetes, however, has been conflicting. We therefore conducted a new meta-analysis that includes novel unpublished data from the ENPP1 Consortium and recent negative findings from large association studies to address the contribution of K121Q to type 2 diabetes.
RESEARCH DESIGN AND METHODS
After a systematic review of the literature, we evaluated the effect of ENPP1 K121Q on diabetes risk under three genetic models using a random-effects approach. Our primary analysis consisted of 30 studies comprising 15,801 case and 26,241 control subjects. Due to considerable heterogeneity and large differences in allele frequencies across populations, we limited our meta-analysis to those of self-reported European descent and, when available, included BMI as a covariate.
RESULTS
We found a modest increase in risk of type 2 diabetes for QQ homozygotes in white populations (combined odds ratio [OR] 1.38 [95% CI 1.10-1.74], P = 0.005). There was no evidence of publication bias, but we noted significant residual heterogeneity among studies (P = 0.02). On meta-regression, 16% of the effect was accounted for by the mean BMI of control subjects. This association was stronger in studies in which control subjects were leaner but disappeared after adjustment for mean control BMI (combined OR 0.93 [95% CI 0.75-1.15], P = 0.50).
CONCLUSIONS
The ENPP1 Q121 variant increases risk of type 2 diabetes under a recessive model of inheritance in whites, an effect that appears to be modulated by BMI.
Topics: Adult; Aged; Amino Acid Substitution; Blood Glucose; Chromosome Mapping; Diabetes Mellitus, Type 2; Genes, Recessive; Humans; Insulin-Secreting Cells; Middle Aged; Phosphoric Diester Hydrolases; Polymorphism, Single Nucleotide; Pyrophosphatases; White People
PubMed: 18071025
DOI: 10.2337/db07-1336