Giuseppe Miscio

Association of the Q121 Variant of ENPP1 Gene With Decreased Kidney Function Among Patients With Type 2 Diabetes

BACKGROUND Insulin resistance has a role in diabetic kidney complications. The K121Q (lysine to glutamine substitution at amino acid 121, encoded by single-nucleotide polymorphism rs1044498) variant of the ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) has been associated with insulin resistance and related vascular complications in patients with type 2 diabetes (T2D) in many, although not all, studies. This study investigated whether the ENPP1 Q121 variant modulates the risk of decreased glomerular filtration rate (GFR) in patients with T2D. STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS 2 diabetes units from Italy (in Gargano and Padua) and 1 from the United States (Boston, MA) recruited a total of 1,392 patients with T2D. PREDICTOR The ENPP1 Q121 variant. MEASUREMENTS Estimated GFR from serum creatinine, urinary albumin excretion, blood pressure, hemoglobin A(1c), triglycerides, total cholesterol, and high-density lipoprotein cholesterol. OUTCOMES Decreased GFRs (ie, estimated GFR <60 mL/min/1.73 m(2)). RESULTS In the Gargano and Boston populations, according to the dominant model of inheritance, Q121 carriers (ie, individual with either KQ or QQ alleles) had an increased risk of decreased GFR: odds ratios (ORs) of 1.69 (95% confidence interval [CI], 1.1 to 2.6) and 1.50 (95% CI, 1.0 to 2.2), respectively. In the Padua set, the association was in the same direction, but did not reach formal statistical significance (OR, 1.77; 95% CI, 0.7 to 4.5). When the 3 studies were pooled, Q121 carriers showed an increased risk of decreased GFR (OR, 1.58; 95% CI, 1.2 to 2.1; P = 0.002). Also, pooled mean differences in absolute GFRs were different across genotype groups, with Q121 carriers showing lower GFRs compared with KK individuals (P = 0.04). LIMITATIONS P values not approaching a genome-wide level of significance. CONCLUSIONS Our data suggest that patients with T2D carrying the ENPP1 Q121 variant are at increased risk of decreased GFR.

The role of HSP70 on ENPP1 expression and insulin-receptor activation

Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin-receptor (IR) signaling and, when over-expressed, induces insulin resistance in vitro and in vivo. Understanding the regulation of ENPP1 expression may, thus, unravel new molecular mechanisms of insulin resistance. Recent data point to a pivotal role of the ENPP1 3’UTR, in modulating ENPP1 mRNA stability and expression. We sought to identify trans-acting proteins binding the ENPP1-3’UTR and to investigate their role on ENPP1 expression and on IR signaling. By RNA electrophoresis mobility shift analysis and tandem mass spectrometry, we demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3’UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation. Taken together these data suggest that HSP70, by affecting ENPP1 expression, may be a novel mediator of altered insulin signaling.

Time related variations in stem cell harvesting of umbilical cord blood

Umbilical cord blood (UCB) contains hematopoietic stem cells and multipotent mesenchymal cells useful for treatment in malignant/nonmalignant hematologic-immunologic diseases and regenerative medicine. Transplantation outcome is correlated with cord blood volume (CBV), number of total nucleated cells (TNC), CD34+ progenitor cells and colony forming units in UCB donations. Several studies have addressed the role of maternal/neonatal factors associated with the hematopoietic reconstruction potential of UCB, including: gestational age, maternal parity, newborn sex and birth weight, placental weight, labor duration and mode of delivery. Few data exist regarding as to how time influences UCB collection and banking patterns. We retrospectively analyzed 17.936 cord blood donations collected from 1999 to 2011 from Tuscany and Apulia Cord Blood Banks. Results from generalized multivariable linear mixed models showed that CBV, TNC and CD34+ cell were associated with known obstetric and neonatal parameters and showed rhythmic patterns in different time domains and frequency ranges. The present findings confirm that volume, total nucleated cells and stem cells of the UCB donations are hallmarked by rhythmic patterns in different time domains and frequency ranges and suggest that temporal rhythms in addition to known obstetric and neonatal parameters influence CBV, TNC and CD34+ cell content in UBC units.

The circadecadal rhythm of oscillation of umbilical cord blood parameters correlates with geomagnetic activity – An analysis of long-term measurements (1999–2011)

ABSTRACT Recently, we have shown that the contents of total nucleated cells (TNCs) and CD34+ hematopoietic stem and progenitor cells (CD34+ HSPCs) as well as the cord blood volume (CBV) in umbilical cord blood (UCB) show a circadecadal (~10 years) rhythm of oscillation. This observation was based on an analysis of 17,936 cord blood donations collected during 1999–2011. The aim of the present study was to investigate whether this circadecadal rhythm of oscillation in TNCs, CD34+ HSPCs and CBV is related to geomagnetic activity. For the analysis, the yearly averages of TNCs, CD34+ HSPCs and CBV in UCB were correlated with geomagnetic activity (Dcx index). Our analysis revealed that (i) all three UCB parameters were statistically significantly correlated with the level of geomagnetic activity, (ii) CBV showed a linear correlation with the Dcx index (r = 0.5290), (iii) the number of TNCs and CD34+ HSPCs were quadratic inversely correlated with the Dcx index (r = −0.5343 and r = −0.7749, respectively). Furthermore, (iv) CBV and the number of TNCs were not statistically significantly correlated with the number of either modest or intense geomagnetic storms per year, but (v) the number of CD34+ HSPCs was statistically significantly correlated with the number of modest (r = 0.9253) as well as intense (r = 0.8683) geomagnetic storms per year. In conclusion, our study suggests that UCB parameters correlate with the state of the geomagnetic field (GMF) modulated by solar activity. Possible biophysical mechanisms underlying this observation, as well as the outcome of these findings, are discussed.

Pharmacogenetics of neurological and psychiatric diseases at older age: has the time come?

ABSTRACT Introduction: In recent years, a number of pharmacological approaches for treating neuropsychiatric conditions at older age have proven to be inadequate. The resulting increased prevalence of therapeutic failures (TF) and a worsening of clinical symptoms often linked to adverse reactions (ADRs), are perhaps among the major causes of the increasing rate of hospitalizations and institutionalizations observed in these patients. Areas covered: This review underlines the importance of pharmacogenetic data to fingerprint the pharmacological treatment of neuropsychiatric late-life conditions throughout the analysis of metabolizing enzymes and transporters of psychotropic drugs, mainly those of the cytochrome P450 (CYP) family. Pharmacodynamic response measures as treatment effects mediated through targets (i.e., receptors in the brain) may also contribute to this image. Expert opinion: CYP genetics is the basis of a continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice with advancing age. Furthermore, other specific polymorphic genes influence drug response through differential effects of their functional genetic variants. The known genotypes associated with an altered metabolizer status and drug transporters may help clinical decision-making to avoid concomitant treatments, reduce therapeutic attempts and increase drug safety in neuropsychiatric conditions in older age, after controlling for other clinical variables.

The pharmacogenetic road to avoid adverse drug reactions and therapeutic failures in revolving door patients with psychiatric illnesses: focus on the CYP2D6 isoenzymes

ABSTRACT Introduction: A periodical hospital readmission caused by therapeutic failures (TFs) and a worsening of clinical symptoms most often linked to adverse drug reactions (ADRs) are probably the major causes for the so-called revolving door condition in psychiatric illnesses. This review underlined the importance that pharmacogenetic data on cytochrome P450 (CYP), particularly CYP2D6 polymorphisms, may offer for the finger printing of the pharmacological treatment of psychiatric illnesses, given the relevance of this enzyme in metabolizing psychotropic drugs. Areas covered: We searched in the medical literature until July 2016 to review the role of functional variants in the CYP2D6 gene on observed ADRs and TFs in revolving door psychiatric patients. Expert commentary: CYP2D6 gene variants could in part explain the revolving door condition in patients attending a psychiatric setting. The preemptive known CYP genotypes associated to a reduced metabolizer status may help clinical decision-making to avoid concomitant treatments, increasing drug safety, so reducing therapeutic attempts, hospital admission, and the overall costs for the national health services. However, CYP2D6 gene is only a part of a complex mechanism in which genetic and non-genetic factors may take part. A possible role of the intrinsic variability of pharmacodynamics and imponderable environmental factors influencing the revolving door condition cannot be excluded.

A functional variant in the gene 3' untranslated region regulates HSP70 expression and is a potential candidate for insulin resistance-related abnormalities

Dear Sir, Insulin resistance is a highly common abnormality that is involved in the aetiology of type 2 diabetes (T2D), dyslipidemia and cardiovascular disease [1]. Understanding the molecular defects underlying insulin resistance is urgently needed, so that new pharmacological tools aimed at preventing this disorder and its devastating sequelae can be developed. Several reports have implicated heat-shock protein 70 (HSP70) in the development of insulin resistance-related abnormalities. HSP70 transcript levels have been found to be variably altered in patients with T2D [2–4] and a beneficial role of HSP70 on insulin resistance has been reported in transgenic animals [5]. We recently described a deleterious role of HSP70 on insulin action through the positive modulation of ENPP1 expression, an inhibitor of insulin receptor signalling [6]. Based on these data [2–6], we hypothesized that HSPA1B – the gene coding for HSP70 – is a candidate gene for insulin resistance-related abnormalities. Indeed, in small previous studies, several HSPA1B single nucleotide polymorphisms (SNPs) were associated with T2D [7] and obesity [7, 8]. More recently, the minor allele of the rs2763979 SNP, which is placed in a nonfunctional region on the 5¢ flank of HSPA1B [9– 11], showed a nominally significant association with reduced risk of T2D in the large dataset of the DIAGRAM Consortium (OR = 0.94, P = 0.027) [12] and a tendency toward association with lower fasting blood glucose (P = 0.056) in non diabetic individuals from the DGI dataset [13]. These genetic associations, although too weak to firmly establish variability in HSPA1B as a genetic determinant of insulin resistance states, leave this hypothesis open and clearly indicate the need for further studies on this topic.