Sandra Mastroianno

A variation in 3 ' UTR of hPTP1B increases specific gene expression and associates with insulin resistance

Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling and, when overexpressed, plays a role in insulin resistance (Ahmad et al. 1997). We identified, in the 3 untranslated region of the PTP1B gene, a 1484insG variation that, in two different populations, is associated with several features of insulin resistance: among male individuals, higher values of the insulin resistance HOMA(IR) index (P=.006), serum triglycerides (P=.0002), and total/HDL cholesterol ratio (P=.025) and, among female individuals, higher blood pressure (P=.01). Similar data were also obtained in a family-based association study by use of sib pairs discordant for genotype (Gu et al. 2000). Subjects carrying the 1484insG variant showed also PTP1B mRNA overexpression in skeletal muscle (6,166 plus minus 1,879 copies/40 ng RNA vs. 2,983 plus minus 1,620; P<.01). Finally, PTP1B mRNA stability was significantly higher (P<.01) in human embryo kidney 293 cells transfected with 1484insG PTP1B, as compared with those transfected with wild-type PTP1B. Our data indicate that the 1484insG allele causes PTP1B overexpression and plays a role in insulin resistance. Therefore, individuals carrying the 1484insG variant might particularly benefit from PTP1B inhibitors, a promising new tool for treatment of insulin resistance (Kennedy and Ramachandran 2000).

Heterogeneous Effect of Peroxisome Proliferator-activated Receptor γ2 Ala12 Variant on Type 2 Diabetes Risk

Conflicting results have been reported regarding whether the PPARγ2 Pro12Ala polymorphism plays a role in the risk of type 2 diabetes (T2D), suggesting genetic heterogeneity. To investigate this issue, a meta‐analysis of 41 published and 2 unpublished studies (a total of 42,910 subjects) was conducted. Ala12 carriers had a 19% T2D risk reduction, but this association was highly heterogeneous (p = 0.005). A great proportion (48%) of heterogeneity was explained by the controls’ BMI, with risk reduction being greater when BMI was lower. Risk reduction of Ala12 carriers in Asia (35%) was higher than in Europe (15%, p = 0.02) and tended to be higher than in North America (18%, p = 0.10). Difference between Asians and Europeans was no longer significant (p = 0.15) after adjusting for the controls’ BMI. Studies from Europe were still heterogeneous (p = 0.02) with risk reduction in Ala12 carriers being progressively smaller (test for trend in the odds ratios, p = 0.02) from Northern (26% reduction, p < 0.0001) to Central (10%, p = 0.04) and Southern (0%, p = 0.94) Europe. In conclusion, in our meta‐analysis, the reduced risk of T2D in Ala12 carriers is not homogeneous. It is greater in Asia than in Europe and, among Europeans, it is higher in Northern Europe, barely significant in Central Europe, and nonexistent in Southern Europe.

ENPP1 Q121 Variant, Increased Pulse Pressure and Reduced Insulin Signaling, and Nitric Oxide Synthase Activity in Endothelial Cells

Objective—Insulin resistance induces increased pulse pressure (PP), endothelial dysfunction (ED), and reduced bioavailability of endothelium-derived nitric oxide (NO). The genetic background of these 3 cardiovascular risk factors might be partly common. The ENPP1 K121Q polymorphism is associated with insulin resistance and cardiovascular risk. Methods and Results—We investigated whether the K121Q polymorphism is associated with increased PP in white Caucasians and with ED in vitro. In 985 individuals, (390 unrelated and 595 from 248 families), the K121Q polymorphism was associated with PP (P=8.0×10−4). In the families, the Q121 variant accounted for 0.08 of PP heritability (P=9.4×10−4). This association was formally replicated in a second sample of 475 individuals (P=2.6×10−2) but not in 2 smaller samples of 289 and 236 individuals (P=0.49 and 0.21, respectively). In the individual patients’ data meta-analysis, comprising 1985 individuals, PP was associated with the Q121 variant (P=1.2×10−3). Human endothelial cells carrying the KQ genotype showed, as compared to KK cells, reduced insulin-mediated insulin receptor autophosphorylation (P=0.03), Ser473-Akt phosphorylation (P=0.03), and NO synthase activity (P=0.003). Conclusions—Our data suggest that the ENPP1 Q121 variant is associated with increased PP in vivo and reduced insulin signaling and ED in vitro, thus indicating a possible pathogenic mechanism for the increased cardiovascular risk observed in ENPP1 Q121 carriers.

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

BACKGROUNDnInsulin 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.nnnSTUDY DESIGNnCross-sectional study.nnnSETTING & PARTICIPANTSn2 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.nnnPREDICTORnThe ENPP1 Q121 variant.nnnMEASUREMENTSnEstimated GFR from serum creatinine, urinary albumin excretion, blood pressure, hemoglobin A(1c), triglycerides, total cholesterol, and high-density lipoprotein cholesterol.nnnOUTCOMESnDecreased GFRs (ie, estimated GFR <60 mL/min/1.73 m(2)).nnnRESULTSnIn 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).nnnLIMITATIONSnP values not approaching a genome-wide level of significance.nnnCONCLUSIONSnOur data suggest that patients with T2D carrying the ENPP1 Q121 variant are at increased risk of decreased GFR.

Identification and Clinical Characterization of Adult Patients with Multigenerational Diabetes Mellitus

Background Some patients diagnosed as having type 2 diabetes mellitus (T2DM) are, instead, affected by multigenerational diabetes whose clinical characteristics are mostly undefined. Objective 1. To identify among patients who had been previously defined as affected by T2DM those, in fact, affected by multigenerational diabetes; 2. After excluding patients carrying the most common MODY genes and mitochondrial mutations, we compared clinical features of remaining patients with those of patients with T2DM. Methods Among 2,583 consecutive adult patients who had been defined as affected by T2DM, we looked for those with diabetes in ≥3 consecutive generations. All probands were screened for mutations in six MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B and NeuroD1) and for the A3243G mitochondrial mutation. After excluding patients with mutations in one of such genes, we compared clinical features of the remaining 67 patients (2.6% of the whole initial sample) affected by multigenerational “familial diabetes of the adulthood” (FDA) and of their diabetic relatives (n = 63) to those with T2DM (n = 1,028) by generalized hierarchical linear models followed by pairwise comparisons. Results Age, age at diagnosis, proportion of hypertension (all p<0.001), and waist circumference (p<0.05) were lower in FDA than T2DM. Nonetheless, the two groups had similar age-adjusted incidence rate of all-cause mortality. Conclusions Beside younger age at diagnosis, FDA patients show lower waist circumference and reduced proportion of hypertension as compared to those with T2DM; despite such reduced potential cardiovascular risk factors, FDA patients did not show a reduced mortality risk than patients with T2DM.

Serum uric acid as a prognostic marker in the setting of advanced vascular disease: A prospective study in the elderly

Background Many epidemiological studies analyze the relationship between hyperuricemia and cardiovascular outcomes. This observational prospective study investigates the association of serum uric acid (SUA) levels with adverse cardiovascular events and deaths in an elderly population affected by advanced atherosclerosis. Methods Two hundred and seventy six elderly patients affected by advanced atherosclerosis (217 males and 59 females; aged 71.2 ± 7.8 years) were included. All patients were assessed for history of cardiovascular disease, cancer, obesity and traditional risk factors. Patients were followed for approximately 31 ± 11 months. Major events were recorded during follow-up, defined as myocardial infarction, cerebral ischemia, myocardial and/or peripheral revascularization and death. Results Mean SUA level was 5.47 ± 1.43 mg/dL; then we further divided the population in two groups, according to the median value (5.36 mg/dL). During a median follow up of 31 months (5 to 49 months), 66 cardiovascular events, 9 fatal cardiovascular events and 14 cancer-related deaths have occurred. The patients with increased SUA level presented a higher significant incidence of total cardiovascular events (HR: 1.867, P = 0.014, 95% CI: 1.134–3.074). The same patients showed a significant increased risk of cancer-related death (HR: 4.335, P = 0.025, 95% CI: 1.204–15.606). Conclusions Increased SUA levels are independently and significantly associated with risk of cardiovascular events and cancer related death in a population of mainly elderly patients affected by peripheral vasculopathy.

Role of the APOE polymorphism in carotid and lower limb revascularization: A prospective study from Southern Italy

Background Atherosclerosis is a complex multifactorial disease and the apolipoprotein E (APOE) polymorphism has been associated to vascular complications of atherosclerosis. Objectives To investigate the relationship between the APOE genotypes and advanced peripheral vascular disease. Materials and methods 258 consecutive patients (201 males and 57 females, mean age 70.83 ± 7.89 years) with severe PVD were enrolled in a 42-months longitudinal study (mean 31.65 ± 21.11 months) for major adverse cardiovascular events. At follow-up genotypes of the APOE polymorphism were investigated in blinded fashion. Results As compared with ε3/ε3, in ε4-carriers a significant higher incidence of major adverse cardiovascular events (35.58% vs. 20.79%; p = 0.025) and total peripheral revascularization (22.64% vs. 5.06%; p < 0.001) was observed. Prospective analysis, showed that ε4-carriers have an increased hazard ratio for major adverse cardiovascular events (adjusted HR 1.829, 95% CI 1.017–3.287; p = 0.044) and total peripheral revascularization (adjusted HR = 5.916, 95% CI 2.405–14.554, p <0.001). Conclusions The ε4 allele seems to be risk factor for major adverse cardiovascular events, and in particular for total peripheral revascularization in patients with advanced atherosclerotic vascular disease.

Sudden cardiac death in J wave syndrome with short QT associated to a novel mutation in Nav 1.8 coding gene SCN10A: First case report for a possible pharmacogenomic role

INTRODUCTIONnSudden cardiac death is an important cause of mortality in the general population. It represents an important challenge for clinicians, often being the only symptom of a broad spectrum of cardiac pathologies and inherited heart conditions. Early repolarization syndrome and Brugada syndrome are part of the wider J-wave syndrome, which may also include the short QT syndrome as a third factor of an ionic channel imbalance in the arrhythmogenic landscape.nnnCASE PRESENTATIONnWe describe the case of a woman struck down by sudden cardiac death, with short QT and early repolarization, in which we found an extremely rare and putatively pathogenic heterozygous variant in the SCN10A gene. Variants involving SCN10A, which encodes a voltage-gated sodium channel, were already associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder, thereby influencing the cardiac physiology and predisposing to arrhythmia.nnnCONCLUSIONnWe underline the role of genetic predisposition to sudden cardiac death and, for the first time, suggest a possible environmental effect, such as a pharmacological therapy in the setting of sudden death, with the purpose to increase awareness in clinical practice.

A Silent Alarm at Occupational Evaluation Two Months after a Normal Painful ECG: A Case of Wellens' syndrome.

We describe a case of a 42-year-old man, with a previous episode of angina and a normal ECG and serum cardiac markers, and a two months later finding of biphasic T wave in leads V2-V3 and deeply inverted T wave in V4-V5 at a asymptomatic occupational evaluation. This is a typical ECG pattern of Wellens syndrome. A subsequent coronary angiography showed a critical stenosis of proximal left anterior descendent. We underline the careful value of prolonged observation in chest pain unit and repetitive ECG evaluation also during pain-free period after an angina episode, to exclude an earlier T wave pseudonormalization.