Elisa Danese

Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%–2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5′ region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10−11). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84–0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860–0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83–0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83–0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful?

Abstract Background: The study is aimed at evaluating the performance of the predictive model ROMA (Risk of Ovarian Malignancy Algorithm), which utilizes the combination of human epididymis protein 4 (HE4) and CA125 values to assess the risk of epithelial ovarian cancer (EOC) in women with a pelvic mass. Methods: One hundred and four women diagnosed with a pelvic mass (55 EOC and 49 benign cases) and scheduled to have surgery were enrolled, along with 49 healthy females. Preoperative serum concentrations of HE4 and CA125 were measured. Separate logistic regression algorithms ROMA for pre-menopausal and post-menopausal women were used to categorize patients into low- and high-risk groups for EOC. The area under the curve (AUC), sensitivity and specificity were calculated for HE4, CA125 and ROMA for the diagnosis of ovarian cancer using receiver operating characteristic (ROC) analysis. Results: The median CA125 and HE4 serum concentrations were significantly higher among EOC patients than in healthy females (both p<0.05) and those with a benign mass (both p<0.05). The pre-menopausal group included 36 benign cases (29 of which were classified by ROMA as low-risk with a specificity of 80.6%; 95% CI: 64.0%–91.8%), and 15 EOC (eight of which were classified by ROMA as high-risk, with a sensitivity of 53.3%; 95% CI: 26.6%–78.7%). The post-menopausal group enclosed 13 benign cases (11 of which were classified by ROMA as low-risk with a specificity of 84.6%; 95% CI: 54.6%–98.0%), and 40 EOC (33 of which were classified by ROMA as high-risk with a sensitivity of 82.5%; 95% CI: 67.2%–92.7%). In the pre-menopausal group, the AUC was 0.64 (p=0.12, 95% CI: 0.44–0.83) for CA125, 0.77 (p=0.003, 95% CI: 0.62–0.92) for HE4 and 0.77 (p=0.002, 95% CI: 0.63–0.92) for ROMA. In the post-menopausal group, the AUC was 0.84 (p=0.0003, 95% CI: 0.73–0.94) for CA125, 0.94 (p<0.0001, 95% CI: 0.88–0.99) for HE4 and 0.92 (p<0.0001, 95% CI: 0.85–0.99) for ROMA. Conclusions: The ROMA is a simple scoring system which shows excellent diagnostic performance for the detection of EOC in post-menopausal women, but not in pre-menopausal women. Moreover, the dual marker combination of HE4 and CA125 (ROMA) does not show better performance than HE4 alone.

Effect of CPAP on Blood Pressure in Patients With OSA/Hypopnea: A Systematic Review and Meta-analysis

BACKGROUND CPAP is considered the therapy of choice for OSA, but the extent to which it can reduce BP is still under debate. We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to quantify the effect size of the reduction of BP by CPAP therapy compared with other passive (sham CPAP, tablets of placebo drug, conservative measures) or active (oral appliance, antihypertensive drugs) treatments. METHODS We searched four different databases (MEDLINE, EMBASE, Web of Science, and the Cochrane Library) with specific search terms and selection criteria. RESULTS From 1,599 articles, we included 31 RCTs that compared CPAP with either passive or active treatment. In a random-effects meta-analysis vs passive treatment (29 RCTs, 1,820 subjects), we observed a mean±SEM net difference in systolic BP of 2.6±0.6 mm Hg and in diastolic BP of 2.0±0.4 mm Hg, favoring treatment with CPAP (P<.001). Among studies using 24-h ambulatory BP monitoring that presented data on daytime and nighttime periods, the mean difference in systolic and diastolic BP was, respectively, 2.2±0.7 and 1.9±0.6 mm Hg during daytime and 3.8±0.8 and 1.8±0.6 mm Hg during nighttime. In meta-regression analysis, a higher baseline apnea/hypopnea index was associated with a greater mean net decrease in systolic BP (beta±SE, 0.08±0.04). There was no evidence of publication bias, and heterogeneity was mild ( I2, 34%-36%). CONCLUSIONS Therapy with CPAP significantly reduces BP in patients with OSA but with a low effect size. Patients with frequent apneic episodes may benefit the most from CPAP.

The utility of serum human epididymis protein 4 (HE4) in patients with a pelvic mass

Aim: Although CA125 is the most widely used cancer marker in the diagnostic approach of pelvic masses in women, its clinical usefulness is limited because it lacks expression of the antigen in the early stages of disease. The human epididymis protein 4 (HE4) is frequently over‐expressed in ovarian cancer, whereas its expression in normal tissues, including the ovary, is low. The aim of this study was to assess the concentration of both HE4 and CA125 in patients with different forms of benign and malign pelvic masses.

HE4 in ovarian cancer: from discovery to clinical application.

Despite the relatively low prevalence, ovarian cancer is the fifth leading cause of death from cancer among women. As such, an early diagnosis for establishing a timely surgical and/or chemotherapeutic treatment is essential for improving the outcome. The most reliable, but not always straightforward, approach to diagnose ovarian cancer relies on multiple, time-consuming and expensive investigative tools. These typically include clinical presentation (i.e., pelvic or abdominal pain, urinary frequency or urgency, increased abdominal size or bloating) with pelvic examination, transvaginal ultrasonography (US), and measurement of carbohydrate antigen 125 (CA125). Although the conventional pathway to develop and market a clinically useful biomarker is challenging, recent advances in genomic and proteomic technologies have led to the identification of previously unknown candidate markers of ovarian cancer. Some of these are currently under clinical validation. The human epididymis protein 4 (HE4) has recently been approved by the Food and Drug Administration for monitoring recurrence or progression of epithelial ovarian cancer. Nevertheless, reliable clinical evidence demonstrates that HE4, used alone or in combination with CA125, substantially improves the accuracy of screening and/or disease monitoring. This chapter will review the current knowledge on biologic and clinical applications of ovarian cancer biomarkers, with particular emphasis on the newly proposed marker, HE4.

Prediction of Blood Pressure Changes Over Time and Incidence of Hypertension by a Genetic Risk Score in Swedes

Recent Genome-Wide Association Studies (GWAS) have pinpointed different single nucleotide polymorphisms consistently associated with blood pressure (BP) and hypertension prevalence. However, little data exist regarding single nucleotide polymorphisms predicting BP variation over time and hypertension incidence. The aim of this study was to confirm the association of a genetic risk score (GRS), based on 29 independent single nucleotide polymorphisms, with cross-sectional BP and hypertension prevalence and to challenge its prediction of BP change over time and hypertension incidence in >17 000 middle-aged Swedes participating in a prospective study, the Malmö Preventive Project, investigated at baseline and over a 23-year average period of follow-up. The GRS was associated with higher systolic and diastolic BP values both at baseline (&bgr;±SEM, 0.968±0.102 mm Hg and 0.585±0.064 mm Hg; P<1E-19 for both) and at reinvestigation (&bgr;±SEM, 1.333±0.161 mm Hg and 0.724±0.086 mm Hg; P<1E-15 for both) and with increased hypertension prevalence (odds ratio [95% CI], 1.192 [1.140–1.245] and 1.144 [1.107–1.183]; P<1E-15 for both). The GRS was positively associated with change (&Dgr;) in BP (&bgr;±SEM, 0.033±0.008 mm Hg/y and 0.023±0.004 mm Hg/y; P<1E-04 for both) and hypertension incidence (odds ratio [95% CI], 1.110 [1.065–1.156]; P=6.7 E-07), independently from traditional risk factors. The relative weight of the GRS was lower in magnitude than obesity or prehypertension, but comparable with diabetes mellitus or a positive family history of hypertension. A C-statistics analysis does not show any improvement in the prediction of incident hypertension on top of traditional risk factors. Our data from a large cohort study show that a GRS is independently associated with BP increase and incidence of hypertension.

The role of osteoprotegerin in cardiovascular disease

Osteoprotegerin (OPG) is a 401 amino acid N-glycosylated protein, which is highly expressed in a large number of tissues. OPG mainly binds to two ligands, i.e. RANKL (receptor activator of nuclear factor κB ligand) and TRAIL (tumor necrosis factor- related apoptosis-inducing ligand). Upon binding to the former ligand, OPG inhibits the activation of osteoclasts and promotes apoptosis of osteoclasts, whereas the binding of OPG with TRAIL prevents apoptosis of tumor cells. There is now emerging evidence that OPG participates in the pathogenesis of atherosclerosis and cardiovascular diseases by amplifying the adverse effects of inflammation and several traditional risk factors such as hyperlipidemia, endothelial dysfunction, diabetes mellitus, and hypertension. Some epidemiological studies also showed a positive association between OPG levels and cardiovascular morbidity and mortality. The aim of this article is to provide an overview of the main biochemical, physiological, and pathological aspects of OPG biology in cardiovascular disease.

The role of resistin in colorectal cancer

BACKGROUND To date the role of resistin in colorectal cancer (CRC) is far from being elucidated. The aim of this study was to investigate the association between serum resistin levels and CRC in relation to known risk/protective factors including anthropometric, metabolic, inflammatory parameters as well as lifestyle individual characteristics. METHODS 40 CRC patients and 40 controls were enrolled. Body weight, height, waist circumference and blood pressure were recorded. Fasting plasma glucose, lipids, C-reactive protein (CRP) and resistin levels were measured. Metabolic Syndrome (MS) was defined according to the harmonized definition. RESULTS Resistin levels were significantly higher in CRC patients than in controls (p=0.028) and gradually increased with tumor stage progression (p=0.042). A high resistin level was statistically significant determinant of CRC after adjusting for age, sex, body mass index and lifestyle parameters (p=0.029). Resistin showed a strong association with CRP levels (p ≤ 0.0001). In stepwise regression analysis CRP remained the only independent predictor of both resistin levels (p=0.001) and CRC risk (p=0.021). CONCLUSIONS These results clarify the nature of the association between resistin and CRC risk suggesting that the proinflammatory state of cancer, rather than the clinical diagnosis of CRC itself or its link with obesity and MS, may govern this association.

Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis.

A systematic review and a meta‐analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC‐homozygotes, T‐allele carriers required an 8.3% (95% confidence interval (CI): 5.6–11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.

Homozygosity for the EPHX2 K55R polymorphism increases the long-term risk of ischemic stroke in men: a study in Swedes.

Objectives The soluble epoxide hydrolase (gene name EPHX2) is responsible for metabolism of 8,9 11,12 and 14,15-epoxyeicosatrienoic acids, vasodilator and anti-inflammatory substances. There are several functional polymorphisms in the EPHX2 gene: two of them, the K55R and R287Q, showing an altered metabolic activity in vitro, were associated with coronary heart disease and ischemic stroke in previous studies. The aim of this study was to evaluate the effect of four polymorphisms in the EPHX2 gene on blood pressure levels, hypertension prevalence, and risk of incident cardiovascular events in a large sample of middle-aged Swedes. Methods The incidence of cardiovascular events (coronary events, n=274; ischemic stroke, n=197) was monitored over 10 years of follow-up. Results In the whole population, all polymorphisms had no effect on the studied parameters but a positive interaction between male sex and three SNPs including the K55R was evident: male, but not female, EPHX2 R55R homozygotes had significantly higher crude and adjusted systolic blood pressure and higher hypertension prevalence with respect to K-carriers. Kaplan–Meier curves showed higher incidence of ischemic strokes in male R55R homozygotes with respect to K-carriers (P=0.015 by log-rank test). After adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke in male R55R homozygotes remained significantly higher (hazard ratio: 4.8; 95% confidence interval: 1.2–19.9). Conclusion The functional K55R polymorphism of the EPHX2 gene confers a higher risk of hypertension prevalence and increases the risk of incident ischemic stroke in male homozygotes. Additional studies are needed to confirm these data and to elucidate the interaction between sex and the EPHX2 K55R polymorphism.