A germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the
(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570 variant ...was reported in PHPT Ashkenazi Jews (AJ).
To evaluate the presence of the
p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management.
Patients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the
p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database.
A total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight
and two
mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the
p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the
p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the
p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%.
In contrast to previous observations, the
p.Tyr394Ser variant-associated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation.
Previous studies have established a correlation between coronary artery calcification (CAC) measured by ECG-gated chest computed tomography (CT) and cardiovascular disease. Recent reports which ...included asymptomatic patients suggest that CAC measured on non-ECG gated CT is similarly associated with cardiovascular risk. This study investigates the correlation between the Framingham Risk Score (FRS) and an incidental finding of CAC on a non-gated chest CT performed for non-cardiac indications in young and seemingly healthy adults.
A cross-sectional study that included 162 CT scans performed in young patients aged 18-50 years old for non-cardiac indications in our institution was conducted. CAC score (CACS) was calculated using the Agatston method. FRS was calculated and compared to the CACS using three different approaches. The correlations between the CACS and several specific factors (i.e. age, body mass index, smoking, statins, etc.), were also evaluated.
Mean age of patients was 36.43 year old and 105 (64.8%) were male. We found a significant positive correlation between the CACS and the FRS in all three approaches (p<0.05). Increased age, smoking and statin use were the only individual factors clearly associated with an increase in CACS (p = 0.002, p = 0.045 and p = 0.009, respectively).
This is the first report indicating that incidental CACS identified in non-gated MDCT is also associated with cardiovascular risk evaluated by FRS in a young population. Our findings suggest that young asymptomatic individuals with incidental CAC should be seriously evaluated for cardiovascular risk factors despite presumption of belonging to a low cardiovascular risk category.
Effective treatments are needed for hepatic steatosis characterized by accumulation of triglycerides in hepatocytes, which leads to hepatocellular carcinoma. MicroRNA 122 (MIR122) is expressed only ...in the liver, where it regulates lipid metabolism. We investigated the mechanism by which free fatty acids (FFAs) regulate MIR122 expression and the effect of MIR122 on triglyceride synthesis.
We analyzed MIR122 promoter activity and validated its target mRNAs by transfection of Luciferase reporter plasmids into Huh7, BNL-1ME, and HEK293 cultured cell lines. We measured levels of microRNAs and mRNAs by quantitative real-time PCR analysis of RNA extracted from plasma, liver, muscle, and adipose tissues of C57BL/6 mice given the FFA-inducer CL316243. MIR122 was inhibited using an inhibitor of MIR122. Metabolic profiles of mice were determined using metabolic chambers and by histologic analyses of liver tissues. We performed RNA sequence analyses to identify metabolic pathways involving MIR122.
We validated human Agpat1 and Dgat1 mRNAs, involved in triglyceride synthesis, as targets of MIR122. FFAs increased MIR122 expression in livers of mice by activating the retinoic acid-related orphan receptor alpha, and induced secretion of MIR122 from liver to blood. Circulating MIR122 entered muscle and adipose tissues of mice, reducing mRNA levels of genes involved in triglyceride synthesis. Mice injected with an inhibitor of MIR122 and then given CL316243, accumulated triglycerides in liver and muscle tissues, and had reduced rates of β-oxidation. There was a positive correlation between level of FFAs and level of MIR122 in plasma samples from 6 healthy individuals, collected before and during fasting.
In biochemical and histologic studies of plasma, liver, muscle, and adipose tissues from mice, we found that FFAs increase hepatic expression and secretion of MIR122, which regulates energy storage vs expenditure in liver and peripheral tissues. Strategies to reduce triglyceride levels, by increasing MIR122, might be developed for treatment of metabolic syndrome.
Recommendations for moderate alcohol consumption remain controversial, particularly in type 2 diabetes mellitus (T2DM). Long-term randomized, controlled trials (RCTs) are lacking.
To assess ...cardiometabolic effects of initiating moderate alcohol intake in persons with T2DM and whether the type of wine matters.
2-year RCT (CASCADE CArdiovaSCulAr Diabetes & Ethanol trial). (ClinicalTrials.gov: NCT00784433).
Ben-Gurion University of the Negev-Soroka Medical Center and Nuclear Research Center Negev, Israel.
Alcohol-abstaining adults with well-controlled T2DM.
Patients were randomly assigned to 150 mL of mineral water, white wine, or red wine with dinner for 2 years. Wines and mineral water were provided. All groups followed a Mediterranean diet without caloric restriction.
Primary outcomes were lipid and glycemic control profiles. Genetic measurements were done, and patients were followed for blood pressure, liver biomarkers, medication use, symptoms, and quality of life.
Of the 224 patients who were randomly assigned, 94% had follow-up data at 1 year and 87% at 2 years. In addition to the changes in the water group (Mediterranean diet only), red wine significantly increased high-density lipoprotein cholesterol (HDL-C) level by 0.05 mmol/L (2.0 mg/dL) (95% CI, 0.04 to 0.06 mmol/L 1.6 to 2.2 mg/dL; P < 0.001) and apolipoprotein(a)1 level by 0.03 g/L (CI, 0.01 to 0.06 g/L; P = 0.05) and decreased the total cholesterol-HDL-C ratio by 0.27 (CI, -0.52 to -0.01; P = 0.039). Only slow ethanol metabolizers (alcohol dehydrogenase alleles ADH1B*1 carriers) significantly benefited from the effect of both wines on glycemic control (fasting plasma glucose, homeostatic model assessment of insulin resistance, and hemoglobin A1c) compared with fast ethanol metabolizers (persons homozygous for ADH1B*2). Across the 3 groups, no material differences were identified in blood pressure, adiposity, liver function, drug therapy, symptoms, or quality of life, except that sleep quality improved in both wine groups compared with the water group (P = 0.040). Overall, compared with the changes in the water group, red wine further reduced the number of components of the metabolic syndrome by 0.34 (CI, -0.68 to -0.001; P = 0.049).
Participants were not blinded to treatment allocation.
This long-term RCT suggests that initiating moderate wine intake, especially red wine, among well-controlled diabetics as part of a healthy diet is apparently safe and modestly decreases cardiometabolic risk. The genetic interactions suggest that ethanol plays an important role in glucose metabolism, and red wine's effects also involve nonalcoholic constituents.
European Foundation for the Study of Diabetes.
Abstract
Aims
Bicuspid aortic valve (BAV) is the commonest congenital heart valve malformation, and is associated with life-threatening complications. Given the high heritability index of BAV, many ...experts recommend echocardiography screening for first-degree relatives (FDRs) of an index case. Here, we aim to evaluate the cost-effectiveness of such cascade screening for BAV.
Methods and results
Using a decision-analytic model, we performed a cost-effectiveness analysis of echocardiographic screening for FDRs of a BAV index case. Data on BAV probabilities and complications among FDRs were derived from our institution's BAV familial cohort and from the literature on population-based BAV cohorts with long-term follow-up. Health gain was measured as quality-adjusted life years (QALYs). Cost inputs were based on list prices and literature data. One-way and probabilistic sensitivity analyses were performed to account for uncertainty in the model's variables. Screening of FDRs was found to be the dominant strategy, being more effective and less costly than no screening, with savings of €644 and gains of 0.3 QALY. Results were sensitive throughout the range of the main model's variables, including the full range of reported BAV rates among FDRs across the literature. A gradual decrease of the incremental effect was found with the increase in screening age.
Conclusion
This economic evaluation model found that echocardiographic screening of FDRs of a BAV index case is not only clinically important but also cost-effective and cost-saving. Sensitivity analysis supported the model's robustness, suggesting its generalization.
Graphical Abstract
Graphical Abstract
Bicuspid aortic valve (BAV) is a common congenital heart disease, with a 10-fold higher prevalence in first-degree relatives. BAV has different phenotypes based on the morphology of cusp fusion. ...These phenotypes are associated with different clinical courses and prognoses. Currently, the determinants of the valve phenotype are unknown. In this study we evaluated the role of genetics using familial cohorts. Patients with BAV and their first-degree relatives were evaluated by echocardiography. The concordance in BAV phenotype between pairs of family members was calculated and compared with the concordance expected by chance. We then performed a systematic literature review to identify additional reports and calculated the overall concordance rate. During the study period, 70 cases from 31 families and 327 sporadic cases were identified. BAV was diagnosed in 14% of the screened relatives. The proportions of the morphologies identified was: 12.3% for type 0, 66.2% for type 1-LR, 15.4% for type 1-RN, 4.6% for type 1-NL, and 1.5% for type 2. For the assessment of morphologic concordance, we included 120 pairs of first-degree relatives with BAV from our original cohort and the literature review. Concordance was found only in 62% of the pairs which was not significantly higher than expected by chance. In conclusion, our finding demonstrates intrafamilial variability in BAV morphology, suggesting that morphology is determined by factors other than Mendelian genetics. As prognosis differs by morphology, our findings may suggest that clinical outcomes may vary even between first-degree relatives.
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Abstract
Bicuspid aortic valve (BAV) is the most common valvular congenital heart disease, with a prevalence of 0.5 to 2% in the general population. Patients with BAV are at risk for developing ...cardiovascular complications, some of which are life-threatening. BAV has a wide spectrum of clinical presentations, ranging from silent malformation to severe and even fatal cardiac events. Despite the significant burden on both the patients and the health systems, data are limited regarding pathophysiology, risk factors, and genetics. Family studies indicate that BAV is highly heritable, with autosomal dominant inheritance, incomplete penetrance, variable expressivity, and male predominance. Owing to its complex genetic model, including high genetic heterogenicity, only a few genes were identified in association with BAV, while the majority of BAV genetics remains obscure. Here, we review the different forms of BAV and the current data regarding its genetics. Given the clear heritably of BAV with the potential high impact on clinical outcome, the clinical value and cost effectiveness of cascade screening are discussed.
Purpose
Patients with familial hyperparathyroidism and low urinary calcium excretion may have familial hypocalciuric hypercalcemia (FHH) with mutations in one of three genes: the calcium-sensing ...receptor (
CaSR
) defining FHH-type 1, the adaptor-related protein complex 2
(AP2S1
) related to FHH-type 3 or the G-protein subunit alpha11 (
GNA11
) associated with FHH-type 2. We aimed to evaluate the presence of mutations in these genes and to identify phenotypic specificities and differences in these patients.
Subjects and methods
Selected patients were recruited for genetic evaluation. After informed consent was signed, blood for DNA extraction was obtained and genetic sequencing of
CaSR
was done. In negative cases, we further performed sequencing of
AP2S1
and
GNA11
.
Results
A total of 10 index cases were recruited.
CaSR
sequencing yielded three missense heterozygous mutations (30%): c.554G > A (p.I32V) previously characterized by our team, c.1394 G > A (p.R465Q) and a novel expected disease-causing mutation c.2479 A > C (p.S827R). We identified 2 additional patients (20%) carrying the deleterious recurrent mutation c.44G > T (p.R15L) in the
AP2S1
gene. No
GNA11
mutation was found. Clinically, patients with
AP2S1
mutations had significant cognitive and behavioral disorders, and higher blood calcium and magnesium levels than patients with FHH1.
Conclusion
CaSR
and
AP2S1
sequencing is worthwhile in patients with familial hyperparathyroidism and phenotype suggesting FHH as it can diagnose up to 50% of cases.
GNA11
mutations seem much rarer. Learning disabilities in these patients, associated with higher serum calcium and magnesium levels may suggest the presence of
AP2S1
rather than
CaSR
mutation and may guide the first step in the genetic evaluation.
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