Genetics of calcium homeostasis in humans: continuum between monogenic diseases and continuous phenotypes

Extracellular calcium participates in several key physiological functions, such as control of blood coagulation, bone calcification or muscle contraction. Calcium homeostasis in humans is regulated in part by genetic factors, as illustrated by rare monogenic diseases characterized by hypo or hypercalcaemia. Both serum calcium and urinary calcium excretion are heritable continuous traits in humans. Serum calcium levels are tightly regulated by two main hormonal systems, i.e. parathyroid hormone and vitamin D, which are themselves also influenced by genetic factors. Recent technological advances in molecular biology allow for the screening of the human genome at an unprecedented level of detail and using hypothesis-free approaches, such as genome-wide association studies (GWAS). GWAS identified novel loci for calcium-related phenotypes (i.e. serum calcium and 25-OH vitamin D) that shed new light on the biology of calcium in humans. The substantial overlap (i.e. CYP24A1, CASR, GATA3; CYP2R1) between genes involved in rare monogenic diseases and genes located within loci identified in GWAS suggests a genetic and phenotypic continuum between monogenic diseases of calcium homeostasis and slight disturbances of calcium homeostasis in the general population. Future studies using whole-exome and whole-genome sequencing will further advance our understanding of the genetic architecture of calcium homeostasis in humans. These findings will likely provide new insight into the complex mechanisms involved in calcium homeostasis and hopefully lead to novel preventive and therapeutic approaches. Keyword: calcium, monogenic, genome-wide association studies, genetics

Salt, blood pressure and cardiovascular risk : what is the most adequate preventive strategy? A Swiss perspective

Among the various strategies to reduce the incidence of non-communicable diseases reduction of sodium intake in the general population has been recognized as one of the most cost-effective means because of its potential impact on the development of hypertension and cardiovascular diseases. Yet, this strategic health recommendation of the WHO and many other international organizations is far from being universally accepted. Indeed, there are still several unresolved scientific and epidemiological questions that maintain an ongoing debate. Thus what is the adequate low level of sodium intake to recommend to the general population and whether national strategies should be oriented to the overall population or only to higher risk fractions of the population such as salt-sensitive patients are still discussed. In this paper, we shall review the recent results of the literature regarding salt, blood pressure and cardiovascular risk and we present the recommendations recently proposed by a group of experts of Switzerland. The propositions of the participating medical societies are to encourage national health authorities to continue their discussion with the food industry in order to reduce the sodium intake of food products with a target of mean salt intake of 5-6 grams per day in the population. Moreover, all initiatives to increase the information on the effect of salt on health and on the salt content of food are supported

Should we adjust for seasonality in food consumption surveys? The answer in Switzerland.

Background : Due to market globalization and high availability of various foods throughout the year, adjustment for seasonality at food level may have become unnecessary. Objective : To describe food consumption across seasons using data from the first National Nutrition Survey in Switzerland. Methods : National population-based cross-sectional survey included the three linguistic regions of Switzerland

Caffeine Consumption in Switzerland: Results from the First National Nutrition Survey MenuCH.

Caffeine is a natural psychostimulant with a potentially positive impact on health when consumed in moderation and a negative impact at high dose (> 400 mg/day). So far, no study has examined self-reported caffeine consumption in Switzerland. Our objectives were to determine 1) the caffeine consumption per adult, 2) the main sources of caffeine intake in the Swiss diet, and 3) the timing of caffeine consumption during the day. We used data from the 2014-2015 national nutrition survey menuCH (adults aged 18 to 75 years old, n = 2057, weighted n = 4,627,878), consisting of two 24-hour dietary recalls. Caffeine content in consumed foods was systematically assessed using laboratory analyses in samples of Swiss caffeinated beverages, information from food composition databases, and estimations from standard recipes. Mean (± SD) daily caffeine consumption per person and percentile 95 were 191 mg/day (± 129) and 426 mg/day, respectively. We observed differences in mean caffeine consumption across age groups (18-34 y: 140 mg/day; 50-64 y: 228 mg/day), linguistic regions (German-speaking: 204 mg/day; French-speaking: 170 mg/day, Italian-speaking: 136 mg/day), and smoking status (never smokers: 171 mg/day; current smokers: 228 mg/day). The three main sources of caffeine intake were 1) coffee (83% of total caffeine intake), 2) tea (9%) and 3) soft drinks (4%). Caffeine consumption was highest between 06:00 and 09:00 (29%) and the circadian rhythm slightly differed across linguistic regions and age groups. The mean caffeine consumption in the Swiss adult population was similar to that reported in neighbouring countries

High participation rate among 25 721 patients with broad age range in a hospital-based research project involving whole-genome sequencing - the Lausanne Institutional Biobank.

We aimed to evaluate the interest of adult inpatients and selected outpatients in engaging in a large, real-life, hospital-based, genomic medicine research project and in receiving clinically actionable incidental findings. Within the framework of the cross-sectional Institutional Biobank of Lausanne, Switzerland, a total of 25721 patients of the CHUV University Hospital were systematically invited to grant researchers access to their biomedical data and to donate blood for future analyses, including whole-genome sequencing. Multivariable logistic regression analysis was used to identify personal factors, including age, gender, religion, ethnicity, citizenship, education level and mode of admission, associated with willingness to participate in this genomic research project and with interest in receiving clinically actionable incidental findings. The overall participation rate was 79% (20343/25721). Participation rate declined progressively with age, averaging 83%, 75%, 67% and 62% in patients aged <64 years (n = 13108), ≥64 years (n = 12613), ≥80 years (n = 4557) and ≥90 years (n = 1050), respectively. Factors associated with participation substantially differed between age strata. Patients less likely to participate included women (odds ratio 0.86, [95% confidence interval 0.79-0.95] and 0.78 [0.71-0.85] before and after age 64, respectively), non-Swiss (0.81 [0.74-0.90] and 0.58 [0.52-0.65]) and those admitted through the emergency ward (0.88 [0.79-0.98] and 0.66 [0.60-0.73]). Religion and marital status were associated with participation among patients aged <64 years. A total of 19 018 (93%) participants were willing to be re-contacted for incidental findings. A high education level was associated with higher participation rate, but not with higher willingness to receive incidental findings within the population who had agreed to participate. A large proportion of adult patients, even among the elderly, are willing to actively participate and receive incidental findings in this systematic hospital-based precision and genomic medicine research program with broad consent

Are internists in an non-prescriptive setting favourable to guidelines? A survey in a Department of Internal Medicine in Switzerland.

A cross-sectional anonymous postal survey was carried out in a Department of Internal Medicine in order to assess physicians' knowledge about and attitudes towards clinical practice guidelines and to evaluate the role of age in determining their use and opinions. The study took place in a Swiss University Hospital where exposure to guidelines had been limited. The questionnaire was sent to the 174 physicians of the Department. The response rate was 67% (116/174). The spontaneous definitions of guidelines were heterogeneous and referred to information of uncertain validity. Most participants, especially the younger groups of junior and senior residents, reported using guidelines and were favourable to their development. Less favourable attitudes were observed among senior staff physicians and consultants. For instance, the latter more often held the opinion that guidelines are too rigid to apply to individual patients, were likely to decrease physician reimbursement and to hamper research (respectively, 32% vs 24%, 50% vs 31% and 18% vs 7% when compared with the opinions of residents). In conclusion, in a non-prescriptive hospital setting, where the development, dissemination and implementation of guidelines are emerging, the concept of 'guideline' was heterogeneous. Despite generally positive attitudes towards guidelines, the opinion of senior staff physicians constitute a barrier to their dissemination and implementation

Speciation and Bioavailability Measurements of Environmental Plutonium Using Diffusion in Thin Films.

The biological uptake of plutonium (Pu) in aquatic ecosystems is of particular concern since it is an alpha-particle emitter with long half-life which can potentially contribute to the exposure of biota and humans. The diffusive gradients in thin films technique is introduced here for in-situ measurements of Pu bioavailability and speciation. A diffusion cell constructed for laboratory experiments with Pu and the newly developed protocol make it possible to simulate the environmental behavior of Pu in model solutions of various chemical compositions. Adjustment of the oxidation states to Pu(IV) and Pu(V) described in this protocol is essential in order to investigate the complex redox chemistry of plutonium in the environment. The calibration of this technique and the results obtained in the laboratory experiments enable to develop a specific DGT device for in-situ Pu measurements in freshwaters. Accelerator-based mass-spectrometry measurements of Pu accumulated by DGTs in a karst spring allowed determining the bioavailability of Pu in a mineral freshwater environment. Application of this protocol for Pu measurements using DGT devices has a large potential to improve our understanding of the speciation and the biological transfer of Pu in aquatic ecosystems

Temporal Trends in Low-Dose Aspirin Use (from the CoLaus|PsyCoLaus Study).

Although established in secondary prevention, the use of low-dose aspirin for primary cardiovascular prevention remains uncertain. We assessed the temporal trend of low-dose aspirin use in people at primary and secondary prevention over 14 years. We used data from the population-based CoLaus|PsyCoLaus study. A baseline survey was conducted from 2003 to 2006, involving 6,733 participants. The first and second follow-up investigations were performed from 2009 to 2012 and 2014 to 2017, respectively. Low-dose aspirin use was defined as ≤300 mg/daily oral administration or administration of an anticoagulant for similar indications. For primary prevention analysis, 6,555, 4,695, and 3,893 participants were included in the analysis at baseline, first and second follow-ups, respectively. Overall, low-dose aspirin use doubled between baseline (4.1%) and second follow-up (8.1%). Appropriate use of low-dose aspirin rose from 32% at baseline to 64% at the second follow-up for primary prevention. In secondary prevention, 71.8%, 75.9%, and 71.7% of participants were taking low-dose aspirin at baseline, first, and second follow-up, respectively. On the basis of a population-based cohort, the appropriateness of low-dose aspirin use increased over a 10-year follow-up in primary prevention, but its inappropriate use still concerned 44% of subjects. In secondary prevention, a quarter of individuals were not taking low-dose aspirin which remained stable over the analyzed period