On the rationale of population screening for chronic kidney disease: a public health perspective

Chronic kidney disease (CKD) and its complications represent an enormous and increasing public health burden worldwide [1]. More than one in ten adults suffers from CKD in the general population [2], with a majority of people being in its early stages (i.e. 1 to 3) [2]. In the general population, the prevalence of CKD sharply increases with age [3]. CKD can be considered as a condition associated with premature ageing with accelerated vascular disease [4]. The large number of people with CKD, or at high risk of CKD (i.e. patients with hypertension, diabetes and/or CVD), implies that primary care providers and specialists other than nephrologists frequently encounter patients with CKD [5], a situation in which most CKD cases are diagnosed via opportunistic kidney function screening or automated eGFR reporting. The aim of this review is to discuss the rationale and currently available evidence for, or against, population-based screening for CKD. The focus will be on the situation of screening asymptomatic individuals at early stages of CKD regardless of the presence or absence of CKD risk factors

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, genetic

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, genetic

Testing Hardy-Weinberg Proportions in a Frequency-Matched Case-Control Genetic Association Study

In case-control genetic association studies, cases are subjects with the disease and controls are subjects without the disease. At the time of case-control data collection, information about secondary phenotypes is also collected. In addition to studies of primary diseases, there has been some interest in studying genetic variants associated with secondary phenotypes. In genetic association studies, the deviation from Hardy-Weinberg proportion (HWP) of each genetic marker is assessed as an initial quality check to identify questionable genotypes. Generally, HWP tests are performed based on the controls for the primary disease or secondary phenotype. However, when the disease or phenotype of interest is common, the controls do not represent the general population. Therefore, using only controls for testing HWP can result in a highly inflated type I error rate for the disease- and/or phenotype-associated variants. Recently, two approaches, the likelihood ratio test (LRT) approach and the mixture HWP (mHWP) exact test were proposed for testing HWP in samples from case-control studies. Here, we show that these two approaches result in inflated type I error rates and could lead to the removal from further analysis of potential causal genetic variants associated with the primary disease and/or secondary phenotype when the study of primary disease is frequency-matched on the secondary phenotype. Therefore, we proposed alternative approaches, which extend the LRT and mHWP approaches, for assessing HWP that account for frequency matching. The goal was to maintain more (possible causative) single-nucleotide polymorphisms in the sample for further analysis. Our simulation results showed that both extended approaches could control type I error probabilities. We also applied the proposed approaches to test HWP for SNPs from a genome-wide association study of lung cancer that was frequency-matched on smoking status and found that the proposed approaches can keep more genetic variants for association studies

P-621: Metabolic determinants of proximal sodium reabsorption in healthy women

Increased reabsorption of sodium (Na) in the proximal segments of the nephron is present in hypertensive patients. Studies performed in men reported an association between proximal Na reabsorption and features of the metabolic syndrome. This study explores the relationship between metabolic variables and proximal Na reabsorption in healthy women. This study is population-based and cross-sectional examining 661 healthy women aged 40-75y. After 15 minutes rest, blood pressure was measured 3 times, blood was drawn and urine was collected. Fractional excretion of endogenous lithium (FELi) was used as an indirect marker of proximal sodium reabsorption, lithium being only reabsorbed in the proximal tubule. All women receiving blood pressure, blood glucose or lipid lowering therapy were excluded. Correlations: FELi was positively correlated with the fractional excretion of sodium (FENa, r=0.3, p<0.001). FELi was negatively associated with total cholesterol (r=-0.14, P<0.0001), LDL-cholesterol (r=-0.16, P<0.0001), BMI (r=-0.08, P<0.05) and weight (r=-0.09, P<0.05). Menopausal status or a family history of hypertension did not affect the associations. Simple linear regression analysis: age, waist circumference, waist/hip ratio, systolic blood pressure, diastolic blood pressure, Hdl cholesterol, triglycerides, serum uric acid or a family history of hypertension were not significant predictors of FELi. BMI was a significant predictor but the strongest relationships were found between FELi and total cholesterol, LDL-cholesterol and FENa. Multivariate linear regression model: When significant predictors of FELi were examined in a multivariate linear regression model also controlling for age, weight, systolic blood pressure and FENa, total cholesterol (p=0.003) or LDL-cholesterol (p=0.001) significantly and independently predicted FELi. In conclusion, these data suggest that metabolic parameters, in particular total cholesterol and LDL-cholesterol and to a lesser extent weight and BMI, are associated with increased proximal Na reabsorption in a healthy untreated women population. Considering the possible link between increased reabsorption of sodium and the development of hypertension, a major cardiovascular risk factor, this association may provide an additional hypothesis for the increased cardiovascular risk of subjects with the metabolic syndrom