Constance Xhaard

Identifying the biomarkers associated with new-onset glomerular filtration rate (GFR) decrease in an initially healthy population could offer a better understanding of kidney function decline and help improving patient management. Here we described the proteomic and transcriptomic footprints associated with new-onset kidney function decline in an initially healthy and well-characterized population with a 20-year follow-up. This study was based on 1087 individuals from the familial longitudinal Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS) cohort who attended both visit 1 (from 1993 to 1995) and visit 4 (from 2011 to 2016). New-onset kidney function decline was approached both in quantitative (GFR slope for each individual) and qualitative (defined as a decrease in GFR of >15 ml/min/1.7 m²) ways. We analysed associations of 445 proteins measured both at visit 1 and visit 4 using Olink Proseek^® panels and 119 765 genes expressions measured at visit 4 with GFR decline. Associations were assessed using multivariable models. The Bonferroni correction was applied. We found several proteins (including PLC, placental growth factor (PGF), members of the tumour necrosis factor receptor superfamily), genes (including CCL18, SESN3), and a newly discovered miRNA—mRNA pair (MIR1205–DNAJC6) to be independently associated with new-onset kidney function decline. Complex network analysis highlighted both extracellular matrix and cardiovascular remodelling (since visit 1) as well as inflammation (at visit 4) as key features of early GFR decrease. These findings lay the foundation to further assess whether the proteins and genes herein identified may represent potential biomarkers or therapeutic targets to prevent renal function impairment.

Dispersal, and in particular the frequency of long-distance dispersal (LDD) events, has strong implications for population dynamics with possibly the acceleration of the colonisation front, and for evolution with possibly the conservation of genetic diversity along the colonised domain. However, accurately inferring LDD is challenging as it requires both large-scale data and a methodology that encompasses the redistribution of individuals in time and space. Here, we propose a mechanistic-statistical framework to estimate dispersal from one-dimensional invasions. The mechanistic model takes into account population growth and grasps the diversity in dispersal processes by using either diffusion, leading to a reaction-diffusion (R.D.) formalism, or kernels, leading to an integro-differential (I.D.) formalism. The latter considers different dispersal kernels ( e.g. Gaussian, Exponential, and Exponential-power) differing in their frequency of LDD events. The statistical model relies on dedicated observation laws that describe two types of samples, clumped or not. As such, we take into account the variability in both habitat suitability and occupancy perception. We first check the identifiability of the parameters and the confidence in the selection of the dispersal process. We observed good identifiability for all parameters (correlation coefficient >0.9 between true and fitted values). The dispersal process that is the most confidently identified is Exponential-Power ( i.e. fat-tailed) kernel. We then applied our framework to data describing an annual invasion of the poplar rust disease along the Durance River valley over nearly 200 km. This spatio-temporal survey consisted of 12 study sites examined at seven time points. We confidently estimated that the dispersal of poplar rust is best described by an Exponential-power kernel with a mean dispersal distance of 1.94 km and an exponent parameter of 0.24 characterising a fat-tailed kernel with frequent LDD events. By considering the whole range of possible dispersal processes our method forms a robust inference framework. It can be employed for a variety of organisms, provided they are monitored in time and space along a one-dimension invasion.

BACKGROUND: The expression of NGAL/lcn2 (neutrophil gelatinase-associated lipocalin) is directly modulated by mineralocorticoid receptor activation but its role in blood pressure control is unclear. METHODS: a potential relationship between NGAL plasma levels, systolic blood pressure and urinary Na excretion was assessed in the STANISLAS cohort. The specific role of NGAL/lcn2 in salt-sensitive hypertension was studied using lcn2-knockout mice (lcn2 KO) fed with low-Na diet (0Na). RESULTS: we show that NGAL plasma levels positively correlate with systolic blood pressure, whereas they negatively correlate with urinary Na excretion in subjects of the STANISLAS cohort. Prolonged feeding of lcn2 KO mice with a 0Na diet induced lower systolic blood pressure than that of the control group (wildtype), suggesting a role for NGAL/lcn2 in Na-balance homeostasis. Short-term or prolonged 0Na increased Na-Cl cotransporter (NCC) phosphorylation in the cortex of wildtype mice, which was prevented in lcn2 KO mice. Recombinant mouse lcn2 injections in lcn2 KO mice induced NCC phosphorylation in the kidney cortex, associated with decreased urinary Na excretion. Ex vivo experiments using kidney slices from lcn2 KO mice showed increased NCC phosphorylation by recombinant murine lcn2. In addition, recombinant murine lcn2 induced activation of CamK2β (calcium/calmodulin-dependent protein kinase II β subunit) phosphorylation in lcn2 KO mice and in kidney slices, providing an underlying mechanism involved in lcn2-induced NCC phosphorylation. Indeed, the inhibition of CamK2β prevented NCC phosphorylation induced by recombinant lcn2 in kidney slices. CONCLUSIONS: we highlight a novel role of NGAL/lcn2 as a modulator of the activity of the renal sodium transporter NCC affecting salt-sensitive blood pressure

Background: Pulse wave velocity (PWV) is a marker of arterial stiffness, which is intrinsically highly correlated with blood pressure (BP). However, the interplay of PWV and BP heritability has not been extensively studied. This study aimed to estimate the heritability of PWV and BP and determine the genetic correlation between PWV and BP. Methods: The heritability of PWV and BP was estimated in 1080 subjects from the STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort with at least one relative using a linear mixed model within one frequentist and one Bayesian framework implemented, respectively, in the Gaston and MCMCglmm R packages. Then their genetic correlations were also estimated. Results: The heritability estimations for PWV were within the same range of the heritability of systolic BP and diastolic BP (23%, 19%, and 27%, respectively). Daytime heritability of BP was higher than nighttime BP. In addition, phenotypic correlations between PWV and systolic BP/diastolic BP were, respectively, 0.34 and 0.23, whereas nonsignificant genetic correlations were 0.08 and 0.22 respectively, indicating that PWV and diastolic BP shared more polygenic codeterminants than PWV and systolic BP. Conclusions: Our results suggest that the heritability of PWV is >20% and within the same range as BP heritability. It also suggests that the link between PWV and BP goes beyond phenotypic association: PWV and BP (in particular diastolic BP) share common genetic determinants. This genetic interdependence of PWV and BP appears largely polygenic.

Myocardial deformation assessed by strain analysis represents a significant advancement in our assessment of cardiac mechanics. However, whether this variable is genetically heritable or whether all/most of its variability is related to environmental factors is currently unknown. We sought to determine the heritability of echocardiographically determined cardiac mechanics indices in a population setting. A total of 1357 initially healthy subjects (women 51.6%; 48.2 ± 14.1 years) were included in this study from 20 years follow-up after the 4^th visit of the longitudinal familial STANISLAS cohort (Lorraine, France). Data were acquired using state-of-the-art cardiac ultrasound equipment, using acquisition and measurement protocols recommended by the EACVI/ASE/Industry Task Force. Layer-specific global longitudinal strain (GLS) and global circumferential strain (GCS) (full-wall, subendocardial and subepicardial) and conventional structural and functional cardiac parameters and their potential heritability were assessed using restricted maximum likelihood analysis, with genetic relatedness matrix calculated from genome-wide association data. Indices of longitudinal/circumferential myocardial function and left ventricular (LV) ejection fraction had low heritability (ranging from 10 to 20%). Diastolic and standard LV function parameters had moderate heritability (ranging from 20 to 30%) except for end-systolic and end-diastolic volumes (respectively 30 and 45%). In contrast, GLSEndo/GLSEpi ratio had a high level of heritability (65%). Except for GLSendo/GLSepi ratio, a large percentage of variance remained unexplained (greater than 50%). In our population cohort, GLSendo/GLSepi ratio had a high level of heritability whereas other classical and mechanical LV function parameters did not. Given the increasing recognition of GLSendo/GLSepi ratio as an early/sensitive imaging biomarker of systolic dysfunction, our results suggest the possible existence of individual genetic predispositions to myocardial decline.

Dispersal, and in particular the frequency of long-distance dispersal (LDD) events, has strong implications for population dynamics with possibly the acceleration of the colonisation front, and for evolution with possibly the conservation of genetic diversity along the colonised domain. However, accurately inferring LDD is challenging as it requires both large-scale data and a methodology that encompasses the redistribution of individuals in time and space. Here, we propose a mechanistic-statistical framework to estimate dispersal from one-dimensional invasions. The mechanistic model takes into account population growth and grasps the diversity in dispersal processes by using either diffusion, leading to a reaction-diffusion (R.D.) formalism, or kernels, leading to an integro-differential (I.D.) formalism. The latter considers different dispersal kernels ( e . g . Gaussian, Exponential, and Exponential-power) differing in their frequency of LDD events. The statistical model relies on dedicated observation laws that describe two types of samples, clumped or not. As such, we take into account the variability in both habitat suitability and occupancy perception. We first check the identifiability of the parameters and the confidence in the selection of the dispersal process. We observed good identifiability for all parameters (correlation coefficient > 0.9 between true and fitted values). The dispersal process that is the most confidently identified is Exponential-Power ( i . e . fat-tailed) kernel. We then applied our framework to data describing an annual invasion of the poplar rust disease along the Durance River valley over nearly 200 km. This spatio-temporal survey consisted of 12 study sites examined at seven time points. We confidently estimated that the dispersal of poplar rust is best described by an Exponential-power kernel with a mean dispersal distance of 1.94 km and an exponent parameter of 0.24 characterising a fat-tailed kernel with frequent LDD events. By considering the whole range of possible dispersal processes our method forms a robust inference framework. It can be employed for a variety of organisms, provided they are monitored in time and space along a one-dimension invasion.

Background: Hyperuricemia is associated with poor cardiovascular outcomes, although it is uncertain whether this relationship is causal in nature. This study aimed to: (1) assess the heritability of serum uric acid (SUA) levels, (2) conduct a genome‐wide association study on SUA levels, and (3) investigate the association between certain single‐nucleotide polymorphisms and target organ damage. Methods and Results: The STANISLAS (Suivi Temporaire Annuel Non‐Invasif de la Santé des Lorrains Assurés Sociaux) study cohort is a single‐center longitudinal cohort recruited between 1993 and 1995 (visit 1), with a last visit (visit 4 [V4]) performed ≈20 years apart. Serum lipid profile, SUA, urinary albumin/creatinine ratio, estimated glomerular filtration rate, 24‐hour ambulatory blood pressure monitoring, transthoracic echocardiography, pulse wave velocity, and genotyping for each participant were assessed at V4. A total of 1573 participants were included at V4, among whom 1417 had available SUA data at visit 1. Genome‐wide association study results highlighted multiple single‐nucleotide polymorphisms on the SLC2A9 gene linked to SUA levels. Carriers of the most associated mutated SLC2A9 allele ( rs16890979 ) had significantly lower SUA levels. Although SUA level at V4 was highly associated with diabetes, prediabetes, higher body mass index, CRP (C‐reactive protein) levels, estimated glomerular filtration rate variation (visit 1–V4), carotid intima‐media thickness, and pulse wave velocity, rs16890979 was only associated with higher carotid intima‐media thickness. Conclusions: Our findings demonstrate that rs16890979 , a genetic determinant of SUA levels located on the SLC2A9 gene, is associated with carotid intima‐media thickness despite significant associations between SUA levels and several clinical outcomes, thereby lending support to the hypothesis of a link between SUA and cardiovascular disease.

Aims Elevated brain natriuretic peptide (BNP) and the N-terminal fragment of its pro-hormone (NT-proBNP) have become established biomarkers for heart failure and are associated with cardiovascular morbidity and mortality. Investigating sources of inter-individual heterogeneity, particularly genetic factors, could help better identify patients at risk of future cardiovascular disease. The aim of this study was to estimate the heritability of circulating NT-proBNP levels, to perform a genome-wide association study (GWAS) and gene-candidate analysis focused on NPPB–NPPA genes on these levels, and to examine their association with cardiovascular or metabolic outcomes. Methods and results A total of 1555 individuals from the STANISLAS study were included. The heritability of circulating NT-proBNP levels was estimated at 15%, with seven single nucleotide polymorphisms (SNPs) reaching the significant threshold in the GWAS. All above SNPs were located on the same gene cluster constituted of MTHFR, CLCN6, NPPA, NPPB, and C1orf167. NPPA gene expression was also associated with NT-proBNP levels. Moreover, six other SNPs from NPPA–NPPB genes were associated with diastolic function (lateral e′ on echocardiography) and metabolic features (glycated haemoglobin). Conclusions The heritability of natriuretic peptides appears relatively low (15%) and mainly based on the same gene cluster constituted of MTHFR, CLCN6, NPPA, NPPB, and C1orf167. Natriuretic peptide polymorphisms are associated with natriuretic peptide levels and diastolic function. These results suggest that natriuretic peptide polymorphisms may have an impact in the early stages of cardiovascular and metabolic disease.

Objective:: Determining the factors associated with new-onset pre-diabetes and type 2 diabetes mellitus (T2D) is important for improving the current prevention strategies and for a better understanding of the disease. Design:: To study the factors (clinical, circulating protein and genetic) associated with new onset pre-diabetes and T2D in an initially healthy (without diabetes) populational familial cohort with a long follow-up (STANISLAS cohort). Methods:: A total of 1506 participants attended both the visit 1 and visit 4, separated by ≈20 years. Over 400 proteins, GWAS and genetic associations were studied using models adjusted for potential confounders. Both prospective (V1 to V4) and cross-sectional (V4) analyses were performed. Results:: People who developed pre-diabetes (n = 555) and/or T2D (n = 73) were older, had higher BMI, blood pressure, glucose, LDL cholesterol, and lower eGFR. After multivariable selection, PAPP-A (pappalysin-1) was the only circulating protein associated with the onset of both pre-diabetes and T2D with associations persisting at visit 4 (i.e. ≈20 years later). FGF-21 (fibroblast growth factor 21) was a strong prognosticator for incident T2D in the longitudinal analysis, but not in the cross-sectional analysis. The heritability of the circulating PAPP-A was estimated at 44%. In GWAS analysis, the SNP rs634737 was associated with PAPP-A both at V1 and V4. External replication also showed lower levels of PAPP-A in patients with T2D. Conclusions:: The risk of developing pre-diabetes and T2D increases with age and with features of the metabolic syndrome. Circulating PAPP-A, which has an important genetic component, was associated with both the development and presence of pre-diabetes and T2D.

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. Here, we conducted a genome-wide association study (GWAS) involving 1,554 cases/1,973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from the EPITHYR consortium. Our results confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 (rs334729) and 16q23.2 (rs16950982), which were associated with TSH levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. The frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans and may explain part of the highest DTC incidence observed in Oceanians.