A 16-month-long experience of COVID-19 in allogeneic haematopoietic stem cell transplantation recipients: An SFGM-TC multicentre cohort study.

This 16-month-long multicentre retrospective study of 225 allogeneic haematopoietic stem cell transplantation (alloHSCT) recipients with COVID-19 examines risk factors for severity and mortality, describing the successive waves of infections (from March to June 2020 and from August 2020 to June 2021). We confirm the negative role of low respiratory tract disease and immunosuppressive treatment. We highlight significantly lower percentages of severe forms and COVID-19-related mortality during the second wave. Monthly comparative evolution of cases in alloHSCT recipients and in the French population shows a higher number of cases in alloHSCT recipients during the first wave and a decrease from February 2021.

Adapted dietary inflammatory index and differentiated thyroid carcinoma risk in two French population-based case-control studies.

PURPOSE: Thyroid cancer is the most common endocrine cancer and its etiology is still not well understood. The aim of the present study was to assess the association between an adapted dietary inflammatory index and differentiated thyroid cancer (DTC) risk in two population-based case-control studies (CATHY and YOUNG-THYR) conducted in France. METHODS: These studies included a total of 1321 DTC cases and 1502 controls, for which an adapted dietary inflammatory index (ADII) was computed based on food frequency questionnaires in each study separately. The association between ADII and thyroid cancer risk was assessed using logistic regression models controlling for potential confounders. RESULTS: Higher ADII scores, corresponding to a higher pro-inflammatory potential of the diet, were associated with higher DTC risk (odds ratio (OR) for 1 standard deviation (SD) increase: 1.09, 95% confidence interval (CI): 1.01, 1.18, P: 0.03). Associations were stronger in analyses restricted to women (OR for 1-SD increase: 1.14, 95% CI 1.04, 1.25, P: 0.005), as well as in women with lower education level, current smoking, or high body mass index. CONCLUSION: Our study suggests that a pro-inflammatory diet is associated with an increased risk of DTC, especially when combined with other inflammatory conditions such as tobacco smoking or overweight. Our findings will help better understand the role of diet-induced inflammation in DTC etiology.

Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium.

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome-wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population-based case-control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray-500K Beadchip (Illumina). We 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 and 16q23.2, which were associated with thyroid-stimulating hormone 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. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.

Anthropometric Risk Factors for Differentiated Thyroid Cancer in Young Men and Women From Eastern France: A Case-Control Study.

The incidence of thyroid cancer has risen over the past decade, along with a rise in obesity. We studied the role of anthropometric risk factors for differentiated thyroid cancer at the time of diagnosis and at age 20 years in a case-control study conducted in eastern France between 2005 and 2010. The study included 761 adults diagnosed with differentiated thyroid cancer before 35 years of age between 2002 and 2006. They were matched with 825 controls from the general population. Odds ratios were calculated using conditional logistic regression models and were reported for all participants, those with papillary cancer only, and women only. The risk of thyroid cancer was higher for participants with a high body surface area (BSA), great height, or excess weight and for women with a high body fat percentage. Conversely, no significant association was found between body mass index and the risk of thyroid cancer. In the present study, we provide further evidence of the role of BSA and excess weight in the risk of thyroid cancer. These epidemiologic observations should be confirmed by further exploration of the biological mechanisms responsible for the associations of obesity and BSA with thyroid cancer.

Common variants at the 9q22.33, 14q13.3 and ATM loci, and risk of differentiated thyroid cancer in the Cuban population.

BACKGROUND: The incidence of differentiated thyroid carcinoma (DTC) in Cuba is low and the contribution of host genetic factors to DTC in this population has not been investigated so far. Our goal was to assess the role of known risk polymorphisms in DTC cases living in Havana. We genotyped five polymorphisms located at the DTC susceptibility loci on chromosome 14q13.3 near NK2 homeobox 1 (NKX2-1), on chromosome 9q22.33 near Forkhead factor E1 (FOXE1) and within the DNA repair gene Ataxia-Telangiectasia Mutated (ATM) in 203 cases and 212 age- and sex- matched controls. Potential interactions between these polymorphisms and other DTC risk factors such as body surface area, body mass index, size, ethnicity, and, for women, the parity were also examined. RESULTS: Significant association with DTC risk was found for rs944289 near NKX2-1 (OR per A allele = 1.6, 95% CI: 1.2-2.1), and three polymorphisms near or within FOXE1, namely rs965513 (OR per A allele = 1.7, 95% CI: 1.2-2.3), rs1867277 in the promoter region of the gene (OR per A allele = 1.5, 95% CI: 1.1-1.9) and the poly-alanine tract expansion polymorphism rs71369530 (OR per Long Allele = 1.8, 95% CI: 1.3-2.5), only the 2 latter remaining significant when correcting for multiple tests. Overall, no association between DTC and the coding SNP D1853N (rs1801516) in ATM (OR per A Allele = 1.1, 95% CI: 0.7-1.7) was seen. Nevertheless women who had 2 or more pregnancies had a 3.5-fold increase in risk of DTC if they carried the A allele (OR 3.5, 95% CI: 3.2-9.8) as compared to 0.8 (OR 0.8, 95% CI: 0.4-1.6) in those who had fewer than 2. CONCLUSIONS: We confirmed in the Cuban population the role of the loci previously associated with DTC susceptibility in European and Japanese populations through genome-wide association studies. Our results on ATM and the number of pregnancies raise interesting questions on the mechanisms by which oestrogens, or other hormones, alter the DNA damage response and DNA repair through the regulation of key effector proteins such as ATM. Due to the small size of our study and to multiple tests, all these results warrant further investigation.

Menstrual and reproductive factors in the risk of differentiated thyroid carcinoma in young women in France: a population-based case-control study.

The incidence of thyroid cancer has increased in eastern Europe since the Chernobyl nuclear power plant accident. Although the radioactive fallout was much less severe and the thyroid radiation dose was much lower in France, a case-control study was initiated in eastern France. The present study included 633 young women who were diagnosed with differentiated thyroid cancer before 35 years of age between 2002 and 2006 and matched with 677 controls. Face-to-face interviews were conducted from 2005 to 2010. Odds ratios were calculated using conditional logistic regressions and were reported in the total group and by histopathological type of cancer ("only papillary" and "excluding microcarcinomas"). The risk of thyroid cancer was higher in women who had a higher number of pregnancies, used a lactation suppressant, or had early menarche. Conversely, breastfeeding, oral contraceptive use, and late age at first pregnancy were associated with a lower risk of thyroid cancer. No association was observed between thyroid cancer and having irregular menstrual cycle, undergoing treatment for menstrual cycle regularity shortly after menarche, having a cessation of menstruation, use of another contraceptive, history of miscarriage or abortion for the first pregnancy, or having had gestational diabetes. This study confirms the role of hormonal and reproductive factors in thyroid cancer, and our results support the fact that exposure to estrogens increases thyroid cancer risk.

NGAL is a Novel Target in Hypertension by Modulating the NCC-Mediated Renal Na Balance.

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 CamK2ß (calcium/calmodulin-dependent protein kinase II ß subunit) phosphorylation in lcn2 KO mice and in kidney slices, providing an underlying mechanism involved in lcn2-induced NCC phosphorylation. Indeed, the inhibition of CamK2ß 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.

Shared Heritability of Blood Pressure and Pulse Wave Velocity: Insights From the STANISLAS Cohort.

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.

Layer myocardial strain is the most heritable echocardiographic trait.

AIMS: 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. METHODS AND RESULTS: A total of 1357 initially healthy subjects (women 51.6%; 48.2 ± 14.1 years) were included in this study from 20-year follow-up after the fourth 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 (European Association of Cardiovascular Imaging)/ASE (American Society of Echocardiography)/Industry Task Force. Layer-specific global longitudinal strain (GLS) and global circumferential strain (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 (30% and 45%, respectively). In contrast, global longitudinal subendocardial strain (GLSEndo)/global longitudinal subepicardial strain (GLSEpi) ratio had a high level of heritability (65%). Except for GLSEndo/GLSEpi ratio, a large percentage of variance remained unexplained (>50%). CONCLUSIONS: 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.

Birth weight and subclinical cardiovascular and renal damage in a population-based study (the STANISLAS cohort study).

OBJECTIVE: Although preterm-born and low-birth-weight individuals have an increased risk of cardiovascular diseases in adulthood, little is known regarding early cardiovascular and renal damage (CVRD) or hypertension in adulthood. Our study investigated the association of birth weight with early CVRD markers as well as the heritability of birth weight in an initially healthy family-based cohort. METHODS: This study was based on 1028 individuals from the familial longitudinal STANISLAS cohort (399 parents/629 children) initiated in 1993-1995, with a fourth examination conducted in 2011-2016. Analyses performed at the fourth visit included pulse-wave velocity, central pressure, ambulatory blood pressure, hypertension status, diastolic dysfunction/distensibility, left ventricular mass indexed (LVMI), carotid intima-media thickness and kidney damage. The family structure of the cohort allowed birth weight heritability estimation. RESULTS: Mean (±SD) birth weight was 3.3 ±â€Š0.6 kg. Heritability was moderate (42-44%). At the fourth visit, individuals were 37 years old (32.0-57.0), 56% were women and 13% had antihypertensive treatment. Birth weight was strongly and negatively associated with hypertension [odds ratio (OR) 95% confidence interval (CI) 0.61 (0.45-0.84)]. A nonlinear association was found with LVMI, participants with a birth weight greater than 3 kg having a higher LVMI. A positive association ( ß 95% CI 5.09 (1.8-8.38)] was also observed between birth weight and distensibility for adults with normal BMI. No associations were found with other CVRD. CONCLUSION: In this middle-aged population, birth weight was strongly and negatively associated with hypertension, and positively associated with distensibility in adults with normal BMI and with LVMI for higher birth weights. No associations were found with other CVRD markers.

Genetic factors for differentiated thyroid cancer in French Polynesia: new candidate loci.

Background: Populations of French Polynesia (FP), where France performed atmospheric tests between 1966 and 1974, experience a high incidence of differentiated thyroid cancer (DTC). However, up to now, no sufficiently large study of DTC genetic factors in this population has been performed to reach definitive conclusion. This research aimed to analyze the genetic factors of DTC risk among the native FP populations. Methods: We analyzed more than 300 000 single nucleotide polymorphisms (SNPs) genotyped in 283 DTC cases and 418 matched controls born in FP, most being younger than 15 years old at the time of the first nuclear tests. We analyzed the genetic profile of our cohort to identify population subgroups. We then completed a genome-wide analysis study on the whole population. Results: We identified a specific genetic structure in the FP population reflecting admixture from Asian and European populations. We identified three regions associated with increased DTC risk at 6q24.3, 10p12.2, and 17q21.32. The lead SNPs at these loci showed respective p-values of 1.66 × 10-7, 2.39 × 10-7, and 7.19 × 10-7 and corresponding odds ratios of 2.02, 1.89, and 2.37. Conclusion: Our study results suggest a role of the loci 6q24.3, 10p12.2 and 17q21.32 in DTC risk. However, a whole genome sequencing approach would be better suited to characterize these factors than genotyping with microarray chip designed for the Caucasian population. Moreover, the functional impact of these three new loci needs to be further explored and validated.

Assessment of Differentiated Thyroid Carcinomas in French Polynesia After Atmospheric Nuclear Tests Performed by France.

Importance: Due to the amount of iodine 131 released in nuclear tests and its active uptake by the thyroid, differentiated thyroid carcinoma (DTC) is the most serious health risk for the population living near sites of nuclear tests. Whether low doses to the thyroid from nuclear fallout are associated with increased risk of thyroid cancer remains a controversial issue in medicine and public health, and a misunderstanding of this issue may be associated with overdiagnosis of DTCs. Design, Setting, and Participants: This case-control study was conducted by extending a case-control study published in 2010 that included DTCs diagnosed between 1984 and 2003 by adding DTCs diagnosed between 2004 and 2016 and improving the dose assessment methodology. Data on 41 atmospheric nuclear tests conducted by France between 1966 and 1974 in French Polynesia (FP) were assessed from original internal radiation-protection reports, which the French military declassified in 2013 and which included measurements in soil, air, water, milk, and food in all FP archipelagos. These original reports led to an upward reassessment of the nuclear fallout from the tests and a doubling of estimates of the mean thyroid radiation dose received by inhabitants from 2 mGy to nearly 5 mGy. Included patients were diagnosed from 1984 to 2016 with DTC at age 55 years or younger and were born in and resided in FP at diagnosis; 395 of 457 eligible cases were included, and up to 2 controls per case nearest by birthdate and matched on sex were identified from the FP birth registry. Data were analyzed from March 2019 through October 2021. Exposure: The radiation dose to the thyroid gland was estimated using recently declassified original radiation-protection service reports, meteorological reports, self-reported lifestyle information, and group interviews of key informants and female individuals who had children at the time of these tests. Main Outcomes and Measures: The lifetime risk of DTC based on Biological Effects of Ionizing Radiation (BEIR) VII models was estimated. Results: A total of 395 DTC cases (336 females [85.1%]; mean [SD] age at end of follow-up, 43.6 [12.9] years) and 555 controls (473 females [85.2%]; mean [SD] age at end of follow-up, 42.3 [12.5] years) were included. No association was found between thyroid radiation dose received before age 15 years and risk of DTC (excess relative risk [ERR] per milligray, 0.04; 95% CI, -0.09 to 0.17; P = .27). When excluding unifocal noninvasive microcarcinomas, the dose response was significant (ERR per milligray, 0.09; 95% CI, -0.03 to 0.02; P = .02), but several incoherencies with the results of the initial study reduce the credibility of this result. The lifetime risk for the entire FP population was 29 cases of DTC (95% CI, 8-97 cases), or 2.3% (95% CI, 0.6%-7.7%) of 1524 sporadic DTC cases in this population. Conclusions and Relevance: This case-control study found that French nuclear tests were associated with an increase in lifetime risk of PTC in FP residents of 29 cases of PTC. This finding suggests that the number of thyroid cancer cases and the true order of magnitude of health outcomes associated with these nuclear tests were small, which may reassure populations of this Pacific territory.

Disentangling the genetic origins of a plant pathogen during disease spread using an original molecular epidemiology approach.

The advent of molecular epidemiology has greatly improved our ability to identify the population sources and track the pathogen movement. Yet the wide spatial and temporal scales usually considered are useful only to infer historical migration pathways. In this study, Bayesian genetic assignments and a landscape epidemiology approach were combined to unravel genetic origin and annual spread during a single epidemic of a plant pathogen: the poplar rust fungus Melampsora larici-populina. The study focused on a particular area-the Durance River valley-which enabled inoculum sources to be identified and channelled spread of the epidemic along a one-dimensional corridor. Spatio-temporal monitoring of disease showed that the epidemic began in the upstream part of the valley and spread out downstream. Using genetic assignment tests, individuals collected at the end of the epidemic were sorted into two genetic groups; very few hybrids were detected, although individuals from both groups coexisted locally downstream in the valley. The epidemic originated from two genetically distinct inoculum sources. Individuals of each group then dispersed southwards along the Durance River and became mixed in poplar riparian stands. These two genetic groups were found previously at a wider spatial scale and proved to result from distinct evolutionary histories on either wild or cultivated poplars. This study showed that the two groups can mix during an epidemic but do not hybridize because they then reproduce asexually. In general, the methods employed here could be useful for elucidating the genetic origin and retracing the colonization history and migration pathways of recent epidemics.

Weak Association Between Genetic Markers of Hyperuricemia and Cardiorenal Outcomes: Insights From the STANISLAS Study Cohort With a 20-Year Follow-Up.

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.

Impact of natriuretic peptide polymorphisms on diastolic and metabolic function in a populational cohort: insights from the STANISLAS cohort.

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.

Fatty acid desaturase genetic variations and dietary omega-3 fatty acid intake associate with arterial stiffness.

Aims: Long-chain polyunsaturated fatty acids (PUFAs) generate diverse bioactive lipid mediators, which tightly regulate vascular inflammation. The effects of omega-3 PUFA supplementation in cardiovascular prevention however remain controversial. In addition to direct dietary intake, fatty acid desaturases (FADS) determine PUFA levels. Increased arterial stiffness represents an independent predictor of mortality and cardiovascular events. The aim of the present study was to determine the association of PUFA intake, FADS1 genotype, and FADS expression with arterial stiffness. Methods and results: A cross-sectional population-based cohort study of 1464 participants without overt cardiovascular disease was conducted. Dietary intake was assessed using a food frequency questionnaire. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV), and the FADS1 locus variant was determined. Blood cell transcriptomics was performed in a subset of 410 individuals. Pulse wave velocity was significantly associated with the FADS1 locus variant. Differential associations between PWV and omega-3 PUFA intake were observed depending on the FADS1 genotype. High omega-3 PUFA intake attenuated the FADS1 genotype-dependent associations. Carriers of the minor FADS1 locus variant exhibited increased expression of FADS2, which is associated with PWV. Conclusion: Taken together, these findings point to FADS1 genotype-dependent associations of omega-3 PUFA intake on subclinical cardiovascular disease. These findings may have implications for identifying responders and non-responders to omega-3 PUFA supplementation and open up for personalized dietary counselling in cardiovascular prevention.

Thyroid Doses to French Polynesians Resulting from Atmospheric Nuclear Weapons Tests: Estimates Based on Radiation Measurements and Population Lifestyle Data.

Thyroid doses were estimated for the subjects of a population-based case-control study of thyroid cancer in a population exposed to fallout after atmospheric nuclear weapons tests conducted in French Polynesia between 1966 and 1974. Thyroid doses due to (1) intake of I and of short-lived radioiodine isotopes (I, I, I) and Te, (2) external irradiation from gamma-emitting radionuclides deposited on the ground, and (3) ingestion of long-lived Cs with foodstuffs were reconstructed for each study subject. The dosimetry model that had been used in 2008 in Phase I of the study was substantially improved with (1) results of radiation monitoring of the environment and foodstuffs, which became available in 2013 for public access, and (2) historical data on population lifestyle related to the period of the tests, which were collected in 2016-2017 using focus-group discussions and key informant interviews. The mean thyroid dose among the study subjects was found to be around 5 mGy while the highest dose was estimated to be around 36 mGy. Doses from I intake ranged up to 27 mGy, while those from intake of short-lived iodine isotopes (I, I, I) and Te ranged up to 14 mGy. Thyroid doses from external exposure ranged up to 6 mGy, and those from internal exposure due to Cs ingestion did not exceed 1 mGy. Intake of I was found to be the main pathway for thyroid exposure accounting for 72% of the total dose. Results of this study are being used to evaluate the risk of thyroid cancer among the subjects of the epidemiologic study of thyroid cancer among French Polynesians.

Heritability of a resting heart rate in a 20-year follow-up family cohort with GWAS data: Insights from the STANISLAS cohort.

BACKGROUND: The association between resting heart rate (HR) and cardiovascular outcomes, especially heart failure, is now well established. However, whether HR is mainly an integrated marker of risk associated with other features, or rather a genetic origin risk marker, is still a matter for debate. Previous studies reported a heritability ranging from 14% to 65%. DESIGN: We assessed HR heritability in the STANISLAS family-study, based on the data of four visits performed over a 20-year period, and adjusted for most known confounding effects. METHODS: These analyses were conducted using a linear mixed model, adjusted on age, sex, tea or coffee consumption, beta-blocker use, physical activity, tobacco use, and alcohol consumption to estimate the variance captured by additive genetic effects, via average information restricted maximum likelihood analysis, with both self-reported pedigree and genetic relatedness matrix (GRM) calculated from genome-wide association study data. RESULTS: Based on the data of all visits, the HR heritability (h2) estimate was 23.2% with GRM and 24.5% with pedigree. However, we found a large heterogeneity of HR heritability estimations when restricting the analysis to each of the four visits (h2 from 19% to 39% using pedigree, and from 14% to 32% using GRM). Moreover, only a little part of variance was explained by the common household effect (<5%), and half of the variance remained unexplained. CONCLUSION: Using a comprehensive analysis based on a family cohort, including the data of multiple visits and GRM, we found that HR variability is about 25% from genetic origin, 25% from repeated measures and 50% remains unexplained.

Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians.

Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality. At 2q35, we highlighted rs16857609 located in DIRC3. This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, p = 1.9 x 10-10). It is also associated with expression of DIRC3 and of the nearby gene IGFBP5 in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, p = 7.6 x 10-8) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, p = 0.001). These SNPs are linked to the expression of NRG1 in thyroid tissue. Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.