Ischemic stroke subtypes: risk factors, treatments, and 1-month prognosis - The Lille, France Stroke Registry.

OBJECTIVES: First, this registry-based study aimed to comprehensively analyze patients' medical histories and treatments based on ischemic strokes' etiology. We focused on the management of atrial fibrillation among patients diagnosed with cardioembolic stroke. Then, our objective was to identify prognostic factors associated with 28-day mortality. MATERIALS AND METHODS: All ischemic strokes occurring in adults between 2014 and 2021 in Lille, France, were categorized using the TOAST classification. Comparative analyses of patients' medical characteristics were conducted across subtypes. Survival rates within 28 days post-stroke were assessed, and factors influencing mortality were identified using a multivariate Cox model. RESULTS: 1912 ischemic strokes were recorded, due to cardioembolism (36%), large-artery atherosclerosis (9%), small-artery occlusion (9%), other determined causes (6%), or undetermined causes (39%). The median NIHSS score after cardioembolic stroke (6, IQR: 3-13) was twice that after small-artery occlusion (3, IQR: 2-5). Among patients with cardioembolic stroke, 26% were diagnosed post-admission with atrial fibrillation. For the 42% diagnosed pre-admission, only 54% had prior prescriptions for oral anticoagulants. Reperfusion therapies were administered in 21% of cases, with significant variations across subtypes. Mortality rates were higher after cardioembolic strokes (17%) than after small-artery occlusions (3%). Prognostic factors included etiology, high NIHSS score, atrial fibrillation, and previous heparin prescription. CONCLUSIONS: While atrial fibrillation was underdiagnosed and undertreated, patients with cardioembolic stroke exhibited high severity and elevated mortality rates. Etiology emerged as an independent predictor of early mortality, regardless of NIHSS score upon admission. These findings underscore the importance of targeted prevention to improve patient outcomes after ischemic stroke.

Interplay of the Mediterranean diet and genetic hypertension risk on blood pressure in European adolescents: Findings from the HELENA study.

Early-life onset of high blood pressure is associated with the development of cardiovascular diseases in adulthood. In adolescents, limited evidence exists regarding the association between adherence to the Mediterranean Diet (MedDiet) and normal blood pressure (BP) levels, as well as its potential to modulate genetic predisposition to HTN. This study investigated the interaction between a MedDiet score and a recently developed HTN-genetic risk score (HTN-GRS) on blood pressure levels in a European adolescent cohort. The MedDiet score was derived from two non-consecutive 24-h dietary recalls and ranged from 0 (indicating low adherence) to 9 (indicating high adherence). Multiple linear regression models, adjusted for covariates, were employed to examine the relationship between the MedDiet score and BP z-scores and to assess the interaction effects between the MedDiet score and HTN-GRS on BP z-scores. MedDiet score showed a negative association with z-systolic BP (SBP) (ß = -0.40, p < 0.001) and z-diastolic BP (DBP) (ß = -0.29, p = 0.001). Additionally, a significant interaction effect was identified between the MedDiet score and HTN-GRS on z-SBP (ß = 0.02, p < 0.001) and z-DBP (ß = 0.02, p < 0.001). The modulatory effect of the MedDiet was more pronounced in females than in males, and HTN-GRS exhibited a stronger influence on DBP than on SBP.   Conclusion: The study suggests that higher adherence to the MedDiet is associated with reduced BP levels in adolescents and provides evidence of a genetic-diet interaction influencing BP in adolescents. What is Known: • Adherence to the Mediterranean diet may reduce BP levels. What is New: • It is the first study to assess the connection between adherence to a Mediterranean diet, a hypertension genetic risk score, and how they interact in influencing blood pressure. • It is conducted within a multicenter cohort of European adolescents.

The body mass index increases the genetic risk scores' ability to predict risk of hepatic damage in European adolescents: The HELENA study.

BACKGROUND: Hepatic disorders are often complex and multifactorial, modulated by genetic and environmental determinants. During the last years, the hepatic disease has been progressively established from early stages in life. The use of genetic risk scores (GRS) to predict the genetic susceptibility to a particular phenotype among youth has gained interest in recent years. Moreover, the alanine aminotransferase (ALT) blood biomarker is often considered as hepatic screening tool, in combination with imaging techniques. The aim of the present study was to develop an ALT-specific GRS to help in the evaluation of hepatic damage risk in European adolescents. METHODS: A total of 972 adolescents (51.3% females), aged 12.5-17.5 years, from the Healthy Lifestyle in Europe by Nutrition in Adolescence study were included in the analyses. The sample incorporated adolescents in all body mass index (BMI) categories and was divided considering healthy/unhealthy ALT levels, using sex-specific cut-off points. From 1212 a priori ALT-related single nucleotide polymorphisms (SNPs) extracted from candidate gene selection, a first screening of 234 SNPs univariately associated was established, selecting seven significant SNPs (p < .05) in the multivariate model. An unweighted GRS (uGRS) was developed by summing the number of reference alleles, and a weighted GRS (wGRS), by multiplying each allele to its estimated coefficient. RESULTS: The uGRS and wGRS were significantly associated with ALT (p < .001). The area under curve was obtained integrating BMI as clinical factor, improving the predictive ability for uGRS (.7039) and wGRS (.7035), using 10-fold internal cross-validation. CONCLUSIONS: Considering BMI status, both GRSs could contribute as complementary tools to help in the early diagnosis of hepatic damage risk in European adolescents.

Development of a genetic risk score to predict the risk of hypertension in European adolescents from the HELENA study.

Introduction: From genome wide association study (GWAS) a large number of single nucleotide polymorphisms (SNPs) have previously been associated with blood pressure (BP) levels. A combination of SNPs, forming a genetic risk score (GRS) could be considered as a useful genetic tool to identify individuals at risk of developing hypertension from early stages in life. Therefore, the aim of our study was to build a GRS being able to predict the genetic predisposition to hypertension (HTN) in European adolescents. Methods: Data were extracted from the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study. A total of 869 adolescents (53% female), aged 12.5-17.5, with complete genetic and BP information were included. The sample was divided into altered (≥130 mmHg for systolic and/or ≥80 mmHg for diastolic) or normal BP. Based on the literature, a total of 1.534 SNPs from 57 candidate genes related with BP were selected from the HELENA GWAS database. Results: From 1,534 SNPs available, An initial screening of SNPs univariately associated with HTN (p < 0.10) was established, to finally obtain a number of 16 SNPs significantly associated with HTN (p < 0.05) in the multivariate model. The unweighted GRS (uGRS) and weighted GRS (wGRS) were estimated. To validate the GRSs, the area under the curve (AUC) was explored using ten-fold internal cross-validation for uGRS (0.802) and wGRS (0.777). Further covariates of interest were added to the analyses, obtaining a higher predictive ability (AUC values of uGRS: 0.879; wGRS: 0.881 for BMI z-score). Furthermore, the differences between AUCs obtained with and without the addition of covariates were statistically significant (p < 0.05). Conclusions: Both GRSs, the uGRS and wGRS, could be useful to evaluate the predisposition to hypertension in European adolescents.

Long-term follow-up of survivors of a first acute coronary syndrome: Results from the French MONICA registries from 2009 to 2017.

AIM: The objectives of the study were to characterize the long-term risk of first recurrence of acute coronary syndrome (ACS) among survivors of an incident ACS, as a function of the STEMI/NSTEMI/UA diagnosis. METHODS: Men and women (aged 35-74) hospitalized between 2009 and 2016 for an incident ACS in the French MONICA registries and still alive on discharge were followed-up until December 2017. Recurrent events were defined as the first (non-fatal or fatal) ACS occurring after hospital discharge from the incident event. RESULTS: The study comprised 15,739 incident ACSs with 63,777 patient-years of follow-up. The cumulative probability [95% confidence interval] of recurrent ACS was 6.7% [6.3-7.1%] at 1 year and 18.4% [17.4-19.5%] at 9 years. The cumulative probability of fatal recurrent ACS was 1.4% [1.2-1.5%] at 1 year and 4.3% [3.6-4.9%] at 9 years. The risk of recurrence did not depend on the type of the incident ACS after adjustment for confounding factors. The most frequent forms of recurrence were NSTEMI and UA. The presence of a major complication (OR = 1.59) and an impaired left ventricular ejection fraction (LVEF) (OR > 1.26) increased the risk of recurrence. The annual 1-year recurrence rates decreased from 7.4% in 2009 to 4.0% in 2016 (p < 0.001). CONCLUSION: The recurrence rate after an incident ACS remained high in France, and the risk of recurrence did not depend on the etiology of the first event. Our results emphasize the importance of targeting patients with a major complication and/or an impaired LVEF who are at a higher risk of recurrence.

How do territorial characteristics affect spatial inequalities in the risk of coronary heart disease?

BACKGROUND: Cardiovascular diseases remain the leading cause of death and disabilities worldwide, with coronary heart diseases being the most frequently diagnosed. Their multifactorial etiology involves individual, behavioral and territorial determinants, and thus requires the implementation of multidimensional approaches to assess links between territorial characteristics and the incidence of coronary heart diseases. CONTEXT AND OBJECTIVES: This study was carried out in a densely populated area located in the north of France with multiple sources of pollutants. The aim of this research was therefore to establish complex territorial profiles that have been characterized by the standardized incidence, thereby identifying the influences of determinants that can be related to a beneficial or a deleterious effect on cardiovascular health. METHODS: Forty-four variables related to economic, social, health, environment and services dimensions with an established or suspected impact on cardiovascular health were used to describe the multidimensional characteristics involved in cardiovascular health. RESULTS: Three complex territorial profiles have been highlighted and characterized by the standardized incidence rate (SIR) of coronary heart diseases after adjustment for age and gender. Profile 1 was characterized by an SIR of 0.895 (sd: 0.143) and a higher number of determinants that revealed favorable territorial conditions. Profiles 2 and 3 were characterized by SIRs of respectively 1.225 (sd: 0.242) and 1.119 (sd: 0.273). Territorial characteristics among these profiles of over-incidence were nevertheless dissimilar. Profile 2 revealed higher deprivation, lower vegetation and lower atmospheric pollution, while profile 3 displayed a rather privileged population with contrasted territorial conditions. CONCLUSION: This methodology permitted the characterization of the multidimensional determinants involved in cardiovascular health, whether they have a negative or a positive impact, and could provide stakeholders with a diagnostic tool to implement contextualized public health policies to prevent coronary heart diseases.

A new 165-SNP low-density lipoprotein cholesterol polygenic risk score based on next generation sequencing outperforms previously published scores in routine diagnostics of familial hypercholesterolemia.

Genetic diagnosis of familial hypercholesterolemia (FH) remains unexplained in 30 to 70% of patients after exclusion of monogenic disease. There is now a growing evidence that a polygenic burden significantly modulates LDL-cholesterol (LDL-c) concentrations. Several LDL-c polygenic risk scores (PRS) have been set up. However, the balance between their diagnosis performance and their practical use in routine practice is not clearly established. Consequently, we set up new PRS based on our routine panel for sequencing and compared their diagnostic performance with previously-published PRS. After a meta-analysis, four new PRS including 165 to 1633 SNP were setup using different softwares. They were established using two French control cohorts (MONA LISA n=1082 and FranceGenRef n=856). Then the explained LDL-c variance and the ability of each PRS to discriminate monogenic negative FH patients (M-) versus healthy controls were compared with 4 previously-described PRS in 785 unrelated FH patients. Between all PRS, the 165-SNP PRS developed with PLINK showed the best LDL-c explained variance (adjusted R²=0.19) and the best diagnosis abilities (AUROC=0.77, 95%CI=0.74-0.79): it significantly outperformed all the previously-published PRS (p<1 × 10-4). By using a cut-off at the 75th percentile, 61% of M- patients exhibited a polygenic hypercholesterolemia with the 165-SNP PRS versus 48% with the previously published 12-SNP PRS (p =3.3 × 10-6). These results were replicated using the UK biobank. This new 165-SNP PRS, usable in routine diagnosis, exhibits better diagnosis abilities for a polygenic hypercholesterolemia diagnosis. It would be a valuable tool to optimize referral for whole genome sequencing.

Association between PTPN1 polymorphisms and obesity-related phenotypes in European adolescents: influence of physical activity.

BACKGROUND: To study the associations of Protein Tyrosine Phosphatase-N1 (PTPN1) polymorphisms with obesity-related phenotypes in European adolescents, and the influence of physical activity on these relationships. METHODS: Five polymorphisms of PTPN1 were genotyped in 1057 European adolescents (12-18 years old). We measured several phenotypes related to obesity, such as adiposity markers, and biochemical and clinical parameters. Physical activity was objectively measured by accelerometry. RESULTS: The T, A, T, T and G alleles of the rs6067472, rs10485614, rs2143511, rs6020608 and rs968701 polymorphisms, respectively, were associated with lower levels of obesity-related phenotypes (i.e., body mass index, body fat percentage, hip circumference, fat mass index, systolic blood pressure and leptin) in European adolescents. In addition, the TATTG haplotype was associated with lower body fat percentage and fat mass index compared to the AACCA haplotype. Finally, when physical activity levels were considered, alleles of the rs6067472, rs2143511, rs6020608 and rs968701 polymorphisms were only associated with lower adiposity in active adolescents. CONCLUSIONS: PTPN1 polymorphisms were associated with adiposity in European adolescents. Specifically, alleles of these polymorphisms were associated with lower adiposity only in physically active adolescents. Therefore, meeting the recommendations of daily physical activity may reduce obesity risk by modulating the genetic predisposition to obesity. IMPACT: Using gene-phenotype and gene*environment analyses, we detected associations between polymorphisms of the Protein Tyrosine Phosphatase-N1 (PTPN1) gene and obesity-related phenotypes, suggesting a mechanism that can be modulated by physical activity. This study shows that genetic variability of PTPN1 is associated with adiposity, while physical activity seems to modulate the genetic predisposition. This brings insights about the mechanisms by which physical activity positively influences obesity.

Identification of several eating habits that mediate the association between eating behaviors and the risk of obesity.

Objective: Eating behaviors play important roles in the development of obesity. A better knowledge of the psychological aspects of eating behaviors in individuals with and without obesity and their consequences on daily eating and lifestyle habits would be informative. The Three-Factor Eating Questionnaire (TFEQ)-R21 assesses the psychometrics of eating behavior. The objectives of the study were to establish which eating habits were or were not associated with TFEQ eating behaviors, and to quantify the extent to which those eating habits mediated the association between TFEQ eating behaviors and obesity risk. Methods: Data were obtained from the Gene and Environment Case-Control Obesity Study from northern France. It included 2237 individuals with obesity and 403 individuals without obesity. Eating behaviors were assessed according to the TFEQ-R21. Two activity levels (physical activity and television watching) and six eating habits (e.g., plate size, having one serving or at least two servings of the main meal, …) were evaluated. Regression and mediation analyses were performed. Results: Higher cognitive restraint, higher uncontrolled eating (UE) and higher emotional eating (EE) were associated with a higher risk of obesity, independently of each other and of age, sex, socio-economic status and physical activity. Cognitive restraint was negatively associated with having at least two servings, while UE and EE were associated with several obesogenic habits such as eating in front of the television or eating at night. Each of these obesogenic habits mediated between 3% and 20% of the association between UE or EE and obesity. Conclusions: Psychological eating behaviors were associated with several lifestyle and eating habits in both individuals with and without obesity. Moreover, some eating habits partially mediated (between 3% and 20%) the association between TFEQ eating behaviors and obesity risk. For clinicians, this study shows that simple, easy-to-ask questions on specific daily eating habits can provide essential information to better understand and manage patients with obesity.

Sex differences in time trends in acute coronary syndrome management and in 12-month lethality: Data from the French MONICA registries.

BACKGROUND: Sex differences in clinical presentation, patient care and fatal outcomes after an acute coronary syndrome (ACS) have been reported. However, recent improvements in the care and treatment of ACSs have not been assessed with regard to possible sex differences. AIM: To assess sex differences in trends between 2006 and 2016 in the characteristics of ACSs, their management, and the associated mortality. METHODS: We assessed all men and women (aged 35-74) covered by the MONICA registries in north, east and south-west France and having been hospitalized for an incident (first) ACS during a 12-month period in 2006 or a 6-month period in 2016. We analyzed the patients' clinical, biochemical, electrocardiographic and care-related data, and their vital status 28 days and 12 months after the ACS. RESULTS: In 2006, women were older (<0.0001) and had more atypical symptoms than men (p < 0.01). These differences were no longer statistically significant in 2016. Medical care improved in both men and women. However, revascularization treatment, prescriptions of platelet aggregation inhibitors, statins, and functional rehabilitation were still more frequently provided to men than to women (p < 0.01) in 2016, independently of confounders. The 28-day or 12-month case fatality was not different between men and women in both 2006 and 2016. CONCLUSIONS: The results of the present study evidenced an improvement over time in the management of ACS. However, although there were no longer sex differences in the patients' age and clinical presentation, women with ACS were still less likely than men to receive revascularization and pharmacological treatments in 2016.

Trends of in-hospital and out-of-hospital coronary heart disease mortality in French registries during the period 2000 to 2016.

PURPOSE: To estimate trends of in- and out-of-hospital Acute Coronary Events (ACE) mortality rates from 2000 to 2016 and their respective contributions to total ACE mortality in France. METHODS: All fatal coronary events occurring between January 2000 and December 2016 were recorded for patients age 35-74 in the French MONICA registries. Trends in age-standardized and crude mortality rates were expressed as annual percentage changes (APC). RESULTS: Between 2000 and 2016, 20,822 fatal events were recorded, of which 69.4% were out-of-hospital. Almost 90% of out-of-hospital deaths occurred at home. Decreases in ACE mortality were greater inside than outside the hospital (APC: -4.3% vs. -2.9% in men; -5.0% vs. -3.2% in women), resulting in a higher contribution of out-of-hospital mortality to overall ACE mortality, from 65.3% in 2000 to 71.4% in 2016. This trend was more pronounced for elderly than younger patients. CONCLUSIONS: Between 2000 and 2016, ACE mortality declined in France. This trend was more pronounced for in- than for out-of-hospital. These results underline the importance of out-of-hospital mortality in driving ACE mortality rates and the need to further investigate ways to reduce it.

Comparison of clinical profiles and care for patients with incident versus recurrent acute coronary syndromes in France: Data from the MONICA registries.

BACKGROUND: Recurrence is common after an acute coronary syndrome (ACS). In order to better assess the prognosis for patients with ACS, we compared clinical profiles, treatments, and case fatality rates for incident vs. recurrent ACS. METHODS: We enrolled 1,459 men and women (age: 35-74) living in three geographical areas covered by French MONICA registries and who had been admitted to hospital for an ACS in 2015/2016. We recorded and compared the clinical characteristics and medical care for patients with an incident vs. a recurrent ACS. RESULTS: Overall, 431 (30%) had a recurrent ACS. Relative to patients with an incident ACS, patients with recurrence were older (p<0.0001), had a greater frequency of NSTEMI or UA (p<0.0001), were less likely to show typical symptoms (p = 0.045), were more likely to have an altered LVEF (p<0.0001) and co-morbidities. Angioplasty was less frequently performed among patients with recurrent than incident NSTEMI (p<0.05). There were no intergroup differences in the prescription of the recommended secondary prevention measures upon hospital discharge, except for functional rehabilitation more frequently prescribed among incident patients (p<0.0001). Although the crude 1-year mortality rate was higher for recurrent cases (14%) than for incident cases (8%) (p<0.05), this difference was no longer significant after adjustment for age, sex, region, diagnosis category and LVEF. CONCLUSION: Compared with incident patients, recurrent cases were more likely to have co-morbidities and to have suboptimal treatments prior to hospital stay, reinforcing the need for secondary prevention.

Interplay of physical activity and genetic variants of the endothelial lipase on cardiovascular disease risk factors.

BACKGROUND: The aim of this study was to investigate the association of endothelial lipase gene (LIPG) polymorphisms with cardiovascular disease (CVD) risk factors in adolescents and their interaction with physical activity. METHODS: Six polymorphisms of LIPG were genotyped in 1057 European adolescents (12-18 years old) enrolled in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) Study. CVD risk factors related to lipid profile, blood pressure, adiposity and glucose regulation were recorded. Physical activity was objectively measured by accelerometry. RESULTS: The major C allele of rs2000813, the minor T allele of rs2276269 and the minor G allele of rs9951026 were associated with lower levels of several CVD risk factors related to lipid profile. We also found a significant association of the TTACA LIPG haplotype (rs2000812, rs2000813, rs8093249, rs2276269 and rs9951026) with higher concentrations of low-density cholesterol and apolipoprotein B. Finally, the interaction between physical activity and the polymorphisms rs2000813, rs2276269 and rs9951026 had a significant influence on several CVD risk factors. CONCLUSIONS: LIPG polymorphisms were significantly associated with CVD risk factors in European adolescents. Interestingly, alleles of these polymorphisms were associated with a better cardiovascular profile in physically active adolescents only. High physical activity may reduce the development of CVD, modulating its genetic risk. IMPACT: Using gene-phenotype and gene × environment analyses, we detected associations between the endothelial lipase gene and cardiovascular risk factors, along with interactions with physical activity. This study shows that physical activity may modulate the influence of LIPG gene on cardiovascular risk in adolescents. These results bring insights into the mechanisms by which physical activity positively influences CVD in adolescents.

Large disparities in 28-day case fatality by stroke subtype: data from a French stroke registry between 2008 and 2017.

BACKGROUND AND PURPOSE: The objectives of the present analysis were to assess 28-day stroke case fatality according to the stroke aetiology and to identify associated factors. METHODS: All stroke events in adults aged ≥35 years between 2008 and 2017 were collected in a population-based stroke registry in northern France. RESULTS: Out of a total of 2933 strokes, there were 479 (16%) haemorrhagic strokes and 2454 (84%) ischaemic strokes; the 28-day case fatality rates were 48% and 15%, respectively. Three-quarters of the 28-day case fatalities occurred within 6 days of the event for haemorrhagic strokes and within 16.5 days for ischaemic strokes. After an ischaemic stroke, the case fatality rate was higher for women (18%) than for men (12%, p < 0.0001); however, this difference disappeared after adjustment for age. Cardioembolic strokes (34%) and strokes of undetermined cause (33%) were the most common ischaemic subtypes, with case fatality rates of 16% and 18%, respectively. Large artery atherosclerosis (11%) and lacunar strokes (10%) were less common, and both types had a case fatality rate of 3%. Age at the time of the event and stroke severity were both significantly associated with case fatality. For some types of stroke, a history of cardiovascular events and residence in a nursing home were associated with a poor prognosis. Medical care in a neurology ward was inversely associated with case fatality, for all stroke subtypes. CONCLUSIONS: In northern France, post-stroke case fatality remains high, especially for haemorrhagic stroke. Being treated in a neurology ward improved survival by around 80%.

The relationship between neighbourhood walkability and cardiovascular risk factors in northern France.

BACKGROUND: Although walkability is known to be associated with obesity and hypertension through increased physical activity; data on cardiovascular risk factors (especially in the Europe) are scarce. We assessed the relationship between neighbourhood walkability and cardiometabolic factors (including obesity, hypertension, the blood lipid profile, and serum glycated haemoglobin (HbA1c) levels) among adults living in northern France. METHODS: Data were extracted from the ELISABET study database (2011-2013). The participants (aged between 40 and 65) resided in or around the cities of Lille and Dunkirk. For each residential address, we determined a neighbourhood walkability index (using a geographic information system) and the Walk Score®. Multilevel linear and logistic models were used to assess the relationships between neighbourhood walkability on one hand and body mass index (BMI), obesity, blood pressure, hypertension, serum HDLC, LDL-C, triglyceride and HbA1c levels, and physical activity level on the other. RESULTS: 3218 participants were included. After adjusting for individual and neighbourhood variables, we found that a higher neighbourhood walkability index was associated with a lower BMI (-0.23 kg.m-2; 95% confidence interval (CI) [-0.44;-0.01] for a one interquartile range (IQR) increment), a lower systolic blood pressure (-1.66 mmHg; 95% CI [-2.46;-0.85] per IQR), a lower prevalence of hypertension (% of increase: -7.12, 95% CI [-13.56;-0.52] per IQR), and a higher prevalence of moderate or high physical activity (% of increase = 6.9; 95% CI [1.2;12.72] per IQR). The walkability index was not significantly associated with other cardiovascular risk factors. Similar results were observed for the Walk Score®. CONCLUSION: Our results showed that residence in a more walkable neighbourhood was associated with a lower prevalence of vascular risk factors. Promoting neighbourhood walkability might help to improve the population's cardiovascular health.

Development of a Genetic Risk Score to predict the risk of overweight and obesity in European adolescents from the HELENA study.

Obesity is the result of interactions between genes and environmental factors. Since monogenic etiology is only known in some obesity-related genes, a genetic risk score (GRS) could be useful to determine the genetic predisposition to obesity. Therefore, the aim of our study was to build a GRS able to predict genetic predisposition to overweight and obesity in European adolescents. A total of 1069 adolescents (51.3% female), aged 11-19 years participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study were genotyped. The sample was divided in non-overweight (non-OW) and overweight/obesity (OW/OB). From 611 single nucleotide polymorphisms (SNP) available, a first screening of 104 SNPs univariately associated with obesity (p < 0.20) was established selecting 21 significant SNPs (p < 0.05) in the multivariate model. Unweighted GRS (uGRS) was calculated by summing the number of risk alleles and weighted GRS (wGRS) by multiplying the risk alleles to each estimated coefficient. The area under curve (AUC) was calculated in uGRS (0.723) and wGRS (0.734) using tenfold internal cross-validation. Both uGRS and wGRS were significantly associated with body mass index (BMI) (p < .001). Both GRSs could potentially be considered as useful genetic tools to evaluate individual's predisposition to overweight/obesity in European adolescents.

Cardiometabolic Risk is Positively Associated with Underreporting and Inversely Associated with Overreporting of Energy Intake Among European Adolescents: The Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) Study.

BACKGROUND: Dietary misreporting is the main limitation of dietary assessments and has been associated with BMI during youth. However there are no prior studies assessing misreporting and cardiometabolic risks (CMRs) in adolescence. OBJECTIVES: To examine the associations between dietary misreporting and CMR factors in adolescents and to assess the potential bias in the association between CMR and energy intake (EI) driven by dietary misreporting. METHODS: Two 24-hour dietary recalls were obtained from 1512 European adolescents (54.8% girls) aged 12.5-17.5 years. Physical activity was measured by accelerometry. Cut-offs suggested by Huang were applied to identify misreporters. Height, waist circumference (WC), the sum of 4 skinfold thicknesses, diastolic blood pressure (DBP), systolic blood pressure (SBP), and cardiorespiratory fitness (CRF) measurements were taken and serum triglycerides and total-/high-density lipoprotein cholesterol ratio were analyzed. A sex- and age-specific clustered CMR score (n = 364) was computed. Associations were investigated by multilevel regression analyses adjusting for age, sex, center, socioeconomic status, and physical activity. RESULTS: Underreporting (24.8% adolescents) was significantly (P < 0.05) associated with a higher WC, waist-to-height ratio (WHeR), and sum of skinfold thickness, whereas overreporting (23.4% adolescents) was significantly associated with a lower WC, WHeR, sum of skinfold thickness, and SBP. Associations between CMR factors and EI were significantly affected by misreporting, considering various approaches. Significant, positive associations became inverse after adjusting for misreporting for WC and WHeR. The opposite was true for the sum of skinfold thickness, SBP, and CMR score. The associations between EI and DBP and CRF did not remain significant after adjusting for misreporting. CONCLUSIONS: CMR factors differed among misreporting groups, and both abdominal and total fat mass indicators were more strongly associated with all forms of misreporting than was BMI. Moreover, misreporting seems to bias EI and CMR associations in adolescents. Therefore, energy misreporting should be taken into account when examining diet-CMR associations.

Interaction Effect of the Mediterranean Diet and an Obesity Genetic Risk Score on Adiposity and Metabolic Syndrome in Adolescents: The HELENA Study.

Obesity and metabolic syndrome (MetS) are worldwide major health challenges. The Mediterranean diet (MD) is associated with a better cardiometabolic profile, but these beneficial effects may be influenced by genetic variations, modulating the predisposition to obesity or MetS. The aim was to assess whether interaction effects occur between an obesity genetic risk score (obesity-GRS) and the MD on adiposity and MetS in European adolescents. Multiple linear regression models were used to assess the interaction effects of an obesity-GRS and the MD on adiposity and MetS and its components. Interaction effects between the MD on adiposity and MetS were observed in both sex groups (p < 0.05). However, those interaction effects were only expressed in a certain number of adolescents, when a limited number of risk alleles were present. Regarding adiposity, a total of 51.1% males and 98.7% females had lower body mass index (BMI) as a result of higher MD adherence. Concerning MetS, only 9.9% of males with higher MD adherence had lower MetS scores. However, the same effect was observed in 95.2% of females. In conclusion, obesity-related genotypes could modulate the relationship between MD adherence and adiposity and MetS in European adolescents; the interaction effect was higher in females than in males.

PCSK9 post-transcriptional regulation: Role of a 3'UTR microRNA-binding site variant in linkage disequilibrium with c.1420G.

BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol homeostasis. A common variant, the G allele in position c.1420 (c.1420G), has been associated with a decrease of both plasma PCSK9 and LDL-cholesterol concentrations. However, the functional effect of this variant is currently not well understood. We hypothesized that it could be explained by functional variants in linkage disequilibrium (LD), more specifically, by variants located in the PCSK9 3' UTR as targets for miR regulation of PCSK9 expression. METHODS: Variations in LD with c.1420G were studied in 1029 patients followed for dyslipidaemia. In silico studies identified potential miRNA binding sites induced by PCSK9 3'UTR variants in LD with c.1420G. Their functionality was studied with a luciferase reporter assay in HuH-7 cells and confirmed by cotransfection of anti-miRNAs. RESULTS: The c.*571C and c.*234T variants located in the PCSK9 3'UTR were found in tight LD with c.1420G (D' = 0.962; LOD = 163.06). The haplotype carrying c.*571C showed a 6.7% decrease in luciferase activity (p = 0.003). Inhibition of hsa-miR-1228-3p and hsa-miR-143-5p counteracted their effect on the haplotype carrying c.*571C allele, suggesting that PCSK9 expression was decreased by the endogenous binding of hsa-miR-1228-3p and hsa-miR-143-5p on its 3'UTR. CONCLUSIONS: This post-transcriptional regulation might contribute towards the association between plasma PCSK9 levels and c.1420G. Such regulation of PCSK9 expression may open new perspectives for the treatment of hypercholesterolemia and atherosclerosis cardiovascular diseases.

Single nucleotide polymorphisms of ADIPOQ gene associated with cardiovascular disease risk factors in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence study.

OBJECTIVES: Cardiovascular diseases (CVDs) are responsible of 31% of all deaths worldwide. Genetic predisposition to CVDs in adolescents remains largely unknown. Aims of present research are to examine the association of ADIPOQ gene polymorphisms with cardiovascular disease risk factors in European adolescents. METHODS: A total of 14 polymorphisms in the ADIPOQ gene were genotyped in 1057 European adolescents (12-18 years old) from the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study. We measured serum lipids and a CVD risk score, along with weight, height, triceps, and subscapular skinfold thickness, leptin, insulin and other markers of glucose regulation. RESULTS: The rs822393, rs822395 and rs7649121 polymorphisms of ADIPOQ gene were significantly associated with several CVD risk factors [i.e. high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) A1, SBP and CVD risk score] in European adolescents. We also found an association of the TGAAGT ADIPOQ haplotype (rs822393, rs16861210, rs822395, rs822396, rs12495941 and rs7649121) with HDL-C and ApoA1 levels. CONCLUSION: Several individual polymorphisms (rs822393, rs822395 and rs7649121) and a haplotype of ADIPOQ gene were significantly associated with cardiovascular disease risk factors in European adolescents.