Molecular Spectrum of Autosomal Dominant Hypercholesterolemia in France

Autosomal Dominant Hypercholesterolemia (ADH), characterized by isolated elevation of plasmatic LDL cholesterol and premature cardiovascular complications, is associated with mutations in 3 major genes: LDLR (LDL receptor), APOB (apolipoprotein B) and PCSK9 (proprotein convertase subtilisin-kexin type 9). Through the French ADH Research Network, we collected molecular data from 1358 French probands from eleven different regions in France. Mutations in the LDLR gene were identified in 1003 subjects representing 391 unique events with 46.0% missense, 14.6% frameshift, 13.6% splice, and 11.3% nonsense mutations, 9.7% major rearrangements, 3.8% small in frame deletions/insertions, and 1.0% UTR mutations. Interestingly, 175 are novel mutational events and represent 45% of the unique events we identified, highlighting a specificity of the LDLR mutation spectrum in France. Furthermore, mutations in the APOB gene were identified in 89 probands and in the PCSK9 gene in 10 probands. Comparison of available clinical and biochemical data showed a gradient of severity for ADH-causing mutations: FH=PCSK9>FDB>‘Others’ genes. The respective contribution of each known gene to ADH in this French cohort is: LDLR 73.9%, APOB 6.6%, PCSK9 0.7%. Finally, in 19.0% of the probands, no mutation was found, thus underscoring the existence of ADH mutations located in still unknown genes. © 2010 Wiley-Liss, Inc

An APOA5 3′ UTR Variant Associated with Plasma Triglycerides Triggers APOA5 Downregulation by Creating a Functional miR-485-5p Binding Site

APOA5 c.∗158C>T (rs2266788), located in the 3′ UTR, belongs to APOA5 haplotype 2 (APOA5∗2), which is strongly associated with plasma triglyceride levels and modulates the occurrence of both moderate and severe hypertriglyceridemia. Individuals with APOA5∗2 display reduced APOA5 expression at the posttranscriptional level. However, the functionality of this haplotype remains unclear. We hypothesized that the hypertriglyceridemic effects of APOA5∗2 could involve miRNA regulation in the APOA5 3′ UTR. Bioinformatic studies have identified the creation of a potential miRNA binding site for liver-expressed miR-485-5p (MIRN485-5p) in the mutant APOA5 3′ UTR with the c.∗158C allele. In human embryonic kidney 293T (HEK293T) cells cotransfected with an APOA5 3′ UTR luciferase reporter vector and a miR485-5p precursor, c.∗158C allele expression was significantly decreased. Moreover, in HuH-7 cells endogenously expressing miR-485-5p, we observed that luciferase activity was significantly lower in the presence of the c.∗158C allele than in the presence of the c.∗158T allele, which was completely reversed by a miR-485-5p inhibitor. We demonstrated that the rare c.∗158C APOA5 allele creates a functional target site for liver-expressed miR-485-5p. Therefore, we propose that the well-documented hypertriglyceridemic effect of APOA5∗2 involves an APOA5 posttranscriptional downregulation mediated by miR-485-5p

Treatment of de novo femoro-popliteal lesions with a new Drug Coated Balloon: early experience of a single Center in the first 50 patients

Angioplasty with drug-coated balloon (DCB) is an emerging and reliable method for the treatment of femoro-popliteal lesions. We report our experience with the Stellarex™ DCB in the first 50 patients. Methods - From July 2015 to November 2017, 50 patients (41 M, 9F), medium age (64 ± 7.4 year) were subject to 33 angioplasties (PTAs) for femoro-popliteal lesions with a paclitaxel-coated balloon (Stellarex™). Based upon clinical data sixteen patients had severe claudication (56% - Rutherford class 3); ten patients suffered from ischemic rest pain (34% - Rutherford class 4); and five presented minor tissue loss (10% - Rutherford class 5). 42% of patients showed femoro-popliteal lesion TASC-II B, and 58% presented lesions pertaining to TASC-II C. Results - Immediate technical success was 100% without perioperative complications. Primary patency rate was 94% at twelve months. In three cases restenosis (6%) was detected within a year from procedure, and a further PTA DCB was performed with primary assisted patency rates of 100% at twelve months. Two patients underwent major lower limb amputation. Three patients died during follow-up and one patient was lost at follow-up. Conclusion - DCB angioplasty with Stellarex™ is a viable alternative to traditional endovascular procedures proving satisfactory primary patency rates at twelve months. Based on our experience, treatment with DCB is a first choice technique for non-complex de novo lesions of the femoro – popliteal tract

Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

BACKGROUND: In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown. METHODS: Common and rare genetic variants in the GPR146 gene locus were used as research instruments in the UK-Biobank. The Lifelines, and The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare GPR146 variants. RESULTS: In the UK-Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease (P=0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between GPR146 gene expression and plasma lipid and liver enzyme levels. CONCLUSIONS: This study shows that carriers of new genetic GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Aspects génotypiques et phénotypiques des dyslipidémies primitives rares affectant le métabolisme des lipoprotéines riches en triglycérides

Abnormal metabolism of triglyceride-rich lipoproteins (LRTG), chylomicrons and VLDL, can result in hypocholesterolemia in case of impaired secretion, or severe hypertriglyceridemia (HTG) and increased risk of atheroma and acute pancreatitis if clearance is affected. We explored patients suffering from genetic defect in the LRTG secretion (chylomicron retention disease, abetalipoproteinemia and homozygous hypobetalipoproteinemia) and identified mutations on respectively SAR1B, and MTTP and APOB gene. Then, we analysed the phenotype of 158 previously published patients with deleterious mutation (i.e. reported cases added to our cohort) and were able to highlight some specific differences like hepatic steatosis, insulin resistance and obesity. Furthermore we developed an assay to evaluate the lipoprotein lipase (LPL) functionality by measuring the triglyceride-VLDL lipolysis in vitro, and provide a reliable phenotypic exploration for patients with past history of severe hypertriglyceridemia. We found an increased LPL activity in some patients with severe hypertriglyceridemia but conversely showed deficits in other patients free from mutation on LPL gene. These results lead to hypothesize that additional factors might contribute to modulate the expression or the activity of LPL. Finally multiple genes of triglycerides metabolism interact together to additionally modulate phenotype. Of high interest is therefore the simultaneous exploration of the key genes involved in dyslipidemia, as provided by the new generation sequencing (NGS), for better understanding of all pathophysiological mechanismsLes anomalies du métabolisme des lipoprotéines riches en triglycérides (LRTG), les chylomicrons et les VLDL exposent à des hypocholestérolémies lors d'un défaut de sécrétion et à des hypertriglycéridémies (HTG) majeures entraînant un risque athéromateux et de pancréatites aigües lors de l'altération de leur clairance. Nous avons diagnostiqué des patients présentant un défaut génétique de sécrétion des LRTG au décours de maladie de rétention des chylomicrons, d'abetalipoprotéinémie et d'hypobetalipoprotéinémie homozygote, causées respectivement par des mutations sur les gènes SAR1B, MTTP et APOB. Nous avons étudié le phénotype des 158 patients publiés avec mutation délétère et mis en évidence des différences portant principalement sur la stéatose hépatique, l'insulinorésistance et l'obésité. Nous avons également mis au point une méthode d'évaluation de l'activité post héparinique de la lipoprotéine lipase (LPL) par mesure de la lipolyse des triglycérides des VLDL in vitro, permettant l'exploration phénotypique des patients présentant une HTG sévère. Nous avons mis en évidence des activités LPL augmentées chez des patients présentant pourtant des antécédents d'HTG sévère et des déficits chez des patients ne présentant pas de mutation identifiable du gène LPL, laissant supposer l'existence de facteurs additionnels modulant l'expression ou l'activité de la LPL. Enfin des interrelations des multiples gènes impliqués dans le métabolisme des triglycérides modulent le phénotype. Elles soulèvent l'intérêt de l'exploration simultanée des principaux gènes impliqués dans les dyslipidémies, telle qu'elle sera effectuée par NGS, pour une meilleure compréhension de leur physiopathologi

Genotypic and phenotypic features of rare primitive dyslipidemias with disorder of triglyceride-rich lipoproteins metabolism

Les anomalies du métabolisme des lipoprotéines riches en triglycérides (LRTG), les chylomicrons et les VLDL exposent à des hypocholestérolémies lors d'un défaut de sécrétion et à des hypertriglycéridémies (HTG) majeures entraînant un risque athéromateux et de pancréatites aigües lors de l'altération de leur clairance. Nous avons diagnostiqué des patients présentant un défaut génétique de sécrétion des LRTG au décours de maladie de rétention des chylomicrons, d'abetalipoprotéinémie et d'hypobetalipoprotéinémie homozygote, causées respectivement par des mutations sur les gènes SAR1B, MTTP et APOB. Nous avons étudié le phénotype des 158 patients publiés avec mutation délétère et mis en évidence des différences portant principalement sur la stéatose hépatique, l'insulinorésistance et l'obésité. Nous avons également mis au point une méthode d'évaluation de l'activité post héparinique de la lipoprotéine lipase (LPL) par mesure de la lipolyse des triglycérides des VLDL in vitro, permettant l'exploration phénotypique des patients présentant une HTG sévère. Nous avons mis en évidence des activités LPL augmentées chez des patients présentant pourtant des antécédents d'HTG sévère et des déficits chez des patients ne présentant pas de mutation identifiable du gène LPL, laissant supposer l'existence de facteurs additionnels modulant l'expression ou l'activité de la LPL. Enfin des interrelations des multiples gènes impliqués dans le métabolisme des triglycérides modulent le phénotype. Elles soulèvent l'intérêt de l'exploration simultanée des principaux gènes impliqués dans les dyslipidémies, telle qu'elle sera effectuée par NGS, pour une meilleure compréhension de leur physiopathologieAbnormal metabolism of triglyceride-rich lipoproteins (LRTG), chylomicrons and VLDL, can result in hypocholesterolemia in case of impaired secretion, or severe hypertriglyceridemia (HTG) and increased risk of atheroma and acute pancreatitis if clearance is affected. We explored patients suffering from genetic defect in the LRTG secretion (chylomicron retention disease, abetalipoproteinemia and homozygous hypobetalipoproteinemia) and identified mutations on respectively SAR1B, and MTTP and APOB gene. Then, we analysed the phenotype of 158 previously published patients with deleterious mutation (i.e. reported cases added to our cohort) and were able to highlight some specific differences like hepatic steatosis, insulin resistance and obesity. Furthermore we developed an assay to evaluate the lipoprotein lipase (LPL) functionality by measuring the triglyceride-VLDL lipolysis in vitro, and provide a reliable phenotypic exploration for patients with past history of severe hypertriglyceridemia. We found an increased LPL activity in some patients with severe hypertriglyceridemia but conversely showed deficits in other patients free from mutation on LPL gene. These results lead to hypothesize that additional factors might contribute to modulate the expression or the activity of LPL. Finally multiple genes of triglycerides metabolism interact together to additionally modulate phenotype. Of high interest is therefore the simultaneous exploration of the key genes involved in dyslipidemia, as provided by the new generation sequencing (NGS), for better understanding of all pathophysiological mechanism