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Patients at high risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) would benefit from being identified before the onset of respiratory symptoms; this can be done by screening patients with the use of chest high-resolution computed tomography (HRCT). Our objective was to develop and validate a risk score for patients who have subclinical RA-ILD.Our study included a discovery population and a replication population from 2 prospective RA cohorts (ESPOIR and TRANSLATE2, respectively) without pulmonary symptoms who had received chest HRCT scans. All patients were genotyped for MUC5B rs35705950. After multiple logistic regression, a risk score based on independent risk factors for subclinical RA-ILD was developed in the discovery population and tested for validation in the replication population.The discovery population included 163 patients with RA, and the replication population included 89 patients with RA. The prevalence of subclinical RA-ILD was 19.0% and 16.9%, respectively. In the discovery population, independent risk factors for subclinical RA-ILD were presence of the MUC5B rs35705950 T allele (odds ratio [OR] 3.74 [95% confidence interval (95% CI) 1.37, 10.39]), male sex (OR 3.93 [95% CI 1.40, 11.39]), older age at RA onset (for each year, OR 1.10 [95% CI 1.04, 1.16]), and increased mean Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (for each unit, OR 2.03 [95% CI 1.24, 3.42]). We developed and validated a derived risk score with receiver operating characteristic areas under the curve of 0.82 (95% CI 0.70-0.94) for the discovery population and 0.78 (95% CI 0.65-0.92) for the replication population. Excluding MUC5B rs35705950 from the model provided a lower goodness of fit (likelihood ratio test, P = 0.01).We developed and validated a risk score that could help identify patients at high risk of subclinical RA-ILD. Our findings support an important contribution of MUC5B rs35705950 to subclinical RA-ILD risk.

Atherosclerotic cardiovascular disease is the leading cause of death globally. Despite its important risk of premature atherosclerosis and cardiovascular disease, familial hypercholesterolemia (FH) is still largely underdiagnosed worldwide. It is one of the most frequently inherited diseases due to mutations, for autosomal dominant forms, in either of the LDLR, APOB, and PCSK9 genes or possibly a few mutations in the APOE gene and, for the rare autosomal forms, in the LDLRAP1 gene. The discovery of the genes implicated in the disease has largely helped to improve the diagnosis and treatment of FH from the LDLR by Brown and Goldstein, as well as the introduction of statins, to PCSK9 discovery in FH by Abifadel et al., and the very rapid availability of PCSK9 inhibitors. In the last two decades, major progress has been made in clinical and genetic diagnostic tools and the therapeutic arsenal against FH. Improving prevention, diagnosis, and treatment and making them more accessible to all patients will help reduce the lifelong burden of the disease.

Pathogenic variant; Precision medicine; Thoracic aortic aneurysm Variante patógena; Medicina de precisión; Aneurisma de la aorta torácica Variant patògena; Medicina de precisió; Aneurisma de l'aorta toràcica Background Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes. Objectives This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene. Methods A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, and location of recruitment. Results Significant differences in aortic event risk were identified among the smooth muscle contraction genes (ACTA2, MYLK, and PRKG1; P = 0.002) and among the genes for Loeys-Dietz syndrome, which encode proteins in the transforming growth factor (TGF)-β pathway (SMAD3, TGFB2, TGFBR1, and TGFBR2; P < 0.0001). Cumulative incidence of type A aortic dissection was higher than elective aneurysm surgery in patients with variants in ACTA2, MYLK, PRKG1, and SMAD3; in contrast, patients with TGFBR2 variants had lower cumulative incidence of type A aortic dissection than elective aneurysm surgery. Cumulative incidence of type B aortic dissection was higher for ACTA2, PRKG1, and TGFBR2 than other genes. After adjusting for proband status, sex, and recruitment location, specific variants in ACTA2 and TGFBR2 were associated with substantially higher risk of aortic event with childhood onset. Conclusions Gene- and variant-specific data on aortic events in individuals with HTAD support personalized aortic surveillance and clinical management. These studies were funded by the National Institutes of Health (NIH) (NIH R01HL109942 to Dr Milewicz DMM and K23HL127266 to Dr Morris), Genetic Aortic Disorders Association Canada, Temerty Family Foundation, and the John Ritter Foundation. Dr LeMaire serves as a consultant for Terumo Aortic and Cerus; and serves as a principal investigator for clinical studies sponsored by Terumo Aortic and CytoSorbents. Dr Morris is on the scientific advisory board for vascular Ehlers Danlos syndrome clinical trial for Aytu Biopharma. Dr Regalado is an employee and shareholder of Invitae. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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Purpose: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. Methods: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. Results: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/− mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/− mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. Conclusion: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.

Background: Alirocumab, an antibody that blocks PCSK9 (proprotein convertase subtilisin/kexin type 9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). In this study, higher baseline levels of low-density lipoprotein cholesterol (LDL-C) predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. We performed post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independent of baseline LDL-C and other known risk factors, who might derive greater benefit from alirocumab treatment. Methods: ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18 924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death of CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6 579 025 genetic variants was evaluated in 11 953 patients with available DNA samples. Analysis of MACE risk was performed in placebo-treated patients, whereas treatment benefit analysis was performed in all patients. Results: The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (≤90th percentile; P P =0.004) versus a 13% reduction in the low PRS group (hazard ratio, 0.87 [95% CI, 0.78–0.98]; P =0.022; interaction P =0.04). Conclusions: A high PRS for CAD is associated with elevated risk for recurrent MACE after acute coronary syndrome and a larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.

Mutations in the fibrillin-1 (FBN1) gene are responsible for the autosomal dominant form of geleophysic dysplasia (GD), which is characterized by short stature and extremities, thick skin and cardiovascular disease. All known FBN1 mutations in patients with GD are localized within the region encoding the transforming growth factor-β binding protein-like 5 (TB5) domain of this protein. Herein, we generated a knock-in mouse model, Fbn1Y1698C by introducing the p.Tyr1696Cys mutation from a patient with GD into the TB5 domain of murine Fbn1 to elucidate the specific role of this domain in endochondral ossification. We found that both Fbn1Y1698C/+ and Fbn1Y1698C/Y1698C mice exhibited a reduced stature reminiscent of the human GD phenotype. The Fbn1 point mutation introduced in these mice affected the growth plate formation owing to abnormal chondrocyte differentiation such that mutant chondrocytes failed to establish a dense microfibrillar network composed of FBN1. This original Fbn1 mutant mouse model offers new insight into the pathogenic events underlying GD. Our findings suggest that the etiology of GD involves the dysregulation of the extracellular matrix composed of an abnormal FBN1 microfibril network impacting the differentiation of the chondrocytes.

Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease. Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of data sets on gene expression and variants in human populations. Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR . The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in nontransfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in nonalcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and 3 rare variants of one spliceosome gene, RBM25 , are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared with overexpression of wild-type RBM25 , overexpression of the 3 rare RBM25 mutants in Huh-7 cells led to lower LDL uptake. Conclusions: We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.

Background A history family of aortic dissection was considered as a risk factor for aortic dissection in patients with Marfan syndrome with a FBN1 mutation. Objectives Evaluate whether a family history of aortic dissection is a risk marker for dissection in this population Methods Retrospective study of patients coming to the reference centre between 1996 and 2018, carrying a FBN1 gene mutation. Pedigrees were obtained for each patient, and familial screening actively pursued. Patients with a family history of aortic dissection were compared with patients without family history of aortic dissection. Results 1700 patients (age 33.2 (±17) years, 51% women) with a FBN1 gene mutation were included. 145 (8,5%) patients underwent aortic dissection at a mean age of 37.9 (±11.4) years and 323 (19%) patients had been operated at 33.8 (±13.9) years. 481 patients had a family history of aortic dissection, including 38 who dissected themselves, and 88 who underwent surgery. 1219 had no family history of aortic dissection, including 107 who dissected themselves, and 235 who underwent surgery. Therefore, the personal risk for aortic dissection was similar in patients with and without a family history of aortic dissection (38/481, i.e. 7.9% vs 107/1219, i.e. 8.8%), as was the personal risk for prophylactic aortic surgery (88/481, i.e. 18.3% vs. 253/1219, i.e. 17.2%), and the risk for either aortic dissection or prophylactic aortic surgery (118/481, i.e. 24.5% vs. 328/1219, i.e. 26.9%). Conclusions In Marfan syndrome with a FBN1 gene mutation, a family history of aortic dissection is not a marker of aortic disease severity. Funding Acknowledgement Type of funding sources: None.

Marfan syndrome (MFS) is an autosomal dominant, age-related but highly penetrant condition with substantial intrafamilial and interfamilial variability. MFS is caused by pathogenetic variants in FBN1, which encodes fibrillin-1, a major structural component of the extracellular matrix that provides support to connective tissues, particularly in arteries, the pericondrium and structures in the eye. Up to 25% of individuals with MFS have de novo variants. The most prominent manifestations of MFS are asymptomatic aortic root aneurysms, aortic dissections, dislocation of the ocular lens (ectopia lentis) and skeletal abnormalities that are characterized by overgrowth of the long bones. MFS is diagnosed based on the Ghent II nosology; genetic testing confirming the presence of a FBN1 pathogenetic variant is not always required for diagnosis but can help distinguish MFS from other heritable thoracic aortic disease syndromes that can present with skeletal features similar to those in MFS. Untreated aortic root aneurysms can progress to life-threatening acute aortic dissections. Management of MFS requires medical therapy to slow the rate of growth of aneurysms and decrease the risk of dissection. Routine surveillance with imaging techniques such as transthoracic echocardiography, CT or MRI is necessary to monitor aneurysm growth and determine when to perform prophylactic repair surgery to prevent an acute aortic dissection.

Aims The COMPARE trial showed a small but significant beneficial effect of 3-year losartan treatment on aortic root dilatation rate in adults with Marfan syndrome (MFS). However, no significant effect was found on clinical endpoints, possibly due to a short follow-up period. The aim of the current study was therefore to investigate the long-term clinical outcomes after losartan treatment. Methods and results In the original COMPARE study (inclusion 2008–2009), adult patients with MFS (n = 233) were randomly allocated to either the angiotensin-II receptor blocker losartan® on top of regular treatment (β-blockers in 71% of the patients) or no additional medication. After the COMPARE trial period of 3 years, study subjects chose to continue their losartan medication or not. In a median follow-up period of 8 years, 75 patients continued losartan medication, whereas 78 patients, originally allocated to the control group, never used losartan after inclusion. No differences existed between baseline characteristics of the two groups except for age at inclusion [losartan 34 (interquartile range, IQR 26–43) years, control 41 (IQR 30–52) years; P = 0.031], and β-blocker use (losartan 81%, control 64%; P = 0.022). A pathological FBN1 mutation was present in 76% of patients and 58% of the patients were male. Clinical endpoints, defined as all-cause mortality, aortic dissection/rupture, elective aortic root replacement, reoperation, and vascular graft implantation beyond the aortic root, were compared between the two groups. A per-patient composite endpoint was also analysed. Five deaths, 14 aortic dissections, 23 aortic root replacements, 3 reoperations, and 3 vascular graft implantations beyond the aortic root occurred during follow-up. Except for aortic root replacement, all endpoints occurred in patients with an operated aortic root. Patients who used losartan during the entire follow-up period showed a reduced number of events compared to the control group (death: 0 vs. 5, P = 0.014; aortic dissection: 3 vs. 11, P = 0.013; elective aortic root replacement: 10 vs. 13, P = 0.264; reoperation: 1 vs. 2, P = 0.463; vascular graft implantations beyond the aortic root 0 vs. 3, P = 0.071; and composite endpoint: 14 vs. 26, P = 0.019). These results remained similar when corrected for age and β-blocker use in a multivariate analysis. Conclusion These results suggest a clinical benefit of combined losartan and β-blocker treatment in patients with MFS.

International audience; Purpose : Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. Methods : Two hundred twenty-six consecutive nshTAAD probands, either young (

BackgroundPathogenic variants inSMAD3cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals withSMAD3variants.MethodsAortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 uniqueSMAD3variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain.ResultsAortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals withSMAD3MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed.ConclusionsSMAD3pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlyingSMAD3variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated withSMAD3variants support gene-specific management of this disorder.

Purpose: Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLKmissense variants are pathogenic and information ...

Background The major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD. Methods Through an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline. Results Out of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern. Conclusion In this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.

Objectives To describe the agreement of self-reported medication use with claim prescription records and to ascertain factors associated with agreement between the two data sources. Methods Baseline data on self-reported medication use was extracted from CARTaGENE, a cohort study in Quebec, Canada, and from the provincial health insurance records (dispensation database) of the same individuals. Kappa statistics were used to estimate concordance beyond chance between the two data sources. Logistic regression models were adjusted to estimate the association between agreement and selected individual’s characteristics (sex, age, education, region, income, utilization of health care system, and comorbidities). Results Agreement between self-reported medication use and administrative data varied considerably across medication classes (kappa 0.54 for respiratory system and 0.91 for systemic hormonal preparations). Overall, agreement improved when a fixed time window of 90 days was used for exposure measurement. Sex, education level, frequency of health care use and the number of reported medications were associated with agreement. Discussion Overall, there was a reasonable agreement between the two data sources, but important variations were found for the different drug classes. These results could be used by researchers to more accurately assess drug exposures using real-world data, which are increasingly important to regulators.

Introduction Marfan syndrome (MFS) is a connective tissue disorder in which several systems, including cardiovascular, ophthalmological and skeletal systems, are affected with great phenotypic variability. Although known to be associated with FBN1 mutations, only few genotype-phenotype correlations have been found in probands’ studies only. Objective The clinical variability and unpredictability remain limiting factors for personalized follow-up and effective genetic counseling. The aim of this study was to provide genotype-phenotype correlations in MFS patients with FBN1 mutations. Method In 1575 consecutive MFS probands and relatives from the most comprehensive database worldwide with mutations in the FBN1 gene, we established survival curves and sought genotype-phenotype correlations. Results A risk chart could be established with clinical and genetic data. The aortic risk was greater for males, and probands were more severely affected than relatives as generally agreed. Global survival was 90% at 60 years. However, lifelong aortic event rate (either dissection or surgery) and survival were impacted by the genotype. Premature termination codon variants were not only associated with a shorter life expectancy, a high lifelong risk of aortic event (83%), but also with the highest risk of severe scoliosis (52%) and a lower risk for ectopia lentis (EL) surgery (13%). In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants (48%) ( Fig. 1 ). Conclusion This study shows that FBN1 genotype–phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs.