Publications by authors named "Christian Dina"

109 Publications

Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse.

Circ Genom Precis Med 2021 10 31;14(5):e003148. Epub 2021 Aug 31.

PARCC, Inserm, Université de Paris, F-75015, Paris, France (M.Y., S.K., X.J., N.B.-N.).

Background: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study has identified 6 risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding data set from the UK Biobank.

Methods: We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used Functional Mapping and Annotation of Genome-Wide Association Studies for post-genome-wide association study annotations and Multi-marker Analysis of GenoMic Annotation for gene-based and gene-set analyses.

Results: We found Trans-Omics for Precision Medicine imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near . We identified an additional risk locus on Chr1 () and 2 suggestive risk loci on chr8 () and chr19 (), all driven by common variants. Gene-based association using Multi-marker Analysis of GenoMic Annotation revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development.

Conclusions: We report an updated meta-analysis genome-wide association study for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530910PMC
October 2021

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 () with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

J Am Soc Nephrol 2021 10 14;32(10):2634-2651. Epub 2021 Jul 14.

Research Division, Joslin Diabetes Center, Boston, Massachusetts.

Background: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage.

Methods: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models.

Results: Protein coding variants in the hydroxysteroid 17- dehydrogenase 14 gene (), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (=4196; value=3.3 × 10). The gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies.

Conclusions: gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2020101457DOI Listing
October 2021

Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome.

Eur Heart J 2021 07;42(29):2854-2863

Omics Research Center, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita 5648565, Japan.

Aims: The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability.

Methods And Results: Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves.

Conclusion: In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehab254DOI Listing
July 2021

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Nat Genet 2020 12 16;52(12):1303-1313. Epub 2020 Nov 16.

Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00725-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116530PMC
December 2020

Genetic and In Vitro Inhibition of and Calcific Aortic Valve Stenosis.

JACC Basic Transl Sci 2020 Jul 1;5(7):649-661. Epub 2020 Jul 1.

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada.

The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p = 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacbts.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393433PMC
July 2020

Lipoprotein-associated phospholipase A2 activity, genetics and calcific aortic valve stenosis in humans.

Heart 2020 09 7;106(18):1407-1412. Epub 2020 Jul 7.

Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec city, Québec, Canada

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans.

Methods And Results: Lp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at the locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351).

Conclusions: Higher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/heartjnl-2020-316722DOI Listing
September 2020

Correction: The genetic history of France.

Eur J Hum Genet 2020 Jul;28(7):988

Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-020-0604-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316808PMC
July 2020

Genetic Association Analyses Highlight , , and As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis.

Circ Genom Precis Med 2019 10 15;12(10):e002617. Epub 2019 Oct 15.

l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France (C.D., S.L.S., R.C., S.R., F.S., A.-S.B., S.L., E.B., S.B., M.K., E.C., I.F., J.-C.R., V.P., R. Redon, T.L.T., J.-J.S.).

Background: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, and , have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS.

Methods: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits.

Results: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: (interleukin 6) on 7p15.3 and (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the locus. The signal identified colocalizes with the expression of the RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors.

Conclusions: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.119.002617DOI Listing
October 2019

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

The genetic history of France.

Eur J Hum Genet 2020 07 10;28(7):853-865. Epub 2020 Feb 10.

Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France.

The study of the genetic structure of different countries within Europe has provided significant insights into their demographic history and population structure. Although France occupies a particular location at the western part of Europe and at the crossroads of migration routes, few population genetic studies have been conducted so far with genome-wide data. In this study, we analyzed SNP-chip genetic data from 2184 individuals born in France who were enrolled in two independent population cohorts. Using FineSTRUCTURE, six different genetic clusters of individuals were found that were very consistent between the two cohorts. These clusters correspond closely to geographic, historical, and linguistic divisions of France, and contain different proportions of ancestry from Stone and Bronze Age populations. By modeling the relationship between genetics and geography using EEMS, we were able to detect gene flow barriers that are similar across the two cohorts and correspond to major rivers and mountain ranges. Estimations of effective population sizes also revealed very similar patterns in both cohorts with a rapid increase of effective population sizes over the last 150 generations similar to other European countries. A marked bottleneck is also consistently seen in the two datasets starting in the 14 century when the Black Death raged in Europe. In conclusion, by performing the first exhaustive study of the genetic structure of France, we fill a gap in genetic studies of Europe that will be useful to medical geneticists, historians, and archeologists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-020-0584-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316781PMC
July 2020

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Nat Genet 2019 08 15;51(8):1207-1214. Epub 2019 Jul 15.

Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%. Mortality rates are higher than those in other psychiatric disorders, and outcomes are unacceptably poor. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0439-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779477PMC
August 2019

Genetic Variation in LPA, Calcific Aortic Valve Stenosis in Patients Undergoing Cardiac Surgery, and Familial Risk of Aortic Valve Microcalcification.

JAMA Cardiol 2019 07;4(7):620-627

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, Québec, Canada.

Importance: Genetic variants at the LPA locus are associated with both calcific aortic valve stenosis (CAVS) and coronary artery disease (CAD). Whether these variants are associated with CAVS in patients with CAD vs those without CAD is unknown.

Objective: To study the associations of LPA variants with CAVS in a cohort of patients undergoing heart surgery and LPA with CAVS in patients with CAD vs those without CAD and to determine whether first-degree relatives of patients with CAVS and high lipoprotein(a) (Lp[a]) levels showed evidence of aortic valve microcalcification.

Design, Setting, And Participants: This genetic association study included patients undergoing cardiac surgery from the Genome-Wide Association Study on Calcific Aortic Valve Stenosis in Quebec (QUEBEC-CAVS) study and patients with CAD, patients without CAD, and control participants from 6 genetic association studies: the UK Biobank, the European Prospective Investigation of Cancer (EPIC)-Norfolk, and Genetic Epidemiology Research on Aging (GERA) studies and 3 French cohorts. In addition, a family study included first-degree relatives of patients with CAVS. Data were collected from January 1993 to September 2018, and analysis was completed from September 2017 to September 2018.

Exposures: Case-control studies.

Main Outcomes And Measures: Presence of CAVS according to a weighted genetic risk score based on 3 common Lp(a)-raising variants and aortic valve microcalcification, defined as the mean tissue to background ratio of 1.25 or more, measured by fluorine 18-labeled sodium fluoride positron emission tomography/computed tomography.

Results: This study included 1009 individuals undergoing cardiac surgery and 1017 control participants in the QUEBEC-CAVS cohort; 3258 individuals with CAVS and CAD, 41 100 controls with CAD, 2069 individuals with CAVS without CAD, and 380 075 control participants without CAD in the UK Biobank, EPIC-Norfolk, and GERA studies and 3 French cohorts combined; and 33 first-degree relatives of 17 patients with CAVS and high Lp(a) levels (≥60 mg/dL) and 23 control participants with normal Lp(a) levels (<60 mg/dL). In the QUEBEC-CAVS study, each SD increase of the genetic risk score was associated with a higher risk of CAVS (odds ratio [OR], 1.35 [95% CI, 1.10-1.66]; P = .003). Each SD increase of the genetic risk score was associated with a higher risk of CAVS in patients with CAD (OR, 1.30 [95% CI, 1.20-1.42]; P < .001) and without CAD (OR, 1.33 [95% CI, 1.14-1.55]; P < .001). The percentage of individuals with a tissue to background ratio of 1.25 or more or CAVS was higher in first-degree relatives of patients with CAVS and high Lp(a) (16 of 33 [49%]) than control participants (3 of 23 [13%]; P = .006).

Conclusions And Relevance: In this study, a genetically elevated Lp(a) level was associated with CAVS independently of the presence of CAD. These findings support further research on the potential usefulness of Lp(a) cascade screening in CAVS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2019.1581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547086PMC
July 2019

Primary cilia defects causing mitral valve prolapse.

Sci Transl Med 2019 05;11(493)

Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, 185 Cambridge St., Boston, MA 02114, USA.

Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the causes of this disease are poorly understood. We now demonstrate that defects in primary cilia genes and their regulated pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene, A mouse model harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with MVP and controls from previously generated genome-wide association studies (GWAS), which confirmed the involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP through altered cilia-dependent regulation of ECM and suggest that defects in primary cilia genes can be causative to disease phenotype in some patients with MVP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aax0290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331025PMC
May 2019

RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome.

Eur Heart J 2019 10;40(37):3081-3094

Division of Cardiovascular Medicine, Department of Medicine, Stanford Cardiovascular Institute, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Aims: The Brugada syndrome (BrS) is an inherited cardiac disorder predisposing to ventricular arrhythmias. Despite considerable efforts, its genetic basis and cellular mechanisms remain largely unknown. The objective of this study was to identify a new susceptibility gene for BrS through familial investigation.

Methods And Results: Whole-exome sequencing performed in a three-generation pedigree with five affected members allowed the identification of one rare non-synonymous substitution (p.R211H) in RRAD, the gene encoding the RAD GTPase, carried by all affected members of the family. Three additional rare missense variants were found in 3/186 unrelated index cases. We detected higher levels of RRAD transcripts in subepicardium than in subendocardium in human heart, and in the right ventricle outflow tract compared to the other cardiac compartments in mice. The p.R211H variant was then subjected to electrophysiological and structural investigations in human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs). Cardiomyocytes derived from induced pluripotent stem cells from two affected family members exhibited reduced action potential upstroke velocity, prolonged action potentials and increased incidence of early afterdepolarizations, with decreased Na+ peak current amplitude and increased Na+ persistent current amplitude, as well as abnormal distribution of actin and less focal adhesions, compared with intra-familial control iPSC-CMs Insertion of p.R211H-RRAD variant in control iPSCs by genome editing confirmed these results. In addition, iPSC-CMs from affected patients exhibited a decreased L-type Ca2+ current amplitude.

Conclusion: This study identified a potential new BrS-susceptibility gene, RRAD. Cardiomyocytes derived from induced pluripotent stem cells expressing RRAD variant recapitulated single-cell electrophysiological features of BrS, including altered Na+ current, as well as cytoskeleton disturbances.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehz308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769825PMC
October 2019

Genome-Wide Association Study-Driven Gene-Set Analyses, Genetic, and Functional Follow-Up Suggest GLIS1 as a Susceptibility Gene for Mitral Valve Prolapse.

Circ Genom Precis Med 2019 05;12(5):e002497

INSERM, UMR970, Paris Cardiovascular Research Center, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.).

Background Mitral valve prolapse (MVP) is a common heart valve disease, the most frequent indication for valve repair or replacement. MVP is characterized by excess extracellular matrix secretion and cellular disorganization, which leads to bulky valves that are unable to coapt correctly during ventricular systole resulting in mitral regurgitation, and it is associated with sudden cardiac death. Here we aim to characterize globally the biological mechanisms underlying genetic susceptibility to MVP to better characterize its triggering mechanisms. Methods We applied i-GSEA4GWAS and DEPICT, two pathway enrichment tools to MVP genome-wide association studies. We followed-up the association with MVP in an independent dataset of cases and controls. This research was conducted using the UK Biobank Resource. Immunohistochemistry staining for Glis1 (GLIS family zinc finger 1) was conducted in developing heart of mice. Knockdown of Glis1 using morpholinos was performed in zebrafish animals 72 hours postfertilization. Results We show that genes at risk loci are involved in biological functions relevant to actin filament organization, cytoskeleton biology, and cardiac development. The enrichment for positive regulation of transcription, cell proliferation, and migration motivated the follow-up of GLIS1, a transcription factor from the Krüppel-like zinc finger family. In combination with previously available data, we now report a genome-wide significant association with MVP (odds ratio, 1.20; P=4.36×10), indicating that Glis1 is expressed during embryonic development predominantly in nuclei of endothelial and interstitial cells of mitral valves in mouse. We also show that Glis1 knockdown causes atrioventricular regurgitation in developing hearts in zebrafish. Conclusions Our findings define globally molecular and cellular mechanisms underlying common genetic susceptibility to MVP and implicate established and unprecedented mechanisms. Through the GLIS1 association and function, we point at regulatory functions during cardiac development as common mechanisms to mitral valve degeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.119.002497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532425PMC
May 2019

The impact of a fine-scale population stratification on rare variant association test results.

PLoS One 2018 6;13(12):e0207677. Epub 2018 Dec 6.

INSERM, CNRS, UNIV Nantes, l'institut du thorax, Nantes, France.

Population stratification is a well-known confounding factor in both common and rare variant association analyses. Rare variants tend to be more geographically clustered than common variants, because of their more recent origin. However, it is not yet clear if population stratification at a very fine scale (neighboring administrative regions within a country) would lead to statistical bias in rare variant analyses. As the inclusion of convenience controls from external studies is indeed a common procedure, in order to increase the power to detect genetic associations, this problem is important. We studied through simulation the impact of a fine scale population structure on different rare variant association strategies, assessing type I error and power. We showed that principal component analysis (PCA) based methods of adjustment for population stratification adequately corrected type I error inflation at the largest geographical scales, but not at finest scales. We also showed in our simulations that adding controls obviously increased power, but at a considerably lower level when controls were drawn from another population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207677PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283567PMC
May 2019

SMMB: a stochastic Markov blanket framework strategy for epistasis detection in GWAS.

Bioinformatics 2018 08;34(16):2773-2780

European Genomic Institute for Diabetes FR3508, Centre National de la Recherche Scientifique UMR 8199, Lille 2 University, Lille, France.

Motivation: Large scale genome-wide association studies (GWAS) are tools of choice for discovering associations between genotypes and phenotypes. To date, many studies rely on univariate statistical tests for association between the phenotype and each assayed single nucleotide polymorphism (SNP). However, interaction between SNPs, namely epistasis, must be considered when tackling the complexity of underlying biological mechanisms. Epistasis analysis at large scale entails a prohibitive computational burden when addressing the detection of more than two interacting SNPs. In this paper, we introduce a stochastic causal graph-based method, SMMB, to analyze epistatic patterns in GWAS data.

Results: We present Stochastic Multiple Markov Blanket algorithm (SMMB), which combines both ensemble stochastic strategy inspired from random forests and Bayesian Markov blanket-based methods. We compared SMMB with three other recent algorithms using both simulated and real datasets. Our method outperforms the other compared methods for a majority of simulated cases of 2-way and 3-way epistasis patterns (especially in scenarii where minor allele frequencies of causal SNPs are low). Our approach performs similarly as two other compared methods for large real datasets, in terms of power, and runs faster.

Availability And Implementation: Parallel version available on https://ls2n.fr/listelogicielsequipe/DUKe/128/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/bty154DOI Listing
August 2018

Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm.

Am J Hum Genet 2018 01;102(1):133-141

INSERM, CNRS, UNIV Nantes, l'institut du thorax, 44007 Nantes, France; CHU Nantes, l'institut du thorax, 44093 Nantes, France. Electronic address:

Intracranial aneurysms (IAs) are acquired cerebrovascular abnormalities characterized by localized dilation and wall thinning in intracranial arteries, possibly leading to subarachnoid hemorrhage and severe outcome in case of rupture. Here, we identified one rare nonsense variant (c.1378A>T) in the last exon of ANGPTL6 (Angiopoietin-Like 6)-which encodes a circulating pro-angiogenic factor mainly secreted from the liver-shared by the four tested affected members of a large pedigree with multiple IA-affected case subjects. We showed a 50% reduction of ANGPTL6 serum concentration in individuals heterozygous for the c.1378A>T allele (p.Lys460Ter) compared to relatives homozygous for the normal allele, probably due to the non-secretion of the truncated protein produced by the c.1378A>T transcripts. Sequencing ANGPTL6 in a series of 94 additional index case subjects with familial IA identified three other rare coding variants in five case subjects. Overall, we detected a significant enrichment (p = 0.023) in rare coding variants within this gene among the 95 index case subjects with familial IA, compared to a reference population of 404 individuals with French ancestry. Among the 6 recruited families, 12 out of 13 (92%) individuals carrying IA also carry such variants in ANGPTL6, versus 15 out of 41 (37%) unaffected ones. We observed a higher rate of individuals with a history of high blood pressure among affected versus healthy individuals carrying ANGPTL6 variants, suggesting that ANGPTL6 could trigger cerebrovascular lesions when combined with other risk factors such as hypertension. Altogether, our results indicate that rare coding variants in ANGPTL6 are causally related to familial forms of IA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2017.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778084PMC
January 2018

Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.

Lancet Neurol 2017 11;16(11):898-907

Center for Restless Legs Study, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

Background: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets.

Methods: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest.

Findings: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1).

Interpretation: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations.

Funding: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(17)30327-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755468PMC
November 2017

New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study.

Eur Heart J 2018 04;39(15):1269-1277

l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.

Aims: Filamin-A (FLNA) was identified as the first gene of non-syndromic mitral valve dystrophy (FLNA-MVD). We aimed to assess the phenotype of FLNA-MVD and its impact on prognosis.

Methods And Results: We investigated the disease in 246 subjects (72 mutated) from four FLNA-MVD families harbouring three different FLNA mutations. Phenotype was characterized by a comprehensive echocardiography focusing on mitral valve apparatus in comparison with control relatives. In this X-linked disease valves lesions were severe in men and moderate in women. Most men had classical features of mitral valve prolapse (MVP), but without chordal rupture. By contrast to regular MVP, mitral leaflet motion was clearly restricted in diastole and papillary muscles position was closer to mitral annulus. Valvular abnormalities were similar in the four families, in adults and young patients from early childhood suggestive of a developmental disease. In addition, mitral valve lesions worsened over time as encountered in degenerative conditions. Polyvalvular involvement was frequent in males and non-diagnostic forms frequent in females. Overall survival was moderately impaired in men (P = 0.011). Cardiac surgery rate (mainly valvular) was increased (33.3 ± 9.8 vs. 5.0 ± 4.9%, P < 0.0001; hazard ratio 10.5 [95% confidence interval: 2.9-37.9]) owing mainly to a lifetime increased risk in men (76.8 ± 14.1 vs. 9.1 ± 8.7%, P < 0.0001).

Conclusion: FLNA-MVD is a developmental and degenerative disease with complex phenotypic expression which can influence patient management. FLNA-MVD has unique features with both MVP and paradoxical restricted motion in diastole, sub-valvular mitral apparatus impairment and polyvalvular lesions in males. FLNA-MVD conveys a substantial lifetime risk of valve surgery in men.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehx505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905589PMC
April 2018

DoEstRare: A statistical test to identify local enrichments in rare genomic variants associated with disease.

PLoS One 2017 24;12(7):e0179364. Epub 2017 Jul 24.

INSERM, CNRS, UNIV Nantes, l'institut du thorax, Nantes, France.

Next-generation sequencing technologies made it possible to assay the effect of rare variants on complex diseases. As an extension of the "common disease-common variant" paradigm, rare variant studies are necessary to get a more complete insight into the genetic architecture of human traits. Association studies of these rare variations show new challenges in terms of statistical analysis. Due to their low frequency, rare variants must be tested by groups. This approach is then hindered by the fact that an unknown proportion of the variants could be neutral. The risk level of a rare variation may be determined by its impact but also by its position in the protein sequence. More generally, the molecular mechanisms underlying the disease architecture may involve specific protein domains or inter-genic regulatory regions. While a large variety of methods are optimizing functionality weights for each single marker, few evaluate variant position differences between cases and controls. Here, we propose a test called DoEstRare, which aims to simultaneously detect clusters of disease risk variants and global allele frequency differences in genomic regions. This test estimates, for cases and controls, variant position densities in the genetic region by a kernel method, weighted by a function of allele frequencies. We compared DoEstRare with previously published strategies through simulation studies as well as re-analysis of real datasets. Based on simulation under various scenarios, DoEstRare was the sole to consistently show highest performance, in terms of type I error and power both when variants were clustered or not. DoEstRare was also applied to Brugada syndrome and early-onset Alzheimer's disease data and provided complementary results to other existing tests. DoEstRare, by integrating variant position information, gives new opportunities to explain disease susceptibility. DoEstRare is implemented in a user-friendly R package.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179364PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524342PMC
September 2017

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

Diabetes 2017 11 31;66(11):2888-2902. Epub 2017 May 31.

MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci ( < 5 × 10), including variants near the , , and genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db16-1253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652602PMC
November 2017

Dysfunction of the Voltage-Gated K+ Channel β2 Subunit in a Familial Case of Brugada Syndrome.

J Am Heart Assoc 2016 06 10;5(6). Epub 2016 Jun 10.

INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France

Background: The Brugada syndrome is an inherited cardiac arrhythmia associated with high risk of sudden death. Although 20% of patients with Brugada syndrome carry mutations in SCN5A, the molecular mechanisms underlying this condition are still largely unknown.

Methods And Results: We combined whole-exome sequencing and linkage analysis to identify the genetic variant likely causing Brugada syndrome in a pedigree for which SCN5A mutations had been excluded. This approach identified 6 genetic variants cosegregating with the Brugada electrocardiographic pattern within the pedigree. In silico gene prioritization pointed to 1 variant residing in KCNAB2, which encodes the voltage-gated K(+) channel β2-subunit (Kvβ2-R12Q). Kvβ2 is widely expressed in the human heart and has been shown to interact with the fast transient outward K(+) channel subunit Kv4.3, increasing its current density. By targeted sequencing of the KCNAB2 gene in 167 unrelated patients with Brugada syndrome, we found 2 additional rare missense variants (L13F and V114I). We then investigated the physiological effects of the 3 KCNAB2 variants by using cellular electrophysiology and biochemistry. Patch-clamp experiments performed in COS-7 cells expressing both Kv4.3 and Kvβ2 revealed a significant increase in the current density in presence of the R12Q and L13F Kvβ2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kvβ2-R12Q were significantly increased in comparison with wild-type Kvβ2.

Conclusions: Altogether, our results indicate that Kvβ2 dysfunction can contribute to the Brugada electrocardiographic pattern.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.115.003122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937261PMC
June 2016

Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I.

Int J Cardiol 2016 Mar 11;207:349-58. Epub 2016 Jan 11.

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, l'institut du thorax, Nantes, France; Centre National de la Recherche Scientifique (CNRS) UMR 6291, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) de Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France. Electronic address:

Background: Progressive cardiac conduction disease (PCCD) is one of the most common cardiac conduction disturbances. It has been causally related to rare mutations in several genes including SCN5A, SCN1B, TRPM4, LMNA and GJA5.

Methods And Results: In this study, by applying targeted next-generation sequencing (NGS) in 95 unrelated patients with PCCD, we have identified 13 rare variants in the TRPM4 gene, two of which are currently absent from public databases. This gene encodes a cardiac calcium-activated cationic channel which precise role and importance in cardiac conduction and disease is still debated. One novel variant, TRPM4-p.I376T, is carried by the proband of a large French 4-generation pedigree. Systematic familial screening showed that a total of 13 family members carry the mutation, including 10 out of the 11 tested affected individuals versus only 1 out of the 21 unaffected ones. Functional and biochemical analyses were performed using HEK293 cells, in whole-cell patch-clamp configuration and Western blotting. TRPM4-p.I376T results in an increased current density concomitant to an augmented TRPM4 channel expression at the cell surface.

Conclusions: This study is the first extensive NGS-based screening of TRPM4 coding variants in patients with PCCD. It reports the third largest pedigree diagnosed with isolated Progressive Familial Heart Block type I and confirms that this subtype of PCCD is caused by mutation-induced gain-of-expression and function of the TRPM4 ion channel.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2016.01.052DOI Listing
March 2016

De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability.

Hum Mutat 2016 Apr 4;37(4):354-8. Epub 2016 Feb 4.

Inserm, UMR 1087, l'institut du thorax, CHU Nantes, Nantes, France.

A rare syndromic form of intellectual disability with impaired speech was recently found associated with mutations in CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), the protein product of which is directly involved in microtubule-kinetochore attachment. Through whole-exome sequencing in six unrelated nonconsanguineous families having a sporadic case of intellectual disability, we identified six novel de novo truncating mutations in CHAMP1: c.1880C>G p.(Ser627*), c.1489C>T; p.(Arg497*), c.1876_1877delAG; p.(Ser626Leufs*4), c.1043G>A; p.(Trp348*), c.1002G>A; p.(Trp334*), and c.958_959delCC; p.(Pro320*). Our clinical observations confirm the phenotypic homogeneity of the syndrome, which represents therefore a distinct clinical entity. Besides, our functional studies show that CHAMP1 protein variants are delocalized from chromatin and are unable to bind to two of its direct partners, POGZ and HP1. These data suggest a pathogenic mechanism of the CHAMP1-associated intellectual disability syndrome mediated by direct interacting partners of CHAMP1, several of which are involved in chromo/kinetochore-related disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22952DOI Listing
April 2016

Utilizing the Jaccard index to reveal population stratification in sequencing data: a simulation study and an application to the 1000 Genomes Project.

Bioinformatics 2016 05 31;32(9):1366-72. Epub 2015 Dec 31.

Institute of Genomic Mathematics, University of Bonn, Bonn, Germany, Department of Biostatistics, Harvard School of Public Health, Boston, USA.

Motivation: Population stratification is one of the major sources of confounding in genetic association studies, potentially causing false-positive and false-negative results. Here, we present a novel approach for the identification of population substructure in high-density genotyping data/next generation sequencing data. The approach exploits the co-appearances of rare genetic variants in individuals. The method can be applied to all available genetic loci and is computationally fast. Using sequencing data from the 1000 Genomes Project, the features of the approach are illustrated and compared to existing methodology (i.e. EIGENSTRAT). We examine the effects of different cutoffs for the minor allele frequency on the performance of the approach. We find that our approach works particularly well for genetic loci with very small minor allele frequencies. The results suggest that the inclusion of rare-variant data/sequencing data in our approach provides a much higher resolution picture of population substructure than it can be obtained with existing methodology. Furthermore, in simulation studies, we find scenarios where our method was able to control the type 1 error more precisely and showed higher power.

Availability And Implementation:

Contact: [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btv752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860507PMC
May 2016

Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta.

Circ Cardiovasc Genet 2016 Feb 7;9(1):86-94. Epub 2015 Dec 7.

Background: Congenital heart defects are the most frequent malformations among newborns and a frequent cause of morbidity and mortality. Although genetic variation contributes to congenital heart defects, their precise molecular bases remain unknown in the majority of patients.

Methods And Results: We analyzed, by high-resolution array comparative genomic hybridization, 316 children with sporadic, nonsyndromic congenital heart defects, including 76 coarctation of the aorta, 159 transposition of the great arteries, and 81 tetralogy of Fallot, as well as their unaffected parents. We identified by array comparative genomic hybridization, and validated by quantitative real-time polymerase chain reaction, 71 rare de novo (n=8) or inherited (n=63) copy-number variants (CNVs; 50 duplications and 21 deletions) in patients. We identified 113 candidate genes for congenital heart defects within these CNVs, including BTRC, CHRNB3, CSRP2BP, ERBB2, ERMARD, GLIS3, PLN, PTPRJ, RLN3, and TCTE3. No de novo CNVs were identified in patients with transposition of the great arteries in contrast to coarctation of the aorta and tetralogy of Fallot (P=0.002; Fisher exact test). A search for transcription factor binding sites showed that 93% of the rare CNVs identified in patients with coarctation of the aorta contained at least 1 gene with FOXC1-binding sites. This significant enrichment (P<0.0001; permutation test) was not observed for the CNVs identified in patients with transposition of the great arteries and tetralogy of Fallot. We hypothesize that these CNVs may alter the expression of genes regulated by FOXC1. Foxc1 belongs to the forkhead transcription factors family, which plays a critical role in cardiovascular development in mice.

Conclusions: These data suggest that deregulation of FOXC1 or its downstream genes play a major role in the pathogenesis of coarctation of the aorta in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGENETICS.115.001213DOI Listing
February 2016

Staphylokinase and ABO group phenotype: new players in Staphylococcus aureus implant-associated infections development.

Future Microbiol 2015 23;10(12):1929-38. Epub 2015 Nov 23.

Laboratoire UPRES EA3826, Thérapeutiques cliniques et expérimentales des infections - Nantes Medicine school, France.

Aim: To identify bacterial and/or clinical features involved in the pathogenesis of Staphylococcus aureus implant-associated infections (IAI).

Materials & Methods: In total, 57 IAI S. aureus and 31 nasal carriage (NC) S. aureus isolates were studied. Staphylococcus aureus genetic background was obtained by microarray analysis. Multilocus sequence typing was performed to determine clonal complexes (CC). Biofilm production was investigated by resazurin and crystal violet methods.

Results: Staphylokinase gene was associated with the occurrence of S. aureus IAI. Patients' ABO blood group phenotype was associated with IAI S. aureus genetic background. CC8 S. aureus strains produce more biofilm than others and carry particular alleles of bbp gene.

Conclusion: This study identifies some predictive markers for S. aureus IAI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fmb.15.112DOI Listing
September 2016
-->