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1. Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk.

Author

Tobias, Deirdre K, Manning, Alisa K, Wessel, Jennifer, Raghavan, Sridharan, Westerman, Kenneth E, Bick, Alexander G, Dicorpo, Daniel, Whitsel, Eric A, Collins, Jason, Correa, Adolfo, Cupples, L Adrienne, Dupuis, Josée, Goodarzi, Mark O, Guo, Xiuqing, Howard, Barbara, Lange, Leslie A, Liu, Simin, Raffield, Laura M, Reiner, Alex P, Rich, Stephen S, Taylor, Kent D, Tinker, Lesley, Wilson, James G, Wu, Peitao, Carson, April P, Vasan, Ramachandran S, Fornage, Myriam, Psaty, Bruce M, Kooperberg, Charles, Rotter, Jerome I, Meigs, James, and Manson, JoAnn E

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Prevention, Cardiovascular, Precision Medicine, Stem Cell Research, Diabetes, Heart Disease, Hematology, Aging, Obesity, Genetics, 2.1 Biological and endogenous factors, Cancer, Metabolic and endocrine, Good Health and Well Being, Humans, Female, Middle Aged, Male, Clonal Hematopoiesis, Diabetes Mellitus, Type 2, Prospective Studies, Hematopoiesis, Clonal Evolution, Coronary Disease, Mutation, TOPMed Diabetes Working Group and National Heart, Lung, and Blood Institute TOPMed Consortium
Abstract

ObjectiveClonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D.Research design and methodsCHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis.ResultsMean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI 1.05, 2.08) and ASXL1 (HR 1.76; CI 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses.ConclusionsCHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

Published
2023

2. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

Palmer, Elizabeth, Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew, Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogné, Benjamin, Beneteau, Claire, Alkuraya, Fowzan, Chedrawi, Aziza, Hashem, Mais, Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stéphanie, Raynaud, Martine, Motter, Constance, Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias, Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda, Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Bénédicte, Abi Warde, Marie-Thérèse, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer, Sands, Tristan, Wilson, Golder, Silvertooth, Erin, Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein, Ockeloen, Charlotte, Pfundt, Rolph, Kroft, Sanne, Field, Michael, Laranjeira, Francisco, Fortuna, Ana, Soares, Ana, Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David, Bird, Lynne, Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Pölsler, Laura, Campeau, Philippe, Blazo, Maria, Bijlsma, Emilia, Rosenfeld, Jill, Beetz, Christian, Powis, Zöe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikaël, Mohammad, Shekeeb, Armstrong, Ruth, and Kalscheuer, Vera

Subjects
Male, Female, Humans, Neurodevelopmental Disorders, Mutation, Missense, Genes, X-Linked, Phenotype, Chloride Channels
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a shift of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

3. Widening of the genetic and clinical spectrum of Lamb–Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Author

Zawerton, Ash, Mignot, Cyril, Sigafoos, Ashley, Blackburn, Patrick R, Haseeb, Abdul, McWalter, Kirsty, Ichikawa, Shoji, Nava, Caroline, Keren, Boris, Charles, Perrine, Marey, Isabelle, Tabet, Anne-Claude, Levy, Jonathan, Perrin, Laurence, Hartmann, Andreas, Lesca, Gaetan, Schluth-Bolard, Caroline, Monin, Pauline, Dupuis-Girod, Sophie, Guillen Sacoto, Maria J, Schnur, Rhonda E, Zhu, Zehua, Poisson, Alice, El Chehadeh, Salima, Alembik, Yves, Bruel, Ange-Line, Lehalle, Daphné, Nambot, Sophie, Moutton, Sébastien, Odent, Sylvie, Jaillard, Sylvie, Dubourg, Christèle, Hilhorst-Hofstee, Yvonne, Barbaro-Dieber, Tina, Ortega, Lucia, Bhoj, Elizabeth J, Masser-Frye, Diane, Bird, Lynne M, Lindstrom, Kristin, Ramsey, Keri M, Narayanan, Vinodh, Fassi, Emily, Willing, Marcia, Cole, Trevor, Salter, Claire G, Akilapa, Rhoda, Vandersteen, Anthony, Canham, Natalie, Rump, Patrick, Gerkes, Erica H, Klein Wassink-Ruiter, Jolien S, Bijlsma, Emilia, Hoffer, Mariëtte JV, Vargas, Marcelo, Wojcik, Antonina, Cherik, Florian, Francannet, Christine, Rosenfeld, Jill A, Machol, Keren, Scott, Daryl A, Bacino, Carlos A, Wang, Xia, Clark, Gary D, Bertoli, Marta, Zwolinski, Simon, Thomas, Rhys H, Akay, Ela, Chang, Richard C, Bressi, Rebekah, Sanchez Russo, Rossana, Srour, Myriam, Russell, Laura, Goyette, Anne-Marie E, Dupuis, Lucie, Mendoza-Londono, Roberto, Karimov, Catherine, Joseph, Maries, Nizon, Mathilde, Cogné, Benjamin, Kuechler, Alma, Piton, Amélie, Klee, Eric W, Lefebvre, Véronique, Clark, Karl J, and Depienne, Christel

Subjects
Intellectual and Developmental Disabilities (IDD), Pediatric, Genetics, Brain Disorders, Clinical Research, Rare Diseases, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Animals, Child, Child, Preschool, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Haploinsufficiency, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Mutation, Missense, Neurodevelopmental Disorders, Pedigree, Phenotype, SOXD Transcription Factors, Young Adult, autism, developmental delay, intellectual disability, epilepsy, missense variants, Deciphering Developmental DisorderStudy, missense variants., Clinical Sciences, Genetics & Heredity
Abstract

PurposeLamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.MethodsClinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated.ResultsMicrodeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.ConclusionsThis study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

Published
2020

4. Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance

Author

Asano, Takaki, Khourieh, Joëlle, Zhang, Peng, Rapaport, Franck, Spaan, András N, Li, Juan, Lei, Wei-Te, Pelham, Simon J, Hum, David, Chrabieh, Maya, Han, Ji Eun, Guérin, Antoine, Mackie, Joseph, Gupta, Sudhir, Saikia, Biman, Baghdadi, Jamila EI, Fadil, Ilham, Bousfiha, Aziz, Habib, Tanwir, Marr, Nico, Ganeshanandan, Luckshman, Peake, Jane, Droney, Luke, Williams, Andrew, Celmeli, Fatih, Hatipoglu, Nevin, Ozcelik, Tayfun, Picard, Capucine, Abel, Laurent, Tangye, Stuart G, Boisson-Dupuis, Stéphanie, Zhang, Qian, Puel, Anne, Béziat, Vivien, Casanova, Jean-Laurent, and Boisson, Bertrand

Subjects
Rare Diseases, Genetics, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Alleles, Alternative Splicing, Child, Child, Preschool, Codon, Nonsense, Evolution, Molecular, Family, Female, Frameshift Mutation, Genes, Dominant, Genetics, Population, HEK293 Cells, Humans, Infant, Infant, Newborn, Job Syndrome, Male, Middle Aged, Mutation, Pedigree, Protein Biosynthesis, RNA, Messenger, STAT3 Transcription Factor, Medical and Health Sciences, Immunology
Abstract

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.

Published
2021

5. Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations.

Author

Haslam, Danielle E, Peloso, Gina M, Guirette, Melanie, Imamura, Fumiaki, Bartz, Traci M, Pitsillides, Achilleas N, Wang, Carol A, Li-Gao, Ruifang, Westra, Jason M, Pitkänen, Niina, Young, Kristin L, Graff, Mariaelisa, Wood, Alexis C, Braun, Kim VE, Luan, Jian'an, Kähönen, Mika, Kiefte-de Jong, Jessica C, Ghanbari, Mohsen, Tintle, Nathan, Lemaitre, Rozenn N, Mook-Kanamori, Dennis O, North, Kari, Helminen, Mika, Mossavar-Rahmani, Yasmin, Snetselaar, Linda, Martin, Lisa W, Viikari, Jorma S, Oddy, Wendy H, Pennell, Craig E, Rosendall, Frits R, Ikram, M Arfan, Uitterlinden, Andre G, Psaty, Bruce M, Mozaffarian, Dariush, Rotter, Jerome I, Taylor, Kent D, Lehtimäki, Terho, Raitakari, Olli T, Livingston, Kara A, Voortman, Trudy, Forouhi, Nita G, Wareham, Nick J, de Mutsert, Renée, Rich, Steven S, Manson, JoAnn E, Mora, Samia, Ridker, Paul M, Merino, Jordi, Meigs, James B, Dashti, Hassan S, Chasman, Daniel I, Lichtenstein, Alice H, Smith, Caren E, Dupuis, Josée, Herman, Mark A, and McKeown, Nicola M

Subjects
Humans, Triglycerides, Polymorphism, Single Nucleotide, Adult, Middle Aged, Female, Male, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cholesterol, HDL, Meta-Analysis as Topic, Sugar-Sweetened Beverages, carbohydrates, dyslipidemia, epidemiology, genetics, nutrition, sugars, triglyceride, Cardiovascular, Genetics, Human Genome
Abstract

BackgroundChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia.MethodsData from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake.ResultsIn a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; P

Published
2021

6. Cerebral small vessel disease genomics and its implications across the lifespan.

Author

Sargurupremraj, Muralidharan, Suzuki, Hideaki, Jian, Xueqiu, Sarnowski, Chloé, Evans, Tavia E, Bis, Joshua C, Eiriksdottir, Gudny, Sakaue, Saori, Terzikhan, Natalie, Habes, Mohamad, Zhao, Wei, Armstrong, Nicola J, Hofer, Edith, Yanek, Lisa R, Hagenaars, Saskia P, Kumar, Rajan B, van den Akker, Erik B, McWhirter, Rebekah E, Trompet, Stella, Mishra, Aniket, Saba, Yasaman, Satizabal, Claudia L, Beaudet, Gregory, Petit, Laurent, Tsuchida, Ami, Zago, Laure, Schilling, Sabrina, Sigurdsson, Sigurdur, Gottesman, Rebecca F, Lewis, Cora E, Aggarwal, Neelum T, Lopez, Oscar L, Smith, Jennifer A, Valdés Hernández, Maria C, van der Grond, Jeroen, Wright, Margaret J, Knol, Maria J, Dörr, Marcus, Thomson, Russell J, Bordes, Constance, Le Grand, Quentin, Duperron, Marie-Gabrielle, Smith, Albert V, Knopman, David S, Schreiner, Pamela J, Evans, Denis A, Rotter, Jerome I, Beiser, Alexa S, Maniega, Susana Muñoz, Beekman, Marian, Trollor, Julian, Stott, David J, Vernooij, Meike W, Wittfeld, Katharina, Niessen, Wiro J, Soumaré, Aicha, Boerwinkle, Eric, Sidney, Stephen, Turner, Stephen T, Davies, Gail, Thalamuthu, Anbupalam, Völker, Uwe, van Buchem, Mark A, Bryan, R Nick, Dupuis, Josée, Bastin, Mark E, Ames, David, Teumer, Alexander, Amouyel, Philippe, Kwok, John B, Bülow, Robin, Deary, Ian J, Schofield, Peter R, Brodaty, Henry, Jiang, Jiyang, Tabara, Yasuharu, Setoh, Kazuya, Miyamoto, Susumu, Yoshida, Kazumichi, Nagata, Manabu, Kamatani, Yoichiro, Matsuda, Fumihiko, Psaty, Bruce M, Bennett, David A, De Jager, Philip L, Mosley, Thomas H, Sachdev, Perminder S, Schmidt, Reinhold, Warren, Helen R, Evangelou, Evangelos, Trégouët, David-Alexandre, International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium (IHGC), Ikram, Mohammad A, Wen, Wei, DeCarli, Charles, Srikanth, Velandai K, Jukema, J Wouter, Slagboom, Eline P, and Kardia, Sharon LR

Subjects
International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium, Humans, Alzheimer Disease, Hypertension, Medical History Taking, Risk Assessment, Risk Factors, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Stroke, Genome-Wide Association Study, Young Adult, Diffusion Tensor Imaging, Genetic Loci, Mendelian Randomization Analysis, Cerebral Small Vessel Diseases, White Matter, and over
Abstract

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Published
2020

7. Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.

Author

Zhao, Xutong, Qiao, Dandi, Yang, Chaojie, Kasela, Silva, Kim, Wonji, Ma, Yanlin, Shrine, Nick, Batini, Chiara, Sofer, Tamar, Taliun, Sarah A Gagliano, Sakornsakolpat, Phuwanat, Balte, Pallavi P, Prokopenko, Dmitry, Yu, Bing, Lange, Leslie A, Dupuis, Josée, Cade, Brian E, Lee, Jiwon, Gharib, Sina A, Daya, Michelle, Laurie, Cecelia A, Ruczinski, Ingo, Cupples, L Adrienne, Loehr, Laura R, Bartz, Traci M, Morrison, Alanna C, Psaty, Bruce M, Vasan, Ramachandran S, Wilson, James G, Taylor, Kent D, Durda, Peter, Johnson, W Craig, Cornell, Elaine, Guo, Xiuqing, Liu, Yongmei, Tracy, Russell P, Ardlie, Kristin G, Aguet, François, VanDenBerg, David J, Papanicolaou, George J, Rotter, Jerome I, Barnes, Kathleen C, Jain, Deepti, Nickerson, Deborah A, Muzny, Donna M, Metcalf, Ginger A, Doddapaneni, Harshavardhan, Dugan-Perez, Shannon, Gupta, Namrata, Gabriel, Stacey, Rich, Stephen S, O'Connor, George T, Redline, Susan, Reed, Robert M, Laurie, Cathy C, Daviglus, Martha L, Preudhomme, Liana K, Burkart, Kristin M, Kaplan, Robert C, Wain, Louise V, Tobin, Martin D, London, Stephanie J, Lappalainen, Tuuli, Oelsner, Elizabeth C, Abecasis, Goncalo R, Silverman, Edwin K, Barr, R Graham, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lung Working Group, Cho, Michael H, and Manichaikul, Ani

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lung Working Group, Lung, Humans, Pulmonary Disease, Chronic Obstructive, Genetic Predisposition to Disease, Intracellular Signaling Peptides and Proteins, Calcium-Binding Proteins, Small Ubiquitin-Related Modifier Proteins, Follow-Up Studies, Feasibility Studies, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, African Americans, Female, Male, Protein Inhibitors of Activated STAT, Respiratory Physiological Phenomena, Genome-Wide Association Study, Genetic Loci, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Whole Genome Sequencing, and over, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive
Abstract

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

Published
2020

8. Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose

Author

Wu, Peitao, Rybin, Denis, Bielak, Lawrence F, Feitosa, Mary F, Franceschini, Nora, Li, Yize, Lu, Yingchang, Marten, Jonathan, Musani, Solomon K, Noordam, Raymond, Raghavan, Sridharan, Rose, Lynda M, Schwander, Karen, Smith, Albert V, Tajuddin, Salman M, Vojinovic, Dina, Amin, Najaf, Arnett, Donna K, Bottinger, Erwin P, Demirkan, Ayse, Florez, Jose C, Ghanbari, Mohsen, Harris, Tamara B, Launer, Lenore J, Liu, Jingmin, Liu, Jun, Mook-Kanamori, Dennis O, Murray, Alison D, Nalls, Mike A, Peyser, Patricia A, Uitterlinden, André G, Voortman, Trudy, Bouchard, Claude, Chasman, Daniel, Correa, Adolfo, de Mutsert, Renée, Evans, Michele K, Gudnason, Vilmundur, Hayward, Caroline, Kao, Linda, Kardia, Sharon LR, Kooperberg, Charles, Loos, Ruth JF, Province, Michael M, Rankinen, Tuomo, Redline, Susan, Ridker, Paul M, Rotter, Jerome I, Siscovick, David, Smith, Blair H, van Duijn, Cornelia, Zonderman, Alan B, Rao, DC, Wilson, James G, Dupuis, Josée, Meigs, James B, Liu, Ching-Ti, and Vassy, Jason L

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Pharmacology and Pharmaceutical Sciences, Tobacco, Aging, Tobacco Smoke and Health, Human Genome, Nutrition, Diabetes, Clinical Research, Prevention, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Aged, Black People, Blood Glucose, Cigarette Smoking, Cohort Studies, Diabetes Mellitus, Type 2, Fasting, Feasibility Studies, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Incidence, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk, White People, General Science & Technology
Abstract

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p

Published
2020

9. Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium

Author

Merino, Jordi, Dashti, Hassan S, Li, Sherly X, Sarnowski, Chloé, Justice, Anne E, Graff, Misa, Papoutsakis, Constantina, Smith, Caren E, Dedoussis, George V, Lemaitre, Rozenn N, Wojczynski, Mary K, Männistö, Satu, Ngwa, Julius S, Kho, Minjung, Ahluwalia, Tarunveer S, Pervjakova, Natalia, Houston, Denise K, Bouchard, Claude, Huang, Tao, Orho-Melander, Marju, Frazier-Wood, Alexis C, Mook-Kanamori, Dennis O, Pérusse, Louis, Pennell, Craig E, de Vries, Paul S, Voortman, Trudy, Li, Olivia, Kanoni, Stavroula, Rose, Lynda M, Lehtimäki, Terho, Zhao, Jing Hua, Feitosa, Mary F, Luan, Jian’an, McKeown, Nicola M, Smith, Jennifer A, Hansen, Torben, Eklund, Niina, Nalls, Mike A, Rankinen, Tuomo, Huang, Jinyan, Hernandez, Dena G, Schulz, Christina-Alexandra, Manichaikul, Ani, Li-Gao, Ruifang, Vohl, Marie-Claude, Wang, Carol A, van Rooij, Frank JA, Shin, Jean, Kalafati, Ioanna P, Day, Felix, Ridker, Paul M, Kähönen, Mika, Siscovick, David S, Langenberg, Claudia, Zhao, Wei, Astrup, Arne, Knekt, Paul, Garcia, Melissa, Rao, DC, Qi, Qibin, Ferrucci, Luigi, Ericson, Ulrika, Blangero, John, Hofman, Albert, Pausova, Zdenka, Mikkilä, Vera, Wareham, Nick J, Kardia, Sharon LR, Pedersen, Oluf, Jula, Antti, Curran, Joanne E, Zillikens, M Carola, Viikari, Jorma S, Forouhi, Nita G, Ordovás, José M, Lieske, John C, Rissanen, Harri, Uitterlinden, André G, Raitakari, Olli T, Kiefte-de Jong, Jessica C, Dupuis, Josée, Rotter, Jerome I, North, Kari E, Scott, Robert A, Province, Michael A, Perola, Markus, Cupples, L Adrienne, Turner, Stephen T, Sørensen, Thorkild IA, Salomaa, Veikko, Liu, Yongmei, Sung, Yun J, Qi, Lu, Bandinelli, Stefania, Rich, Stephen S, de Mutsert, Renée, Tremblay, Angelo, Oddy, Wendy H, Franco, Oscar H, and Paus, Tomas

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Obesity, Human Genome, Genetics, Prevention, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Metabolic and endocrine, Aged, Aging, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Cohort Studies, Energy Intake, Female, Fibroblast Growth Factors, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Genotype, Heart Diseases, Humans, Male, Membrane Proteins, Middle Aged, Nutrients, Polymorphism, Single Nucleotide, Receptors, Retinoic Acid, White People, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P

Published
2019

10. Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis.

Author

Hobbs, Brian D, Putman, Rachel K, Araki, Tetsuro, Nishino, Mizuki, Gudmundsson, Gunnar, Gudnason, Vilmundur, Eiriksdottir, Gudny, Zilhao Nogueira, Nuno Rodrigues, Dupuis, Josée, Xu, Hanfei, O'Connor, George T, Manichaikul, Ani, Nguyen, Jennifer, Podolanczuk, Anna J, Madahar, Purnema, Rotter, Jerome I, Lederer, David J, Barr, R Graham, Rich, Stephen S, Ampleford, Elizabeth J, Ortega, Victor E, Peters, Stephen P, O'Neal, Wanda K, Newell, John D, Bleecker, Eugene R, Meyers, Deborah A, Allen, Richard J, Oldham, Justin M, Ma, Shwu-Fan, Noth, Imre, Jenkins, R Gisli, Maher, Toby M, Hubbard, Richard B, Wain, Louise V, Fingerlin, Tasha E, Schwartz, David A, Washko, George R, Rosas, Ivan O, Silverman, Edwin K, Hatabu, Hiroto, Cho, Michael H, and Hunninghake, Gary M

Subjects
Humans, Lung Diseases, Interstitial, Genetic Predisposition to Disease, beta Karyopherins, TATA Box Binding Protein-Like Proteins, Case-Control Studies, Polymorphism, Single Nucleotide, Aged, Middle Aged, Female, Male, Promoter Regions, Genetic, Idiopathic Pulmonary Fibrosis, Genome-Wide Association Study, Mucin-5B, Genetic Loci, SNP, genetics, genome-wide association study, idiopathic pulmonary fibrosis, interstitial lung abnormalities, Genetics, Lung, Rare Diseases, Chronic Obstructive Pulmonary Disease, Clinical Research, Prevention, Human Genome, Autoimmune Disease, Aging, 2.1 Biological and endogenous factors, Aetiology, Respiratory, Medical and Health Sciences, Respiratory System
Abstract

Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P

Published
2019

11. Childhood Tobacco Smoke Exposure and Risk of Atrial Fibrillation in Adulthood

Author

Groh, Christopher A, Vittinghoff, Eric, Benjamin, Emelia J, Dupuis, Josée, and Marcus, Gregory M

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Tobacco, Tobacco Smoke and Health, Prevention, Heart Disease, Clinical Research, Cardiovascular, Cancer, 2.3 Psychological, social and economic factors, Aetiology, Respiratory, Adult, Atrial Fibrillation, Child, Cohort Studies, Cross-Sectional Studies, Electrocardiography, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Risk Factors, Tobacco Smoke Pollution, Young Adult, atrial fibrillation, secondhand smoke, smoking, Cardiorespiratory Medicine and Haematology, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BACKGROUND:Cigarette smoking is known to increase the risk of atrial fibrillation (AF), and a recent cross-sectional analysis suggested that parental smoking may be an AF risk factor. OBJECTIVES:The purpose of this study was to assess if parental smoking predicts offspring AF in the Framingham Heart Study. METHODS:This study analyzed Framingham Offspring cohort participants with parents in the Original cohort with known smoking status during the offspring's childhood. Framingham participants were evaluated every 2 to 8 years and were under routine surveillance for incident AF. The authors assessed AF incidence among Offspring participants exposed to parental smoking through age 18 years and performed a mediation analysis to determine the extent to which offspring smoking might explain observed associations. RESULTS:Of 2,816 Offspring cohort participants with at least 1 parent in the Original cohort, 82% were exposed to parental smoking. For every pack/day increase in parental smoking, there was an 18% increase in offspring AF incidence (adjusted hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 1.00 to 1.39; p = 0.04). Additionally, parental smoking was a risk factor for offspring smoking (adjusted odds ratio [OR]: 1.34; 95% CI: 1.17 to 1.54; p

Published
2019

12. Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program

Author

Sarnowski, Chloé, Leong, Aaron, Raffield, Laura M, Wu, Peitao, de Vries, Paul S, DiCorpo, Daniel, Guo, Xiuqing, Xu, Huichun, Liu, Yongmei, Zheng, Xiuwen, Hu, Yao, Brody, Jennifer A, Goodarzi, Mark O, Hidalgo, Bertha A, Highland, Heather M, Jain, Deepti, Liu, Ching-Ti, Naik, Rakhi P, O’Connell, Jeffrey R, Perry, James A, Porneala, Bianca C, Selvin, Elizabeth, Wessel, Jennifer, Psaty, Bruce M, Curran, Joanne E, Peralta, Juan M, Blangero, John, Kooperberg, Charles, Mathias, Rasika, Johnson, Andrew D, Reiner, Alexander P, Mitchell, Braxton D, Cupples, L Adrienne, Vasan, Ramachandran S, Correa, Adolfo, Morrison, Alanna C, Boerwinkle, Eric, Rotter, Jerome I, Rich, Stephen S, Manning, Alisa K, Dupuis, Josée, Meigs, James B, Group, TOPMed Diabetes Working, Group, TOPMed Hematology Working, Group, TOPMed Hemostasis Working, and National Heart, Lung

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Prevention, Diabetes, Clinical Research, Metabolic and endocrine, Good Health and Well Being, Cohort Studies, Diabetes Mellitus, Female, Genetic Variation, Glycated Hemoglobin, Humans, Male, Polymorphism, Single Nucleotide, Population Groups, Precision Medicine, TOPMed Diabetes Working Group, TOPMed Hematology Working Group, TOPMed Hemostasis Working Group, National Heart, Lung, and Blood Institute TOPMed Consortium, The Trans-Omics for Precision Medicine (TOPMed) program, hemoglobin A1c, multi-ancestry sample, whole-genome sequence association analyses, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

Published
2019

13. An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis

Author

Liu, Jun, Carnero-Montoro, Elena, van Dongen, Jenny, Lent, Samantha, Nedeljkovic, Ivana, Ligthart, Symen, Tsai, Pei-Chien, Martin, Tiphaine C, Mandaviya, Pooja R, Jansen, Rick, Peters, Marjolein J, Duijts, Liesbeth, Jaddoe, Vincent WV, Tiemeier, Henning, Felix, Janine F, Willemsen, Gonneke, de Geus, Eco JC, Chu, Audrey Y, Levy, Daniel, Hwang, Shih-Jen, Bressler, Jan, Gondalia, Rahul, Salfati, Elias L, Herder, Christian, Hidalgo, Bertha A, Tanaka, Toshiko, Moore, Ann Zenobia, Lemaitre, Rozenn N, Jhun, Min A, Smith, Jennifer A, Sotoodehnia, Nona, Bandinelli, Stefania, Ferrucci, Luigi, Arnett, Donna K, Grallert, Harald, Assimes, Themistocles L, Hou, Lifang, Baccarelli, Andrea, Whitsel, Eric A, van Dijk, Ko Willems, Amin, Najaf, Uitterlinden, André G, Sijbrands, Eric JG, Franco, Oscar H, Dehghan, Abbas, Spector, Tim D, Dupuis, Josée, Hivert, Marie-France, Rotter, Jerome I, Meigs, James B, Pankow, James S, van Meurs, Joyce BJ, Isaacs, Aaron, Boomsma, Dorret I, Bell, Jordana T, Demirkan, Ayşe, and van Duijn, Cornelia M

Subjects
Biological Sciences, Genetics, Nutrition, Diabetes, Human Genome, Obesity, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Adult, Aged, Aged, 80 and over, Computer Simulation, CpG Islands, DNA Methylation, Diabetes Mellitus, Type 2, Epigenesis, Genetic, Epigenomics, Female, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Glucose, Homeostasis, Humans, Insulin, Male, Metabolic Networks and Pathways, Middle Aged, Polymorphism, Single Nucleotide, Young Adult
Abstract

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.

Published
2019

14. Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function

Author

Xu, Jiayi, Bartz, Traci M, Chittoor, Geetha, Eiriksdottir, Gudny, Manichaikul, Ani W, Sun, Fangui, Terzikhan, Natalie, Zhou, Xia, Booth, Sarah L, Brusselle, Guy G, de Boer, Ian H, Fornage, Myriam, Frazier-Wood, Alexis C, Graff, Mariaelisa, Gudnason, Vilmundur, Harris, Tamara B, Hofman, Albert, Hou, Ruixue, Houston, Denise K, Jacobs, David R, Kritchevsky, Stephen B, Latourelle, Jeanne, Lemaitre, Rozenn N, Lutsey, Pamela L, O’Connor, George, Oelsner, Elizabeth C, Pankow, James S, Psaty, Bruce M, Rohde, Rebecca R, Rich, Stephen S, Rotter, Jerome I, Smith, Lewis J, Stricker, Bruno H, Voruganti, V Saroja, Wang, Thomas J, Zillikens, M Carola, Barr, R Graham, Dupuis, Josée, Gharib, Sina A, Lahousse, Lies, London, Stephanie J, North, Kari E, Smith, Albert V, Steffen, Lyn M, Hancock, Dana B, and Cassano, Patricia A

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Complementary and Integrative Health, Aging, Clinical Research, Adult, Aged, Black People, Cross-Sectional Studies, Female, Forced Expiratory Volume, Genome, Human, Heart, Heart Diseases, Humans, Lung, Lung Diseases, Male, Middle Aged, Molecular Epidemiology, Prospective Studies, Regression Analysis, Respiratory Function Tests, Smoking, Vital Capacity, Vitamin D, White People, 1, 25(OH)D 25-hydroxyvitamin D, AA African ancestry, AGES Age, ARIC Atherosclerosis Risk in Communities Study, Aging, CARDIA Coronary Artery Risk Development in Young Adults Study, CHARGE Cohorts for Heart and Aging Research in Genomic Epidemiology, CHS Cardiovascular Health Study, COPD chronic obstructive pulmonary disease, EA European ancestry, Environment, FEV1 forced expiratory volume in the 1st second, FHS (Gen3) Framingham Heart Study – Generation 3 Cohort, FHS (Offspring) Framingham Heart Study –Offspring Cohort, FVC forced vital capacity, Gene, HABC Health, Iceland, MESA Multi-Ethnic Study of Atherosclerosis, PFT pulmonary function test, RIA radioimmunoassay, Susceptibility Study − Reykjavik, and Body Composition Study, 25-(OH)2D 1, 25-dihydroxyvitamin D, African Americans, Forced expiratory volume, Respiratory function tests, Vital capacity, Whites, Animal Production, Food Sciences, Nutrition & Dietetics, Animal production, Food sciences, Nutrition and dietetics
Abstract

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P

Published
2018

15. Whole genome sequence analyses of brain imaging measures in the Framingham Study

Author

Sarnowski, Chloé, Satizabal, Claudia L, DeCarli, Charles, Pitsillides, Achilleas N, Cupples, L Adrienne, Vasan, Ramachandran S, Wilson, James G, Bis, Joshua C, Fornage, Myriam, Beiser, Alexa S, DeStefano, Anita L, Dupuis, Josée, Seshadri, Sudha, Arnett, Donna K, Becker, Diane, Bis, Joshua, Boerwinkle, Eric, Bowers, Michael, Bressler, Jan, Correa, Adolfo, DeStefano, Anita, Ding, Jingzhong ding, Fardo, David, Lugo, Alex Garcia, Glahn, David, Gonzalez, Hector, Hayden, Kathleen, Heckbert, Susan, Hoth, Karin, Hughes, Timothy, Jaquish, Cashell, Jian, Xueqiu, Knowles, Emma, Launer, Lenore, Lin, Honghuang, Longstreth, Will, Mayeux, Richard, Misra, Biswapriya, Mosley, Thomas, Nyquist, Paul, Olivier, Michael, Peprah, Emmanuel, Psaty, Bruce, Purcell, Shaun, Rotter, Jerome, Satizabal, Claudia, Schellenberg, Gerard, Simino, Jeannette, Smith, Jennifer, Smoller, Sylvia, Snively, Beverly, Sokolow, Sophie, Wehr, Kate, Yanek, Lisa, Yang, Qiong, Namiko, Abe, Goncalo, Abecasis, Christine, Albert, Nicholette (Nichole) Palmer, Allred, Laura, Almasy, Alvaro, Alonso, Seth, Ament, Peter, Anderson, Pramod, Anugu, Deborah, Applebaum-Bowden, Dan, Arking, Donna K, Arnett, Allison, Ashley-Koch, Stella, Aslibekyan, Tim, Assimes, Paul, Auer, Dimitrios, Avramopoulos, John, Barnard, Kathleen, Barnes, Graham, Barr R, Emily, Barron-Casella, Terri, Beaty, Diane, Becker, Lewis, Becker, Rebecca, Beer, Ferdouse, Begum, Amber, Beitelshees, Emelia, Benjamin, Marcos, Bezerra, Larry, Bielak, Joshua, Bis, Thomas, Blackwell, John, Blangero, Eric, Boerwinkle, Ingrid, Borecki, Russell, Bowler, Jennifer, Brody, Ulrich, Broeckel, Jai, Broome, Karen, Bunting, Esteban, Burchard, and Jonathan, Cardwell

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Genetics, Biotechnology, Human Genome, Aging, Brain Disorders, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Good Health and Well Being, Aged, Brain, Female, Genetic Variation, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Massachusetts, Middle Aged, Organ Size, Phenotype, Prospective Studies, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Neurocognitive Working Group, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveWe sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program.MethodsWe performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants.ResultsWe detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10-8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10-4) and in 17q25 for WMH (rs7214628, p = 2.0 × 10-3) were confirmed. Gene-based tests detected associations (p ≤ 2.3 × 10-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- (UNC5D) and Parkinson disease-associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways.ConclusionsWhole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.

Published
2018

16. Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees

Author

Jun, Goo, Manning, Alisa, Almeida, Marcio, Zawistowski, Matthew, Wood, Andrew R, Teslovich, Tanya M, Fuchsberger, Christian, Feng, Shuang, Cingolani, Pablo, Gaulton, Kyle J, Dyer, Thomas, Blackwell, Thomas W, Chen, Han, Chines, Peter S, Choi, Sungkyoung, Churchhouse, Claire, Fontanillas, Pierre, King, Ryan, Lee, SungYoung, Lincoln, Stephen E, Trubetskoy, Vasily, DePristo, Mark, Fingerlin, Tasha, Grossman, Robert, Grundstad, Jason, Heath, Alison, Kim, Jayoun, Kim, Young Jin, Laramie, Jason, Lee, Jaehoon, Li, Heng, Liu, Xuanyao, Livne, Oren, Locke, Adam E, Maller, Julian, Mazur, Alexander, Morris, Andrew P, Pollin, Toni I, Ragona, Derek, Reich, David, Rivas, Manuel A, Scott, Laura J, Sim, Xueling, Tearle, Rick G, Teo, Yik Ying, Williams, Amy L, Zöllner, Sebastian, Curran, Joanne E, Peralta, Juan, Akolkar, Beena, Bell, Graeme I, Burtt, Noël P, Cox, Nancy J, Florez, Jose C, Hanis, Craig L, McKeon, Catherine, Mohlke, Karen L, Seielstad, Mark, Wilson, James G, Atzmon, Gil, Below, Jennifer E, Dupuis, Josée, Nicolae, Dan L, Lehman, Donna, Park, Taesung, Won, Sungho, Sladek, Robert, Altshuler, David, McCarthy, Mark I, Duggirala, Ravindranath, Boehnke, Michael, Frayling, Timothy M, Abecasis, Gonçalo R, and Blangero, John

Subjects
Diabetes, Genetics, Human Genome, Clinical Research, Obesity, Genetic Testing, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Diabetes Mellitus, Type 2, Family Health, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Mexican Americans, Pedigree, Phenotype, Quantitative Trait Loci, Whole Genome Sequencing, genetics, sequencing, type 2 diabetes, eQTL, rare variants
Abstract

A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.

Published
2018

17. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, Xia, O’Reilly, Paul F, Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A, Albanes, Demetrius, Lutsey, Pamela L, Yao, Lu, Tang, Weihong, Econs, Michael J, Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I, Michos, Erin D, Boerwinkle, Eric, Weinstein, Stephanie J, Freedman, Neal D, Huang, Wen-Yi, Van Schoor, Natasja M, van der Velde, Nathalie, Groot, Lisette CPGM de, Enneman, Anke, Cupples, L Adrienne, Booth, Sarah L, Vasan, Ramachandran S, Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G, Shea, M Kyla, Houston, Denise K, Kritchevsky, Stephen B, Liu, Yongmei, Lohman, Kurt K, Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E, März, Winfried, de Boer, Ian H, Wood, Alexis C, Rotter, Jerome I, Rich, Stephen S, Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K, Wilson, James F, Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M Carola, Uitterlinden, Andre G, Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M, Timofeeva, Maria, Dunlop, Malcolm G, Valdes, Ana M, Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T, Mikkilä, Vera, Ikram, M Arfan, Sattar, Naveed, Jukema, J Wouter, Wareham, Nicholas J, Langenberg, Claudia, Forouhi, Nita G, Gundersen, Thomas E, Khaw, Kay-Tee, Butterworth, Adam S, Danesh, John, and Spector, Timothy

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Amidohydrolases, Autoimmune Diseases, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Vesicular Transport Proteins, Vitamin D, White People
Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Published
2018

18. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Author

Wyss, Annah B, Sofer, Tamar, Lee, Mi Kyeong, Terzikhan, Natalie, Nguyen, Jennifer N, Lahousse, Lies, Latourelle, Jeanne C, Smith, Albert Vernon, Bartz, Traci M, Feitosa, Mary F, Gao, Wei, Ahluwalia, Tarunveer S, Tang, Wenbo, Oldmeadow, Christopher, Duan, Qing, de Jong, Kim, Wojczynski, Mary K, Wang, Xin-Qun, Noordam, Raymond, Hartwig, Fernando Pires, Jackson, Victoria E, Wang, Tianyuan, Obeidat, Ma’en, Hobbs, Brian D, Huan, Tianxiao, Gui, Hongsheng, Parker, Margaret M, Hu, Donglei, Mogil, Lauren S, Kichaev, Gleb, Jin, Jianping, Graff, Mariaelisa, Harris, Tamara B, Kalhan, Ravi, Heckbert, Susan R, Paternoster, Lavinia, Burkart, Kristin M, Liu, Yongmei, Holliday, Elizabeth G, Wilson, James G, Vonk, Judith M, Sanders, Jason L, Barr, R Graham, de Mutsert, Renée, Menezes, Ana Maria Baptista, Adams, Hieab HH, van den Berge, Maarten, Joehanes, Roby, Levin, Albert M, Liberto, Jennifer, Launer, Lenore J, Morrison, Alanna C, Sitlani, Colleen M, Celedón, Juan C, Kritchevsky, Stephen B, Scott, Rodney J, Christensen, Kaare, Rotter, Jerome I, Bonten, Tobias N, Wehrmeister, Fernando César, Bossé, Yohan, Xiao, Shujie, Oh, Sam, Franceschini, Nora, Brody, Jennifer A, Kaplan, Robert C, Lohman, Kurt, McEvoy, Mark, Province, Michael A, Rosendaal, Frits R, Taylor, Kent D, Nickle, David C, Williams, L Keoki, Burchard, Esteban G, Wheeler, Heather E, Sin, Don D, Gudnason, Vilmundur, North, Kari E, Fornage, Myriam, Psaty, Bruce M, Myers, Richard H, O’Connor, George, Hansen, Torben, Laurie, Cathy C, Cassano, Patricia A, Sung, Joohon, Kim, Woo Jin, Attia, John R, Lange, Leslie, Boezen, H Marike, Thyagarajan, Bharat, Rich, Stephen S, Mook-Kanamori, Dennis O, Horta, Bernardo Lessa, Uitterlinden, André G, Im, Hae Kyung, Cho, Michael H, Brusselle, Guy G, Gharib, Sina A, and Dupuis, Josée

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Lung, Biotechnology, Asian, Black People, Female, Forced Expiratory Volume, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Hispanic or Latino, Humans, Linkage Disequilibrium, Lung Diseases, Male, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, Regression Analysis, Sample Size, Smoking, Vital Capacity, White People
Abstract

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

Published
2018

19. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Author

Hobbs, Brian D, de Jong, Kim, Lamontagne, Maxime, Bossé, Yohan, Shrine, Nick, Artigas, María Soler, Wain, Louise V, Hall, Ian P, Jackson, Victoria E, Wyss, Annah B, London, Stephanie J, North, Kari E, Franceschini, Nora, Strachan, David P, Beaty, Terri H, Hokanson, John E, Crapo, James D, Castaldi, Peter J, Chase, Robert P, Bartz, Traci M, Heckbert, Susan R, Psaty, Bruce M, Gharib, Sina A, Zanen, Pieter, Lammers, Jan W, Oudkerk, Matthijs, Groen, HJ, Locantore, Nicholas, Tal-Singer, Ruth, Rennard, Stephen I, Vestbo, Jørgen, Timens, Wim, Paré, Peter D, Latourelle, Jeanne C, Dupuis, Josée, O'Connor, George T, Wilk, Jemma B, Kim, Woo Jin, Lee, Mi Kyeong, Oh, Yeon-Mok, Vonk, Judith M, de Koning, Harry J, Leng, Shuguang, Belinsky, Steven A, Tesfaigzi, Yohannes, Manichaikul, Ani, Wang, Xin-Qun, Rich, Stephen S, Barr, R Graham, Sparrow, David, Litonjua, Augusto A, Bakke, Per, Gulsvik, Amund, Lahousse, Lies, Brusselle, Guy G, Stricker, Bruno H, Uitterlinden, André G, Ampleford, Elizabeth J, Bleecker, Eugene R, Woodruff, Prescott G, Meyers, Deborah A, Qiao, Dandi, Lomas, David A, Yim, Jae-Joon, Kim, Deog Kyeom, Hawrylkiewicz, Iwona, Sliwinski, Pawel, Hardin, Megan, Fingerlin, Tasha E, Schwartz, David A, Postma, Dirkje S, MacNee, William, Tobin, Martin D, Silverman, Edwin K, Boezen, H Marike, and Cho, Michael H

Subjects
Biological Sciences, Genetics, Chronic Obstructive Pulmonary Disease, Lung, Human Genome, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Respiratory, Adult, Aged, Aged, 80 and over, Alleles, Asthma, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Pulmonary Fibrosis, Risk Factors, Smoking, COPDGene Investigators, ECLIPSE Investigators, LifeLines Investigators, SPIROMICS Research Group, International COPD Genetics Network Investigators, UK BiLEVE Investigators, International COPD Genetics Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Published
2017

20. Sex-Based Genetic Association Study Identifies CELSR1 as a Possible Chronic Obstructive Pulmonary Disease Risk Locus among Women

Author

Hardin, Megan, Cho, Michael H, Sharma, Sunita, Glass, Kimberly, Castaldi, Peter J, McDonald, Merry-Lynn, Aschard, Hugues, Senter-Sylvia, Jody, Tantisira, Kelan, Weiss, Scott T, Hersh, Craig P, Morrow, Jarrett D, Lomas, David, Agusti, Alvar, Bakke, Per, Gulsvik, Amund, O'Connor, George T, Dupuis, Josée, Hokanson, John, Crapo, James D, Beaty, Terri H, Laird, Nan, Silverman, Edwin K, and DeMeo, Dawn L

Subjects
Biological Sciences, Genetics, Chronic Obstructive Pulmonary Disease, Tobacco Smoke and Health, Prevention, Clinical Research, Lung, Tobacco, Human Genome, Respiratory, Aged, Alleles, Cadherins, Demography, Female, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Risk Factors, chronic obstructive pulmonary disease, genetics, growth and development, sex, genome-wide association study, COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points Investigators, Cardiorespiratory Medicine and Haematology, Respiratory System, Biochemistry and cell biology, Cardiovascular medicine and haematology
Abstract

Chronic obstructive pulmonary disease (COPD) is a complex disease with strong environmental and genetic influences and sexually dimorphic features. Although genetic risk factors for COPD have been identified, much of the heritability remains unexplained. Sex-based genetic association studies may uncover additional COPD genetic risk factors. We studied current and former smokers from COPD case-control cohorts (COPDGene non-Hispanic whites and African Americans, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, and Genetics of Chronic Obstructive Lung Disease). COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity less than 0.70 and forced expiratory volume in 1 second percent predicted less than 80. Testing was performed across all cohorts and combined in a meta-analysis adjusted for age, pack-years, and genetic ancestry. We first performed genome-wide single-nucleotide polymorphism (SNP)-by-sex interaction testing on the outcome of COPD affection status. We performed sex-stratified association testing for SNPs with interaction P less than 10-6. We examined over 8 million SNPs in four populations, including 6,260 subjects with COPD (40.6% female) and 5,269 smoking control subjects (47.3% female). The SNP rs9615358 in the cadherin gene CELSR1 approached genome-wide significance for an interaction with sex (P = 1.24 × 10-7). In the sex-stratified meta-analysis, this SNP was associated with COPD among females (odds ratio, 1.37 [95% confidence interval, 1.25-1.49]; P = 3.32 × 10-7) but not males (odds ratio, 0.90 [95% confidence interval, 0.79-1.01]; P = 0.06). CELSR1 is involved in fetal lung development. In a human fetal lung tissue dataset, we observed greater CELSR1 expression in female compared with male samples. This SNP-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for COPD. Identifying sex-specific genetic risk factors may reveal new insights into sexually dimorphic features of COPD.

Published
2017

21. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Author

Lévy, Romain, Okada, Satoshi, Béziat, Vivien, Moriya, Kunihiko, Liu, Caini, Chai, Louis Yi Ann, Migaud, Mélanie, Hauck, Fabian, Al Ali, Amein, Cyrus, Cyril, Vatte, Chittibabu, Patiroglu, Turkan, Unal, Ekrem, Ferneiny, Marie, Hyakuna, Nobuyuki, Nepesov, Serdar, Oleastro, Matias, Ikinciogullari, Aydan, Dogu, Figen, Asano, Takaki, Ohara, Osamu, Yun, Ling, Della Mina, Erika, Bronnimann, Didier, Itan, Yuval, Gothe, Florian, Bustamante, Jacinta, Boisson-Dupuis, Stéphanie, Tahuil, Natalia, Aytekin, Caner, Salhi, Aicha, Al Muhsen, Saleh, Kobayashi, Masao, Toubiana, Julie, Abel, Laurent, Li, Xiaoxia, Camcioglu, Yildiz, Celmeli, Fatih, Klein, Christoph, AlKhater, Suzan A, Casanova, Jean-Laurent, and Puel, Anne

Subjects
Pediatric, Genetics, Clinical Research, Infectious Diseases, Rare Diseases, Emerging Infectious Diseases, Aetiology, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Alleles, Bacterial Infections, Candida, Candidiasis, Cell Membrane, Child, Child, Preschool, Family Health, Female, Fibroblasts, Genes, Recessive, Genome-Wide Association Study, HEK293 Cells, Homozygote, Humans, Immunophenotyping, Infant, Infant, Newborn, Interleukin-17, Male, Mutation, Mycoses, Open Reading Frames, Pedigree, Receptors, Interleukin-17, Skin, T-Lymphocytes, genetics, immunodeficiency, candidiasis
Abstract

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.

Published
2016

22. Pro-epileptogenic effects of viral-like inflammation in both mature and immature brains

Author

Dupuis, Nina, Mazarati, Andrey, Desnous, Béatrice, Chhor, Vibol, Fleiss, Bobbi, Le Charpentier, Tifenn, Lebon, Sophie, Csaba, Zsolt, Gressens, Pierre, Dournaud, Pascal, and Auvin, Stéphane

Subjects
Biomedical and Clinical Sciences, Neurosciences, Immunology, Epilepsy, Brain Disorders, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Age Factors, Animals, Animals, Newborn, Anticonvulsants, Antiviral Agents, Brain, Cells, Cultured, Cytokines, Encephalitis, Encephalitis, Viral, Gene Expression Regulation, Hippocampus, Kindling, Neurologic, Macrophages, Male, Microglia, Minocycline, Poly I-C, RNA, Messenger, Rats, Rats, Wistar, Statistics, Nonparametric, Epileptogenesis, Kindling, Toll-like receptor, Virus, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundInfectious encephalitides are most often associated with acute seizures during the infection period and are risk factors for the development of epilepsy at later times. Mechanisms of viral encephalitis-induced epileptogenesis are poorly understood. Here, we evaluated the contribution of viral encephalitis-associated inflammation to ictogenesis and epileptogenesis using a rapid kindling protocol in rats. In addition, we examined whether minocycline can improve outcomes of viral-like brain inflammation.MethodsTo produce viral-like inflammation, polyinosinic-polycytidylic acid (PIC), a toll-like receptor 3 (TLR3) agonist, was applied to microglial/macrophage cell cultures and to the hippocampus of postnatal day 13 (P13) and postnatal day 74 (P74) rats. Cell cultures permit the examination of the inflammation induced by PIC, while the in vivo setting better suits the analysis of cytokine production and the effects of inflammation on epileptogenesis. Minocycline (50 mg/kg) was injected intraperitoneally for 3 consecutive days prior to the kindling procedure to evaluate its effects on inflammation and epileptogenesis.ResultsPIC injection facilitated kindling epileptogenesis, which was evident as an increase in the number of full limbic seizures at both ages. Furthermore, in P14 rats, we observed a faster seizure onset and prolonged retention of the kindling state. PIC administration also led to an increase in interleukin 1β (IL-1β) levels in the hippocampus in P14 and P75 rats. Treatment with minocycline reversed neither the pro-epileptogenic effects of PIC nor the increase of IL-1β in the hippocampus in both P14 and P75 rats.ConclusionsHippocampal injection of PIC facilitates rapid kindling epileptogenesis at both P14 and P75, suggesting that viral-induced inflammation increases epileptogenesis irrespective of brain maturation. Minocycline, however, was unable to reverse the increase of epileptogenesis, which might be linked to its absence of effect on hippocampal IL-1β levels at both ages.

Published
2016

23. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Author

Walford, Geoffrey A, Gustafsson, Stefan, Rybin, Denis, Stančáková, Alena, Chen, Han, Liu, Ching-Ti, Hong, Jaeyoung, Jensen, Richard A, Rice, Ken, Morris, Andrew P, Mägi, Reedik, Tönjes, Anke, Prokopenko, Inga, Kleber, Marcus E, Delgado, Graciela, Silbernagel, Günther, Jackson, Anne U, Appel, Emil V, Grarup, Niels, Lewis, Joshua P, Montasser, May E, Landenvall, Claes, Staiger, Harald, Luan, Jian’an, Frayling, Timothy M, Weedon, Michael N, Xie, Weijia, Morcillo, Sonsoles, Martínez-Larrad, María Teresa, Biggs, Mary L, Chen, Yii-Der Ida, Corbaton-Anchuelo, Arturo, Færch, Kristine, Gómez-Zumaquero, Juan Miguel, Goodarzi, Mark O, Kizer, Jorge R, Koistinen, Heikki A, Leong, Aaron, Lind, Lars, Lindgren, Cecilia, Machicao, Fausto, Manning, Alisa K, Martín-Núñez, Gracia María, Rojo-Martínez, Gemma, Rotter, Jerome I, Siscovick, David S, Zmuda, Joseph M, Zhang, Zhongyang, Serrano-Rios, Manuel, Smith, Ulf, Soriguer, Federico, Hansen, Torben, Jørgensen, Torben J, Linnenberg, Allan, Pedersen, Oluf, Walker, Mark, Langenberg, Claudia, Scott, Robert A, Wareham, Nicholas J, Fritsche, Andreas, Häring, Hans-Ulrich, Stefan, Norbert, Groop, Leif, O’Connell, Jeff R, Boehnke, Michael, Bergman, Richard N, Collins, Francis S, Mohlke, Karen L, Tuomilehto, Jaakko, März, Winfried, Kovacs, Peter, Stumvoll, Michael, Psaty, Bruce M, Kuusisto, Johanna, Laakso, Markku, Meigs, James B, Dupuis, Josée, Ingelsson, Erik, and Florez, Jose C

Subjects
Biomedical and Clinical Sciences, Genetics, Prevention, Human Genome, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Chemokines, CC, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Male, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-bcl-2, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Published
2016

24. Association of the IGF1 gene with fasting insulin levels

Author

Willems, Sara M, Cornes, Belinda K, Brody, Jennifer A, Morrison, Alanna C, Lipovich, Leonard, Dauriz, Marco, Chen, Yuning, Liu, Ching-Ti, Rybin, Denis V, Gibbs, Richard A, Muzny, Donna, Pankow, James S, Psaty, Bruce M, Boerwinkle, Eric, Rotter, Jerome I, Siscovick, David S, Vasan, Ramachandran S, Kaplan, Robert C, Isaacs, Aaron, Dupuis, Josée, van Duijn, Cornelia M, and Meigs, James B

Subjects
Biological Sciences, Genetics, Human Genome, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Adult, Aged, Fasting, Female, Humans, Insulin, Insulin-Like Growth Factor I, Male, Middle Aged, Polymorphism, Single Nucleotide, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) these noncoding variants either tag other functional variants in the region or are directly functional. In our study, analyses including 5141 individuals from population-based cohorts suggest that FI associations near IGF1 are not mediated by IGF-I. Analyses of targeted sequencing data in 3539 individuals reveal a large number of novel rare variants at the IGF1 locus and show a FI association with a subset of rare nonsynonymous variants (PSKAT=5.7 × 10(-4)). Conditional analyses suggest that this association is partly explained by the GWAS signal and the presence of a residual independent rare variant effect (Pconditional=0.019). Annotation using ENCODE data suggests that the GWAS variants may have a direct functional role in insulin biology. In conclusion, our study provides insight into variation present at the IGF1 locus and into the genetic architecture underlying FI levels, suggesting that FI associations of SNVs near IGF1 are not mediated by IGF-I and suggesting a role for both rare nonsynonymous and common functional variants in insulin biology.

Published
2016

25. General Framework for Meta‐Analysis of Haplotype Association Tests

Author

Wang, Shuai, Zhao, Jing Hua, An, Ping, Guo, Xiuqing, Jensen, Richard A, Marten, Jonathan, Huffman, Jennifer E, Meidtner, Karina, Boeing, Heiner, Campbell, Archie, Rice, Kenneth M, Scott, Robert A, Yao, Jie, Schulze, Matthias B, Wareham, Nicholas J, Borecki, Ingrid B, Province, Michael A, Rotter, Jerome I, Hayward, Caroline, Goodarzi, Mark O, Meigs, James B, and Dupuis, Josée

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Aging, Human Genome, Co-Repressor Proteins, Cohort Studies, DNA-Binding Proteins, Fasting, Female, Genetic Association Studies, Genetic Variation, Glucose, Glucose-6-Phosphatase, Haplotypes, Heart, Humans, Least-Squares Analysis, Male, Meta-Analysis as Topic, Models, Genetic, Molecular Epidemiology, Multivariate Analysis, Neoplasm Proteins, Phenotype, Reproducibility of Results, Research Design, meta-analysis, haplotype association tests, family samples, linear mixed effects model, Public Health and Health Services
Abstract

For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates.

Published
2016

26. Association Between Interstitial Lung Abnormalities and All-Cause Mortality

Author

Putman, Rachel K, Hatabu, Hiroto, Araki, Tetsuro, Gudmundsson, Gunnar, Gao, Wei, Nishino, Mizuki, Okajima, Yuka, Dupuis, Josée, Latourelle, Jeanne C, Cho, Michael H, El-Chemaly, Souheil, Coxson, Harvey O, Celli, Bartolome R, Fernandez, Isis E, Zazueta, Oscar E, Ross, James C, Harmouche, Rola, San José Estépar, Raúl, Diaz, Alejandro A, Sigurdsson, Sigurdur, Gudmundsson, Elías F, Eiríksdottír, Gudny, Aspelund, Thor, Budoff, Matthew J, Kinney, Gregory L, Hokanson, John E, Williams, Michelle C, Murchison, John T, MacNee, William, Hoffmann, Udo, O’Donnell, Christopher J, Launer, Lenore J, Harrris, Tamara B, Gudnason, Vilmundur, Silverman, Edwin K, O’Connor, George T, Washko, George R, Rosas, Ivan O, and Hunninghake, Gary M

Subjects
Epidemiology, Health Sciences, Chronic Obstructive Pulmonary Disease, Lung, Human Genome, Clinical Research, Genetics, Aetiology, 2.4 Surveillance and distribution, Respiratory, Cause of Death, Cohort Studies, Coronary Artery Disease, Female, Humans, Male, Neoplasms, Prevalence, Proportional Hazards Models, Prospective Studies, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Radiography, Smoking, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators, COPDGene Investigators, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceInterstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated.ObjectiveTo investigate whether interstitial lung abnormalities are associated with increased mortality.Design, setting, and populationProspective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006).ExposuresInterstitial lung abnormality status as determined by chest CT evaluation.Main outcomes and measuresAll-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.ResultsInterstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P

Published
2016

27. Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.

Author

Hochner, Hagit, Allard, Catherine, Granot-Hershkovitz, Einat, Chen, Jinbo, Sitlani, Colleen M, Sazdovska, Sandra, Lumley, Thomas, McKnight, Barbara, Rice, Kenneth, Enquobahrie, Daniel A, Meigs, James B, Kwok, Pui, Hivert, Marie-France, Borecki, Ingrid B, Gomez, Felicia, Wang, Ting, van Duijn, Cornelia, Amin, Najaf, Rotter, Jerome I, Stamatoyannopoulos, John, Meiner, Vardiella, Manor, Orly, Dupuis, Josée, Friedlander, Yechiel, and Siscovick, David S

Subjects
Humans, Obesity, Cholesterol, Insulin, Glucose, Body Mass Index, Waist-Hip Ratio, Genomic Imprinting, Polymorphism, Single Nucleotide, Adult, Female, Male, Adiposity, Apolipoprotein B-100, Waist Circumference, Genome-Wide Association Study, Young Adult, Developmental Biology, Genetics
Abstract

Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits.

Published
2015

28. Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels

Author

Kwan, Johnny SH, Hsu, Yi-Hsiang, Cheung, Ching-Lung, Dupuis, Josée, Saint-Pierre, Aude, Eriksson, Joel, Handelman, Samuel K, Aragaki, Aaron, Karasik, David, Pramstaller, Peter P, Kooperberg, Charles, Lacroix, Andrea Z, Larson, Martin G, Lau, Kam-Shing, Lorentzon, Mattias, Pichler, Irene, Sham, Pak C, Taliun, Daniel, Vandenput, Liesbeth, Kiel, Douglas P, Hicks, Andrew A, Jackson, Rebecca D, Ohlsson, Claes, Benjamin, Emelia J, and Kung, Annie WC

Subjects
Biological Sciences, Genetics, Human Genome, Biotechnology, Atherosclerosis, Asian People, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 17, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Humans, Male, Osteoprotegerin, Polymorphism, Genetic, Quantitative Trait, Heritable, White People, Medical and Health Sciences, Genetics & Heredity
Abstract

Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.

Published
2014

29. Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity

Author

Dimas, Antigone S, Lagou, Vasiliki, Barker, Adam, Knowles, Joshua W, Mägi, Reedik, Hivert, Marie-France, Benazzo, Andrea, Rybin, Denis, Jackson, Anne U, Stringham, Heather M, Song, Ci, Fischer-Rosinsky, Antje, Boesgaard, Trine Welløv, Grarup, Niels, Abbasi, Fahim A, Assimes, Themistocles L, Hao, Ke, Yang, Xia, Lecoeur, Cécile, Barroso, Inês, Bonnycastle, Lori L, Böttcher, Yvonne, Bumpstead, Suzannah, Chines, Peter S, Erdos, Michael R, Graessler, Jurgen, Kovacs, Peter, Morken, Mario A, Narisu, Narisu, Payne, Felicity, Stancakova, Alena, Swift, Amy J, Tönjes, Anke, Bornstein, Stefan R, Cauchi, Stéphane, Froguel, Philippe, Meyre, David, Schwarz, Peter EH, Häring, Hans-Ulrich, Smith, Ulf, Boehnke, Michael, Bergman, Richard N, Collins, Francis S, Mohlke, Karen L, Tuomilehto, Jaakko, Quertemous, Thomas, Lind, Lars, Hansen, Torben, Pedersen, Oluf, Walker, Mark, Pfeiffer, Andreas FH, Spranger, Joachim, Stumvoll, Michael, Meigs, James B, Wareham, Nicholas J, Kuusisto, Johanna, Laakso, Markku, Langenberg, Claudia, Dupuis, Josée, Watanabe, Richard M, Florez, Jose C, Ingelsson, Erik, McCarthy, Mark I, Prokopenko, Inga, and Investigators, on behalf of the MAGIC

Subjects
Biomedical and Clinical Sciences, Genetics, Diabetes, Autoimmune Disease, Clinical Research, Prevention, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Alleles, Cluster Analysis, Diabetes Mellitus, Type 2, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Insulin, Insulin Resistance, Insulin Secretion, Insulin-Secreting Cells, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Transcription Factors, MAGIC Investigators, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

Published
2014

30. Association of Levels of Fasting Glucose and Insulin With Rare Variants at the Chromosome 11p11.2-MADD Locus

Author

Cornes, Belinda K, Brody, Jennifer A, Nikpoor, Naghmeh, Morrison, Alanna C, Chu, Huan, Ahn, Byung Soo, Wang, Shuai, Dauriz, Marco, Barzilay, Joshua I, Dupuis, Josée, Florez, Jose C, Coresh, Josef, Gibbs, Richard A, Kao, WH Linda, Liu, Ching-Ti, McKnight, Barbara, Muzny, Donna, Pankow, James S, Reid, Jeffrey G, White, Charles C, Johnson, Andrew D, Wong, Tien Y, Psaty, Bruce M, Boerwinkle, Eric, Rotter, Jerome I, Siscovick, David S, Sladek, Robert, and Meigs, James B

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Human Genome, Diabetes, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Metabolic and endocrine, Aged, Aged, 80 and over, Aging, Blood Glucose, Chromosomes, Human, Pair 11, Cohort Studies, Death Domain Receptor Signaling Adaptor Proteins, Diabetes Mellitus, Type 2, Fasting, Female, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genomics, Guanine Nucleotide Exchange Factors, Heart Diseases, Humans, Insulin, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, genetic epidemiology, glucose, human genetics, insulin, molecular genetics, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundCommon variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.Methods and resultsSequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency 2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.ConclusionsSequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.

Published
2014

31. Genome-Wide Study of Percent Emphysema on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study

Author

Manichaikul, Ani, Hoffman, Eric A, Smolonska, Joanna, Gao, Wei, Cho, Michael H, Baumhauer, Heather, Budoff, Matthew, Austin, John HM, Washko, George R, Carr, J Jeffrey, Kaufman, Joel D, Pottinger, Tess, Powell, Charles A, Wijmenga, Cisca, Zanen, Pieter, Groen, Harry JM, Postma, Dirkje S, Wanner, Adam, Rouhani, Farshid N, Brantly, Mark L, Powell, Rhea, Smith, Benjamin M, Rabinowitz, Dan, Raffel, Leslie J, Stukovsky, Karen D Hinckley, Crapo, James D, Beaty, Terri H, Hokanson, John E, Silverman, Edwin K, Dupuis, Josée, O’Connor, George T, Boezen, H Marike, Rich, Stephen S, and Barr, R Graham

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Chronic Obstructive Pulmonary Disease, Human Genome, Emphysema, Lung, Genetics, Cardiovascular, Atherosclerosis, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Aged, Aged, 80 and over, Female, Follow-Up Studies, Genetic Markers, Genome-Wide Association Study, Genotyping Techniques, Humans, Male, Mannosidases, Middle Aged, N-Acetylglucosaminyltransferases, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Pulmonary Emphysema, RNA Helicases, Thiolester Hydrolases, Tomography, X-Ray Computed, United States, alpha-Mannosidase, snRNP Core Proteins, emphysema, computed tomography, multiethnic, cohort study, genetic association, Medical and Health Sciences, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract

RationalePulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.ObjectivesTo complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.MethodsWe determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than -950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.Measurements and main resultsAmong 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10(-8)) and PPT2 (rs10947233; P = 3.2 × 10(-8)), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase-related gene MAN2B1 (rs10411619; P = 1.1 × 10(-9); minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10(-10); MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10(-8); MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase-related gene, MAN1C1 (rs12130495; P = 9.9 × 10(-6); MAF, 13.3%) was associated with percent emphysema.ConclusionsOur results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.

Published
2014

32. Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

Author

Tang, Wenbo, Kowgier, Matthew, Loth, Daan W, Soler Artigas, María, Joubert, Bonnie R, Hodge, Emily, Gharib, Sina A, Smith, Albert V, Ruczinski, Ingo, Gudnason, Vilmundur, Mathias, Rasika A, Harris, Tamara B, Hansel, Nadia N, Launer, Lenore J, Barnes, Kathleen C, Hansen, Joyanna G, Albrecht, Eva, Aldrich, Melinda C, Allerhand, Michael, Barr, R Graham, Brusselle, Guy G, Couper, David J, Curjuric, Ivan, Davies, Gail, Deary, Ian J, Dupuis, Josée, Fall, Tove, Foy, Millennia, Franceschini, Nora, Gao, Wei, Gläser, Sven, Gu, Xiangjun, Hancock, Dana B, Heinrich, Joachim, Hofman, Albert, Imboden, Medea, Ingelsson, Erik, James, Alan, Karrasch, Stefan, Koch, Beate, Kritchevsky, Stephen B, Kumar, Ashish, Lahousse, Lies, Li, Guo, Lind, Lars, Lindgren, Cecilia, Liu, Yongmei, Lohman, Kurt, Lumley, Thomas, McArdle, Wendy L, Meibohm, Bernd, Morris, Andrew P, Morrison, Alanna C, Musk, Bill, North, Kari E, Palmer, Lyle J, Probst-Hensch, Nicole M, Psaty, Bruce M, Rivadeneira, Fernando, Rotter, Jerome I, Schulz, Holger, Smith, Lewis J, Sood, Akshay, Starr, John M, Strachan, David P, Teumer, Alexander, Uitterlinden, André G, Völzke, Henry, Voorman, Arend, Wain, Louise V, Wells, Martin T, Wilk, Jemma B, Williams, O Dale, Heckbert, Susan R, Stricker, Bruno H, London, Stephanie J, Fornage, Myriam, Tobin, Martin D, O'Connor, George T, Hall, Ian P, and Cassano, Patricia A

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Chronic Obstructive Pulmonary Disease, Human Genome, Lung, Clinical Research, Prevention, Respiratory, Adult, Chromosomes, Human, Pair 11, Female, Gene Expression Regulation, Genetic Loci, Genome-Wide Association Study, Humans, Longitudinal Studies, Male, Respiration, General Science & Technology
Abstract

BackgroundGenome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.MethodsWe performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.ResultsThe overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.ConclusionsIn this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

Published
2014

33. Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study.

Author

Legrand, Matthieu, Dupuis, Claire, Simon, Christelle, Gayat, Etienne, Mateo, Joaquim, Lukaszewicz, Anne-Claire, and Payen, Didier

Subjects
Humans, Sepsis, Shock, Septic, Length of Stay, Survival Rate, Retrospective Studies, Aged, Aged, 80 and over, Middle Aged, Intensive Care Units, Female, Male, Hemodynamics, Acute Kidney Injury, Emergency & Critical Care Medicine, Medical and Health Sciences
Abstract

IntroductionThe role of systemic hemodynamics in the pathogenesis of septic acute kidney injury (AKI) has received little attention. The purpose of this study was to investigate the association between systemic hemodynamics and new or persistent of AKI in severe sepsis.MethodsA retrospective study between 2006 and 2010 was performed in a surgical ICU in a teaching hospital. AKI was defined as development (new AKI) or persistent AKI during the five days following admission based on the Acute Kidney Injury Network (AKIN) criteria. We studied the association between the following hemodynamic targets within 24 hours of admission and AKI: central venous pressure (CVP), cardiac output (CO), mean arterial pressure (MAP), diastolic arterial pressure (DAP), central venous oxygen saturation (ScvO2) or mixed venous oxygen saturation (SvO2).ResultsThis study included 137 ICU septic patients. Of these, 69 had new or persistent AKI. AKI patients had a higher Simplified Acute Physiology Score (SAPS II) (57 (46 to 67) vs. 45 (33 to 52), P

Published
2013

34. Functional elements associated with hepatic regeneration in living donors after right hepatic lobectomy

Author

Everson, Gregory T, Hoefs, John C, Niemann, Claus U, Olthoff, Kim M, Dupuis, Robert, Lauriski, Shannon, Herman, Andrea, Milne, Norah, Gillespie, Brenda W, Goodrich, Nathan P, and Everhart, James E

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Regenerative Medicine, Biomedical Imaging, Liver Disease, Digestive Diseases, Adult, Alanine Transaminase, Bilirubin, Breath Tests, Caffeine, Cholates, Colorado, Erythromycin, Female, Hepatectomy, Humans, International Normalized Ratio, Linear Models, Liver, Liver Circulation, Liver Regeneration, Liver Transplantation, Living Donors, Male, Middle Aged, Organ Size, Predictive Value of Tests, Prospective Studies, Recovery of Function, San Francisco, Serum Albumin, Serum Albumin, Human, Time Factors, Tomography, Emission-Computed, Single-Photon, Tomography, X-Ray Computed, Treatment Outcome, Young Adult, Surgery, Clinical sciences
Abstract

We quantified the rates of hepatic regeneration and functional recovery for 6 months after right hepatic lobectomy in living donors for liver transplantation. Twelve donors were studied pre-donation (baseline); 8 were retested at a mean ± SD of 11±3 days after donation (T1), 10 were retested at a mean of 91±9 days after donation (T2), and 10 were retested at a mean of 185±17 days after donation (T3). Liver and spleen volumes were measured with computed tomography (CT) and single-photon emission computed tomography (SPECT). Hepatic metabolism was assessed with caffeine and erythromycin, and hepatic blood flow (HBF) was assessed with cholates, galactose, and the perfused hepatic mass (PHM) by SPECT. The regeneration rates (mL kg(-1) of body weight day(-1)) by CT were 0.60±0.22 mL from the baseline to T1, 0.05±0.02 mL from T1 to T2, and 0.01±0.01 from T2 to T3; by SPECT they were 0.54±0.20, 0.04±0.01, and 0.01±0.02, respectively. At T3, the liver volumes were 84%±7% of the baseline according to CT and 92%±13% of the baseline according to SPECT. Changes in the hepatic metabolism did not achieve statistical significance. At T1, the unadjusted clearance ratios with respect to the baseline were 0.75±0.07 for intravenous cholate (P

Published
2013

35. A genome-wide association search for type 2 diabetes genes in African Americans.

Author

Palmer, Nicholette D, McDonough, Caitrin W, Hicks, Pamela J, Roh, Bong H, Wing, Maria R, An, S Sandy, Hester, Jessica M, Cooke, Jessica N, Bostrom, Meredith A, Rudock, Megan E, Talbert, Matthew E, Lewis, Joshua P, DIAGRAM Consortium, MAGIC Investigators, Ferrara, Assiamira, Lu, Lingyi, Ziegler, Julie T, Sale, Michele M, Divers, Jasmin, Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N, Ng, Maggie CY, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Morris, Andrew P, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Langenberg, Claudia, Hofmann, Oliver M, Dupuis, Josée, Qi, Lu, Segrè, Ayellet V, van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Couper, David J, Crawford, Gabe, Doney, Alex SF, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul RV, Jørgensen, Torben, Kao, Wen HL, Klopp, Norman, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, and Midthjell, Kristian

Subjects
DIAGRAM Consortium, MAGIC Investigators, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Case-Control Studies, Cohort Studies, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, African Americans, Female, Male, Meta-Analysis as Topic, Validation Studies as Topic, Genome-Wide Association Study, Diabetes Mellitus, Type 2, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

Published
2012

36. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

Author

Strawbridge, Rona J, Dupuis, Josée, Prokopenko, Inga, Barker, Adam, Ahlqvist, Emma, Rybin, Denis, Petrie, John R, Travers, Mary E, Bouatia-Naji, Nabila, Dimas, Antigone S, Nica, Alexandra, Wheeler, Eleanor, Chen, Han, Voight, Benjamin F, Taneera, Jalal, Kanoni, Stavroula, Peden, John F, Turrini, Fabiola, Gustafsson, Stefan, Zabena, Carina, Almgren, Peter, Barker, David JP, Barnes, Daniel, Dennison, Elaine M, Eriksson, Johan G, Eriksson, Per, Eury, Elodie, Folkersen, Lasse, Fox, Caroline S, Frayling, Timothy M, Goel, Anuj, Gu, Harvest F, Horikoshi, Momoko, Isomaa, Bo, Jackson, Anne U, Jameson, Karen A, Kajantie, Eero, Kerr-Conte, Julie, Kuulasmaa, Teemu, Kuusisto, Johanna, Loos, Ruth JF, Luan, Jian'an, Makrilakis, Konstantinos, Manning, Alisa K, Martínez-Larrad, María Teresa, Narisu, Narisu, Nastase Mannila, Maria, Ohrvik, John, Osmond, Clive, Pascoe, Laura, Payne, Felicity, Sayer, Avan A, Sennblad, Bengt, Silveira, Angela, Stancáková, Alena, Stirrups, Kathy, Swift, Amy J, Syvänen, Ann-Christine, Tuomi, Tiinamaija, van 't Hooft, Ferdinand M, Walker, Mark, Weedon, Michael N, Xie, Weijia, Zethelius, Björn, DIAGRAM Consortium, GIANT Consortium, MuTHER Consortium, CARDIoGRAM Consortium, C4D Consortium, Ongen, Halit, Mälarstig, Anders, Hopewell, Jemma C, Saleheen, Danish, Chambers, John, Parish, Sarah, Danesh, John, Kooner, Jaspal, Ostenson, Claes-Göran, Lind, Lars, Cooper, Cyrus C, Serrano-Ríos, Manuel, Ferrannini, Ele, Forsen, Tom J, Clarke, Robert, Franzosi, Maria Grazia, Seedorf, Udo, Watkins, Hugh, Froguel, Philippe, Johnson, Paul, Deloukas, Panos, Collins, Francis S, Laakso, Markku, Dermitzakis, Emmanouil T, Boehnke, Michael, McCarthy, Mark I, Wareham, Nicholas J, Groop, Leif, Pattou, François, Gloyn, Anna L, and Dedoussis, George V

Subjects
DIAGRAM Consortium, GIANT Consortium, MuTHER Consortium, CARDIoGRAM Consortium, C4D Consortium, Humans, Diabetes Mellitus, Type 2, Insulin, Proinsulin, Fasting, Genotype, Polymorphism, Single Nucleotide, Genome, Human, Adult, Female, Male, Genetic Variation, Diabetes Mellitus, Type 2, Polymorphism, Single Nucleotide, Genome, Human, Endocrinology & Metabolism, Medical and Health Sciences
Abstract

ObjectiveProinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.Research design and methodsWe have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.ResultsNine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.ConclusionsWe have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011

37. Thoracic sarcopenia as a predictive factor of SARS-COV2 evolution

Author

J, Koehler, Y, Boirie, L, Bensid, B, Pereira, N, Ghelis, C, Dupuis, A, Tournadre, L, Boyer, L, Cassagnes, CHU Clermont-Ferrand, Unité de Nutrition Humaine (UNH), and Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA)

Subjects
Male, Sarcopenia, SMI, Nutrition and Dietetics, SARS-CoV-2, SMD, Malnutrition, Middle Aged, Critical Care and Intensive Care Medicine, SARS-COV2, Humans, RNA, Viral, Female, Tomography, X-Ray Computed, Muscle, Skeletal, Covid-19, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Retrospective Studies, COVID
Abstract

Purpose: Evaluation of CT sarcopenia as a predictor of intensive care hospitalization during SARS-COV2 infection.Materials and methods: Single-center retrospective study of patients admitted to hospital with SARS-COV2 infection. The estimation of muscle mass (skeletal muscle index (SMI)) for sarcopenia, measure-ment of muscle density for muscle quality and body adiposity, were based on CT views on the T4 and L3 levels measured at admission. Demographic data, percentage of pulmonary parenchymal involvement as well as the orientation of patients during hospitalization and the risk of hospitalization in intensive care were collected.Results: A total of 162 patients hospitalized for SARS-COV2 infection were included (92 men and 70 women, with an average age of 64.6 years and an average BMI of 27.4). The muscle area measured at the level of L3 was significantly associated with the patient's unfavorable evolution (124.4cm2 [97; 147] vs 141.5 cm2 [108; 173]) (p 1/4 0.007), as was a lowered SMI (p < 0.001) and the muscle area measured in T4 (OR 1/4 0.98 [0.97; 0.99]), (p 1/4 0.026). Finally, an abdominal visceral fat area measured at the level of L3 was also associated with a risk of hospitalization in intensive care (249.4cm2 [173; 313] vs 147.5cm2 [93.1; 228] (p < 0.001).Conclusion: This study demonstrates that thoracic and abdominal sarcopenia are independently asso-ciated with an increased risk of hospitalization in an intensive care unit, suggesting the need to assess sarcopenia on admission during SARS-COV2 infection.

Published
2022
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38. Rapid changes in shape and number of MHC class II expressing cells in rat airways after Mycoplasma pulmonis infection

Author

Umemoto, Eric Y, Brokaw, James J, Dupuis, Marc, and McDonald, Donald M

Subjects
Biomedical and Clinical Sciences, Immunology, Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Animals, Antibodies, Bacterial, Antibodies, Monoclonal, Antigen-Presenting Cells, Dendritic Cells, Enzyme-Linked Immunosorbent Assay, Histocompatibility Antigens Class II, Immunohistochemistry, Male, Mycoplasma, Mycoplasma Infections, Rats, Rats, Wistar, Respiratory Mucosa, Specific Pathogen-Free Organisms, Trachea, antigen-presenting cells, chronic inflammation, dendritic cells, immunohistochemistry, morphometry, OX6, trachea
Abstract

Mycoplasma pulmonis infection in rodents causes a chronic inflammatory airway disease with a strong immunological component, leading to mucosal remodeling and angiogenesis. We sought to determine the effect of this infection on the shape and number of dendritic cells and other major histocompatibility complex (MHC) class II expressing cells in the airway mucosa of Wistar rats. Changes in the shape of subepithelial OX6 (anti-MHC class II)-immunoreactive cells were evident in the tracheal mucosa 2 days after intranasal inoculation with M. pulmonis. By 1 week, the shape of the cells had changed from stellate to rounded (mean shape index increased from 0.42 to 0.77). The number of OX6-positive cells was increased 6-fold at 1 week and 16-fold at 4 weeks. Coincident with these changes, many columnar epithelial cells developed OX6 immunoreactivity, which was still present at 4 weeks. We conclude that M. pulmonis infection creates a potent immunologic stimulus that augments and transforms the OX6-immunoreactive cell population in the airways by changing the functional state of airway dendritic cells, initiating an influx of MHC class II expressing cells, and activating expression of MHC class II molecules by airway epithelial cells.

Published
2002

39. Loss of hypothalamic MCH decreases food intake in amyotrophic lateral sclerosis

Author

Matei Bolborea, Pauline Vercruysse, Tselmen Daria, Johanna C. Reiners, Najwa Ouali Alami, Simon J. Guillot, Stéphane Dieterlé, Jérôme Sinniger, Jelena Scekic-Zahirovic, Amela Londo, Hippolyte Arcay, Marc-Antoine Goy, Claudia Nelson de Tapia, Dietmar R. Thal, Kazumoto Shibuya, Ryo Otani, Kimihito Arai, Satoshi Kuwabara, Albert C. Ludolph, Francesco Roselli, Deniz Yilmazer-Hanke, and Luc Dupuis

Subjects
Male, metabolism [Neuropeptides], Clinical Neurology, MELANIN-CONCENTRATING HORMONE, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Eating, Superoxide Dismutase-1, Weight Loss, Animals, ddc:610, BRAIN, RISK, Orexins, Science & Technology, SUPEROXIDE-DISMUTASE SOD1, Amyotrophic Lateral Sclerosis, Neuropeptides, Neurosciences, MOUSE MODEL, BODY-MASS INDEX, MICE, PATHOLOGY, SURVIVAL, Neurology (clinical), Neurosciences & Neurology, OVEREXPRESSION, Life Sciences & Biomedicine
Abstract

Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with survival. Neural mechanisms underlying metabolic impairment in ALS remain unknown. ALS patients and presymptomatic gene carriers have early hypothalamic atrophy. The lateral hypothalamic area (LHA) controls metabolic homeostasis through the secretion of neuropeptides such as orexin/hypocretin and melanin-concentrating hormone (MCH). Here, we show loss of MCH-positive neurons in three mouse models of ALS based on SOD1 or FUS mutations. Supplementation with MCH (1.2 µg/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1G86R mice. MCH supplementation increased food intake, rescued expression of the key appetite-related neuropeptide AgRP (agouti-related protein) and modified respiratory exchange ratio, suggesting increased carbohydrate usage during the inactive phase. Importantly, we document pTDP-43 pathology and neurodegeneration in the LHA of sporadic ALS patients. Neuronal cell loss was associated with pTDP-43-positive inclusions and signs of neurodegeneration in MCH-positive neurons. These results suggest that hypothalamic MCH is lost in ALS and contributes to the metabolic changes, including weight loss and decreased appetite.

Published
2023
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40. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Author

Richard A. Jensen, Denis Rybin, Jaakko Tuomilehto, Reedik Mägi, Inga Prokopenko, Jeffrey R. O'Connell, Marcus E. Kleber, Han Chen, Geoffrey A. Walford, Allan Linnenberg, Anke Tönjes, Francis S. Collins, Sonsoles Morcillo, Gemma Rojo-Martínez, Kenneth Rice, Jose C. Florez, Leif Groop, Manuel Serrano-Ríos, Josée Dupuis, Alisa K. Manning, Peter Kovacs, Torben Jørgensen, Graciela E. Delgado, Alena Stančáková, Hans-Ulrich Häring, Claudia Langenberg, Joshua P. Lewis, Norbert Stefan, Markku Laakso, Torben Hansen, Bruce M. Psaty, Jian'an Luan, Michael Stumvoll, Mark O. Goodarzi, Robert A. Scott, Oluf Pedersen, Ching-Ti Liu, Michael N. Weedon, Michael Boehnke, Ulf Smith, David S. Siscovick, Aaron Leong, Weijia Xie, James B. Meigs, Claes Landenvall, Anne U. Jackson, Joseph M. Zmuda, Mary L. Biggs, Jerome I. Rotter, Federico Soriguer, Winfried März, Zhongyang Zhang, May E. Montasser, Arturo Corbatón-Anchuelo, J M Gómez-Zumaquero, Günther Silbernagel, Kristine Færch, Karen L. Mohlke, Heikki A. Koistinen, Yii-Der Ida Chen, Jaeyoung Hong, Gracia María Martín-Núñez, María Teresa Martínez-Larrad, Emil V. R. Appel, Niels Grarup, Harald Staiger, Johanna Kuusisto, Lars Lind, Nicholas J. Wareham, Andreas Fritsche, Stefan Gustafsson, Andrew P. Morris, Richard N. Bergman, Mark Walker, Cecilia M. Lindgren, Erik Ingelsson, Jorge R. Kizer, Timothy M. Frayling, and Fausto Machicao

Subjects
0301 basic medicine, Male, Insulin Receptor Substrate Proteins, Endocrinology, Diabetes and Metabolism, Locus (genetics), Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, Endocrinology & Metabolism, Insulin resistance, Genotype, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Genetic association, Genetics, business.industry, Insulin sensitivity, Genetics/Genomes/Proteomics/Metabolomics, 11 Medical And Health Sciences, medicine.disease, IRS1, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, Chemokines, CC, Female, Insulin Resistance, business, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Published
2023
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41. Rapid Improvement after Starting Elexacaftor–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease

Author

Pierre-Régis Burgel, Isabelle Durieu, Raphaël Chiron, Sophie Ramel, Isabelle Danner-Boucher, Anne Prevotat, Dominique Grenet, Christophe Marguet, Martine Reynaud-Gaubert, Julie Macey, Laurent Mely, Annlyse Fanton, Sébastien Quetant, Lydie Lemonnier, Jean-Louis Paillasseur, Jennifer Da Silva, Clémence Martin, Claire Andrejak, Arnaud Becourt, Julie Mounard, Claire Poulet, Cinthia Rames, Marie Talleux, Marie-Chantal Chevalier, Estelle Darviot, Marie Jouvenot, Caroline Marien, Audrey Paris, Cécile Pelatan, Christine Person, Pascaline Priou, Françoise Troussier, Thierry Urban, Marie-Laure Dalphin, Jean-Charles Dalphin, Alice Ladaurade, Didier Pernet, Bénédicte Richaud-Thiriez, Pauline Roux-Claude, Nathalia Blanc, Vincent Boisserie-Lacroix, Stephanie Bui, Cyrielle Collet, Stéphane Debelleix, Emmanuel Bergot, Jacques Brouard, Karine Campbell, Muriel Laurans, Virginie Ribault, Corinne Borderon, Marie-Christine Heraud, Guillaume Labbe, Sylvie Montcouquiol, Isabelle Petit, Marc Ruivard, Céline Delestrain, Benoit Douvry, Ralph Epaud, Bernard Maitre, Natascha Remus, Guillaume Beltramo, Anne Houzel, Frédéric Huet, Stéphanie Perez, Amale Boldron-Ghaddar, Manuela Scalbert, Rabah Bouzioukh, Charles Simon, Boubou Camara, Rébecca Hamidfar, Catherine Llerena, Isabelle Pin, Antoine Deschildre, Alice Gicquello, Olivier Le Rouzic, Clara Leroy, Nicolas Paris, Thierry Perez, Caroline Thumerelle, Dominique Turck, Nathalie Wizla, Magali Dupuy-Grasset, Jane Languepin, Alexandra Masson-Rouchaud, Céline Menetrey, Stéphane Durupt, Sophie L’Excellent, Raphaele Nove-Josserand, Camille Ohlmann, Phillipe Reix, Quitterie Reynaud, Marie-Christine Werck-Gallois, Mélissandre Baravalle, Bérangère Coltey, Nadine Desmazes-Dufeu, Jean-Christophe Dubus, Clarisse Gautier, Jean-Baptiste Rey, Nathalie Stremler, Davide Caimmi, Margot Devrait, Johan Moreau, Yves Billon, Aurore Blondé, Anne Guillaumot, Sébastien Kiefer, Laura Peretti, Aurélie Tatopoulos, Angélica Tiotiu, Myriam Benhamida, Tiphaine Bihouee, Emmanuel Eschapasse, Adrien Tissot, Marie Giannantonio, Sylvie Leroy, Carole Piccini-Bailly, Johana Pradelli, Jonathan Messika, Véronique Boussaud, Nicolas Carlier, Isabelle Honoré, Dominique Hubert, Reem Kanaan, Céline Bailly-Botuha, Frédérique Chedevergne, Jacques De Blic, Christophe Delacourt, David Drummond, Brigitte Fauroux, Chantal Karila, Muriel Le Bourgeois, Isabelle Sermet, Bertrand Delaisi, Michèle Gerardin, Veronique Houdouin, Laurence Leclainche, Guillaume Aubertin, Laura Berdah, Annick Clement, Harriet Corvol, Nadia Nathan, Blandine Prevost, Nicolas Richard, Aline Tamalet, Jessica Taytard, Guillaume Thouvenin, Barbara Tourniaire, Michel Abely, Katia Bessaci-Kabouya, Sandra Dury, Bruno Ravoninjatovo, Alain Dabadie, Michel Dagorne, Eric Deneuville, Marie Jamin, Mélanie Ribault, Clémentine Vigier, Chantal Belleguic, Graziella Brinchault, Benoit Desrues, Audrey Barzic, Anne Dirou-Prigent, Jean Le Bihan, Krista Revert, Thomas Ropars, Laure Couderc, Stéphane Dominique, Hélène Morisse-Pradier, Stéphanie Pramil, Luc Thiberville, Nathalie Allou, Laurent Enaud, Elsa Gachelin, Eric Huchot, Annabelle Payet, Caroline Perisson, Saguiraly Piyaraly, Sophie Valois, Audrey Herzog, Romain Kessler, Michele Porzio, Laurence Weiss, Laurence Beaumont, Olivier Brugiere, Sylvie Colin, de Verdiere, Elise Cuquemelle, Sandra De Miranda, Adbdul Monem Hamid, François Parquin, Clément Picard, Antoine Roux, Charlotte Roy, François Bremont, Alain Didier, Marion Dupuis, Guillaume Faviez, Géraldine Labouret, Marie Mittaine, Marlène Murris-Espin, Léa Roditis, Laure Cosson, Patrice Diot, Thomas Flament, Charlotte Giraut, Julie Mankikian, Baptiste Arnouat, Gaétane Mousset, Véronique Storni, Philippe Vigneron, Emmanuelle Coirier-Duet, Asma Gabsi, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), Université de Lyon, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Fondation ILDYS (ILDYS), Institut du Thorax [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Foch [Suresnes], CHU Rouen, Normandie Université (NU), INSERM-TRANSFERT [Paris] (IT), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rouen Normandie (UNIROUEN), Hôpital Nord [CHU - APHM], Aix Marseille Université (AMU), CHU Bordeaux [Bordeaux], Hôpital Renée Sabran [CHU - HCL], CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire [Grenoble] (CHU), Vaincre la Mucoviscidose, Association de lutte contre la Mucoviscidose, EFFI-STAT, URC/CIC Paris Descartes Necker Cochin, Hôpital Necker, Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Supported by Vaincre la Mucoviscidose, Fondation Sauver la Vie, Universite Paris Descartes, Filiere Maladies Rares Muco-CFTR, and Legs PascalBonnet., Participating Investigators of the FrenchCystic Fibrosis Reference Network StudyGroup:Claire Andrejak, Arnaud Becourt, JulieMounard, Claire Poulet, Cinthia Rames, MarieTalleux (Amiens), Marie-Chantal Chevalier,Estelle Darviot, Marie Jouvenot, Caroline Marien,Audrey Paris, C ecile Pelatan, Christine Person,Pascaline Priou, Franc ̧oise Troussier, ThierryUrban (Angers-Le Mans), Marie-Laure Dalphin,Jean-Charles Dalphin, Alice Ladaurade, DidierPernet, B en edicte Richaud-Thiriez, PaulineRoux-Claude (Besanc ̧on), Nathalia Blanc,Vincent Boisserie-Lacroix, Stephanie Bui,Cyrielle Collet, St ephane Debelleix, Julie Macey(Bordeaux), Emmanuel Bergot, JacquesBrouard, Karine Campbell, Muriel Laurans,Virginie Ribault (Caen), Corinne Borderon,Marie-Christine Heraud, Guillaume Labbe,SylvieMontcouquiol, Isabelle Petit, Marc Ruivard(Clermont-Ferrand), C eline Delestrain, BenoitDouvry, Ralph Epaud, Bernard Maitre, NataschaRemus (Cr eteil), Guillaume Beltramo, AnnlyseFanton, Anne Houzel, Fr ed eric Huet, St ephaniePerez (Dijon), AmaleBoldron-Ghaddar, ManuelaScalbert (Dunkerque), Rabah Bouzioukh,Laurent Mely, Charles Simon (Giens), BoubouCamara, R ebecca Hamidfar, Catherine Llerena,Isabelle Pin, S ebastien Quetant (Grenoble), Antoine Deschildre, Alice Gicquello, Olivier LeRouzic, Clara Leroy, Nicolas Paris, Thierry Perez,Anne Prevotat, Caroline Thumerelle, DominiqueTurck, Nathalie Wizla (Lille), Magali Dupuy-Grasset, Jane Languepin, Alexandra Masson-Rouchaud, C eline Menetrey (Limoges), IsabelleDurieu, St ephane Durupt, Sophie L’Excellent,Raphaele Nove-Josserand, Camille Ohlmann,Phillipe Reix, Quitterie Reynaud, Marie-ChristineWerck-Gallois (Lyon), M elissandre Baravalle,B erang ere Coltey, Nadine Desmazes-Dufeu,Jean-Christophe Dubus, Clarisse Gautier, Jean-Baptiste Rey, Martine Reynaud-Gaubert,Nathalie Stremler (Marseille), Davide Caimmi,Rapha€el Chiron, Margot Devrait, Johan Moreau(Montpellier), Yves Billon, Aurore Blond e, AnneGuillaumot, S ebastien Kiefer, Laura Peretti,Aur elie Tatopoulos, Ang elica Tiotiu (Nancy), Myriam Benhamida, Tiphaine Bihouee, IsabelleDanner-Boucher, Emmanuel Eschapasse,Adrien Tissot (Nantes), Marie Giannantonio,Sylvie Leroy, Carole Piccini-Bailly, JohanaPradelli (Nice), Jonathan Messika (Paris, Bichat), V eronique Boussaud, Pierre-R egis Burgel,Nicolas Carlier, Isabelle Honor e, DominiqueHubert, Reem Kanaan, Cl emence Martin (Paris,Cochin), C eline Bailly-Botuha, Fr ed eriqueChedevergne, Jacques De Blic, ChristopheDelacourt, David Drummond, Brigitte Fauroux,Chantal Karila, Muriel Le Bourgeois, IsabelleSermet (Paris, Necker), Bertrand Delaisi,Mich ele Gerardin, Veronique Houdouin,Laurence Leclainche (Paris, Robert Debr e), Guillaume Aubertin, Laura Berdah, AnnickClement, Harriet Corvol, Nadia Nathan, BlandinePrevost, Nicolas Richard, Aline Tamalet, JessicaTaytard, Guillaume Thouvenin, BarbaraTourniaire (Paris, Trousseau), Michel Abely,Katia Bessaci-Kabouya, Sandra Dury, BrunoRavoninjatovo (Reims), Alain Dabadie, MichelDagorne, Eric Deneuville, Marie Jamin, M elanieRibault, Cl ementine Vigier (Rennes – SaintBrieuc), Chantal Belleguic, Graziella Brinchault,Benoit Desrues (Rennes), Audrey Barzic, AnneDirou-Prigent, Jean Le Bihan, Sophie Ramel,Krista Revert, Thomas Ropars (Roscoff), LaureCouderc, St ephane Dominique, ChristopheMarguet, H el ene Morisse-Pradier, St ephaniePramil, Luc Thiberville (Rouen), Nathalie Allou,Laurent Enaud, Elsa Gachelin, Eric Huchot,Annabelle Payet, Caroline Perisson, SaguiralyPiyaraly, Sophie Valois (La R eunion), AudreyHerzog, Romain Kessler, Michele Porzio,Laurence Weiss (Strasbourg), LaurenceBeaumont, Olivier Brugiere, Sylvie Colin deVerdiere, Elise Cuquemelle, Sandra De Miranda,Dominique Grenet, Adbdul Monem Hamid,Franc ̧ois Parquin, Cl ementPicard, Antoine Roux,Charlotte Roy (Suresnes), Franc ̧ois Bremont,Alain Didier, Marion Dupuis, Guillaume Faviez,G eraldine Labouret, Marie Mittaine, Marl eneMurris-Espin, L ea Roditis (Toulouse), LaureCosson, Patrice Diot, Thomas Flament, CharlotteGiraut, JulieMankikian(Tours), Baptiste Arnouat,Ga etane Mousset, V eronique Storni, PhilippeVigneron (Vannes-Lorient), and Emmanuelle Coirier-Duet, and Asma Gabsi (Versailles)

Subjects
Lung Diseases, Male, elexacaftor, Indoles, Cystic Fibrosis, Pyridines, medicine.medical_treatment, Regulator, Aminophenols, Critical Care and Intensive Care Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Cystic fibrosis, Gastroenterology, Membrane Potentials, Ivacaftor, 0302 clinical medicine, Prospective Studies, 030212 general & internal medicine, Chloride Channel Agonists, Aged, 80 and over, Middle Aged, Transmembrane protein, Drug Combinations, Quinolines, Female, France, medicine.drug, Adult, Pulmonary and Respiratory Medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, cystic fibrosis transmembrane conductance regulator modulators, Adolescent, Pulmonary disease, Young Adult, 03 medical and health sciences, Internal medicine, lung transplantation, medicine, Humans, Lung transplantation, In patient, Aged, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Editorials, medicine.disease, 030228 respiratory system, Tezacaftor, Pyrazoles, business
Abstract

International audience; Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1)

Published
2021
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42. External validation of a commercially available deep learning algorithm for fracture detection in children

Author

Raphael Veil, Michel Dupuis, Catherine Adamsbaum, and Léo Delbos

Subjects
Male, Adolescent, Radiography, Sensitivity and Specificity, Deep Learning, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Child, Retrospective Studies, Radiological and Ultrasound Technology, business.industry, Deep learning, Infant, Newborn, External validation, Infant, Retrospective cohort study, Mean age, General Medicine, Predictive value, Child, Preschool, Cohort, Fracture (geology), Female, Artificial intelligence, business, Algorithm, Algorithms
Abstract

The purpose of this study was to conduct an external validation of a fracture assessment deep learning algorithm (Rayvolve®) using digital radiographs from a real-life cohort of children presenting routinely to the emergency room.This retrospective study was conducted on 2634 radiography sets (5865 images) from 2549 children (1459 boys, 1090 girls; mean age, 8.5 ± 4.5 [SD] years; age range: 0-17 years) referred by the pediatric emergency room for trauma. For each set was recorded whether one or more fractures were found, the number of fractures, and their location found by the senior radiologists and the algorithm. Using the senior radiologist diagnosis as the standard of reference, the diagnostic performance of deep learning algorithm (Rayvolve®) was calculated via three different approaches: a detection approach (presence/absence of a fracture as a binary variable), an enumeration approach (exact number of fractures detected) and a localization approach (focusing on whether the detected fractures were correctly localized). Subgroup analyses were performed according to the presence of a cast or not, age category (0-4 vs. 5-18 years) and anatomical region.Regarding detection approach, the deep learning algorithm yielded 95.7% sensitivity (95% CI: 94.0-96.9), 91.2% specificity (95% CI: 89.8-92.5) and 92.6% accuracy (95% CI: 91.5-93.6). Regarding enumeration and localization approaches, the deep learning algorithm yielded 94.1% sensitivity (95% CI: 92.1-95.6), 88.8% specificity (95% CI: 87.3-90.2) and 90.4% accuracy (95% CI: 89.2-91.5) for both approaches. Regarding age-related subgroup analyses, the deep learning algorithm yielded greater sensitivity and negative predictive value in the 5-18-years age group than in the 0-4-years age group for the detection approach (P0.001 and P = 0.002) and for the enumeration and localization approaches (P = 0.012 and P = 0.028). The high negative predictive value was robust, persisting in all of the subgroup analyses, except for patients with casts (P = 0.001 for the detection approach and P0.001 for the enumeration and localization approaches).The Rayvolve® deep learning algorithm is very reliable for detecting fractures in children, especially in those older than 4 years and without cast.

Published
2022
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43. Swallowing the pill of adverse effects: A qualitative study of patients' and pharmacists' experiences and decision‐making regarding the adverse effects of chronic pain medications

Author

Lise Dassieu, Emilie Paul‐Savoie, Élise Develay, Ana Cecilia Villela Guilhon, Anaïs Lacasse, Line Guénette, Kadija Perreault, Hélène Beaudry, Laurent Dupuis, and the Quebec Consortium on Adverse Effects of Pain Medications

Subjects
Male, Medicine (General), education, Public Health, Environmental and Occupational Health, Community Pharmacy Services, Pharmacists, Deglutition, Professional Role, R5-920, community pharmacists, Quality of Life, adverse effects, analgesics, Humans, decision‐making, Public aspects of medicine, RA1-1270, chronic pain, person‐centred care
Abstract

Introduction Pharmacological treatments of chronic pain can lead to numerous and sometimes serious adverse effects. Drawing on a social science approach to chronic illness, this study aimed to understand the experiences of people living with chronic pain and community pharmacists regarding the definition, prevention and management of analgesic adverse effects. Methods This qualitative study proceeded through 12 online focus groups (FGs) with people living with chronic pain (n = 26) and community pharmacists (n = 19), conducted between July 2020 and February 2021 in the province of Quebec, Canada. The semistructured discussion guides covered participants' definitions of adverse effects and decision‐making regarding their prevention and management. Discussions were audio‐recorded, transcribed verbatim and analysed using grounded theory. Results Both people with chronic pain and pharmacists provided varying definitions of analgesic adverse effects depending on patients' social and clinical characteristics. Present quality of life and serious long‐term risks related to treatment were described as key dimensions influencing adverse effect appraisal. Dilemmas and discrepancies occurred between patients and pharmacists when choosing to prioritize pain relief or adverse effect prevention. Some patients lacked information about their medications and wanted to be more involved in decisions, while many pharmacists were concerned by patients' self‐management of adverse effects. Preventing opioid‐related overdoses often led pharmacists to policing practices. Despite most pharmacists wishing they could have a key role in the management of pain and adverse effects face organizational and financial barriers. Conclusion Defining, preventing and managing adverse effects in the treatment of chronic pain requires a person‐centred approach and shared decision‐making. Clinical training improvements and healthcare organization changes are needed to support pharmacists in providing patients with community‐based follow‐up and reliable information about the adverse effects of chronic pain treatments. Patient or Public Contribution A person with lived experience of chronic pain was involved as a coinvestigator in the study. He contributed to shaping the study design and objectives, including major methodological decisions such as the choice of pharmacists as the most appropriate professionals to investigate. In addition, 26 individuals with chronic pain shared their experiences extensively during the FGs.

Published
2022

44. Right ventricular function and its coupling to pulmonary circulation predicts exercise tolerance in systolic heart failure

Author

Valéry Legris, Bernard Thibault, Jocelyn Dupuis, Michel White, Anita W. Asgar, Annik Fortier, Céline Pitre, Nadia Bouabdallaoui, Christine Henri, Eileen O'Meara, Anique Ducharme, and EARTH Investigators

Subjects
Male, Pulmonary Circulation, Stroke Volume, Original Articles, RV to pulmonary arterial coupling, Middle Aged, Heart failure with reduced ejection fraction, Right ventricular function, Ventricular Function, Left, Exercise tolerance, Echocardiography, RC666-701, Ventricular Function, Right, Humans, Diseases of the circulatory (Cardiovascular) system, Original Article, Female, Cardiology and Cardiovascular Medicine, Aged, Heart Failure, Systolic
Abstract

Aims Right ventricular (RV) dysfunction, pulmonary hypertension, and exercise intolerance have prognostic values, but their interrelation is not fully understood. We investigated how RV function alone and its coupling with pulmonary circulation (RV‐PA) predict cardio‐respiratory fitness in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results The Evaluation of Resynchronization Therapy for Heart Failure (EARTH) study included 205 HFrEF patients with narrow (n = 85) and prolonged (n = 120) QRS duration undergoing implantable cardioverter defibrillator implantation. All patients underwent a comprehensive evaluation with exercise tolerance tests and echocardiography. We investigated the correlations at baseline between RV parameters {size, function [tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RV‐FAC), and RV myocardial performance index (RV‐MPI)], pulmonary artery systolic pressure (PASP), and tricuspid regurgitation}; left ventricular ejection fraction (LVEF), left ventricular end‐diastolic volume index (LVEDVi), and left atrial volume index (LAVi); and cardiopulmonary exercise test (CPET) [peak VO2, minute ventilation/carbon dioxide production (VE/VCO2), 6 min walk distance (6MWD), and submaximal exercise duration (SED)]. We also studied the relationship between RV‐PA coupling (TAPSE/PASP ratio) and echocardiographic parameters in patients with both data available. Univariate and multivariate linear regression models were used. Patients enrolled in EARTH (overall population) were mostly male (73.2%), mean age 61.0 ± 9.8 years, New York Heart Association class II–III (87.8%), mean LVEF of 26.6 ± 7.7%, and reduced peak VO2 (15.1 ± 4.6 mL/kg/min). Of these, 100 had both TAPSE and PASP available (TAPSE/PASP population): they exhibited higher BNP, wider QRS duration, larger LVEDVi, with more having tricuspid regurgitation compared with the 105 patients for whom these values were not available (all P

Published
2022

45. An Integrative Genomic Strategy Identifies sRAGE as a Causal and Protective Biomarker of Lung Function

Author

Edwin K. Silverman, Shih-Jen Hwang, Paul Courchesne, Daniel Levy, George R. Washko, Josée Dupuis, Joshua Keefe, George T. O'Connor, Gha Young Lee, Joseph P. Mizgerd, Chen Yao, and Michael H. Cho

Subjects
Adult, Lung Diseases, Male, Pulmonary and Respiratory Medicine, Quantitative Trait Loci, Receptor for Advanced Glycation End Products, Vital Capacity, Single-nucleotide polymorphism, Genome-wide association study, Quantitative trait locus, Critical Care and Intensive Care Medicine, Bioinformatics, Framingham Heart Study, Forced Expiratory Volume, Mendelian randomization, Humans, SNP, Medicine, Lung, Aged, Genetic association, business.industry, Genomics, Mendelian Randomization Analysis, Middle Aged, Protective Factors, Respiratory Function Tests, Biomarker (cell), Female, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract

Background There are few clinically useful circulating biomarkers of lung function and lung disease. We hypothesized that genome-wide association studies (GWAS) of circulating proteins in conjunction with GWAS of pulmonary traits represents a clinically relevant approach to identifying causal proteins and therapeutically useful insights into mechanisms related to lung function and disease. Study Question Can an integrative genomic strategy using GWAS of plasma soluble receptor for advanced glycation end-products (sRAGE) levels in conjunction with GWAS of lung function traits identify putatively causal relations of sRAGE to lung function? Study Design and Methods Plasma sRAGE levels were measured in 6,861 Framingham Heart Study participants and GWAS of sRAGE was conducted to identify protein quantitative trait loci (pQTL), including cis-pQTL variants at the sRAGE protein-coding gene locus (AGER). We integrated sRAGE pQTL variants with variants from GWAS of lung traits. Colocalization of sRAGE pQTL variants with lung trait GWAS variants was conducted, and Mendelian randomization was performed using sRAGE cis-pQTL variants to infer causality of sRAGE for pulmonary traits. Cross-sectional and longitudinal protein-trait association analyses were conducted for sRAGE in relation to lung traits. Results Colocalization identified shared genetic signals for sRAGE with lung traits. Mendelian randomization analyses suggested protective causal relations of sRAGE to several pulmonary traits. Protein-trait association analyses demonstrated higher sRAGE levels to be cross-sectionally and longitudinally associated with preserved lung function. Interpretation sRAGE is produced by type I alveolar cells, and it acts as a decoy receptor to block the inflammatory cascade. Our integrative genomics approach provides evidence for sRAGE as a causal and protective biomarker of lung function, and the pattern of associations is suggestive of a protective role of sRAGE against restrictive lung physiology. We speculate that targeting the AGER/sRAGE axis may be therapeutically beneficial for the treatment and prevention of inflammation-related lung disease.

Published
2022
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46. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Elizabeth E. Palmer, Michael Pusch, Alessandra Picollo, Caitlin Forwood, Matthew H. Nguyen, Vanessa Suckow, Jessica Gibbons, Alva Hoff, Lisa Sigfrid, Andre Megarbane, Mathilde Nizon, Benjamin Cogné, Claire Beneteau, Fowzan S. Alkuraya, Aziza Chedrawi, Mais O. Hashem, Hannah Stamberger, Sarah Weckhuysen, Arnaud Vanlander, Berten Ceulemans, Sulekha Rajagopalan, Kenneth Nunn, Stéphanie Arpin, Martine Raynaud, Constance S. Motter, Catherine Ward-Melver, Katrien Janssens, Marije Meuwissen, Diane Beysen, Nicola Dikow, Mona Grimmel, Tobias B. Haack, Emma Clement, Amy McTague, David Hunt, Sharron Townshend, Michelle Ward, Linda J. Richards, Cas Simons, Gregory Costain, Lucie Dupuis, Roberto Mendoza-Londono, Tracy Dudding-Byth, Jackie Boyle, Carol Saunders, Emily Fleming, Salima El Chehadeh, Marie-Aude Spitz, Amelie Piton, Bénédicte Gerard, Marie-Thérèse Abi Warde, Gillian Rea, Caoimhe McKenna, Sofia Douzgou, Siddharth Banka, Cigdem Akman, Jennifer M. Bain, Tristan T. Sands, Golder N. Wilson, Erin J. Silvertooth, Lauren Miller, Damien Lederer, Rani Sachdev, Rebecca Macintosh, Olivier Monestier, Deniz Karadurmus, Felicity Collins, Melissa Carter, Luis Rohena, Marjolein H. Willemsen, Charlotte W. Ockeloen, Rolph Pfundt, Sanne D. Kroft, Michael Field, Francisco E. R. Laranjeira, Ana M. Fortuna, Ana R. Soares, Vincent Michaud, Sophie Naudion, Sailaja Golla, David D. Weaver, Lynne M. Bird, Jennifer Friedman, Virginia Clowes, Shelagh Joss, Laura Pölsler, Philippe M. Campeau, Maria Blazo, Emilia K. Bijlsma, Jill A. Rosenfeld, Christian Beetz, Zöe Powis, Kirsty McWalter, Tracy Brandt, Erin Torti, Mikaël Mathot, Shekeeb S. Mohammad, Ruth Armstrong, Vera M. Kalscheuer, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Growth and Development, Pediatrics, Centre for Medical Genetics, Brussels Heritage Lab, and Medical Genetics

Subjects
Male, DISRUPTION, Chloride Channels/genetics, EXCHANGER, Mutation, Missense, LYSOSOMAL STORAGE DISEASE, VARIANTS, Neurodevelopmental Disorders/genetics, PHENOTYPE, Cellular and Molecular Neuroscience, All institutes and research themes of the Radboud University Medical Center, Genes, X-Linked, CLC CHLORIDE, Medicine and Health Sciences, Humans, Molecular Biology, MUTATION, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CHANNELS, LINKED MENTAL-RETARDATION, ASSOCIATION, GENE, Psychiatry and Mental health, Chemistry, Female, Human medicine
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023
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47. Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers

Author

Johannes Dorst, Patrick Weydt, David Brenner, Simon Witzel, Katharina Kandler, André Huss, Christine Herrmann, Maximilian Wiesenfarth, Antje Knehr, Kornelia Günther, Kathrin Müller, Jochen H. Weishaupt, Johannes Prudlo, Karin Forsberg, Peter M. Andersen, Angela Rosenbohm, Joachim Schuster, Francesco Roselli, Luc Dupuis, Benjamin Mayer, Hayrettin Tumani, Jan Kassubek, and Albert C. Ludolph

Subjects
Male, Adult, Mutations carriers, diagnosis [Amyotrophic Lateral Sclerosis], Intermediate Filaments, Neurosciences, Presymptomatic, General Medicine, Middle Aged, Amyotrophic lateral sclerosis, General Biochemistry, Genetics and Molecular Biology, genetics [Superoxide Dismutase-1], genetics [Amyotrophic Lateral Sclerosis], Metabolism, Humans, Female, ddc:610, Metabolic, genetics [C9orf72 Protein], Medical Genetics, Biomarkers, Neurovetenskaper, Medicinsk genetik
Abstract

The emergence of potentially effective new therapies for genetic forms of amyotrophic lateral sclerosis (ALS) necessitates the identification of biomarkers to facilitate early treatment, prior to the onset of motor symptoms. Here, we sought to investigate whether metabolic alterations are detectable in presymptomatic ALS gene mutation carriers, and whether such alterations precede neurofilament light chain (NfL) changes in serum.Between 02/2014 and 11/2021, we prospectively studied 60 presymptomatic ALS gene mutation carriers (40% male, age 48.7 ± 14.9; 28 C9orf72, 22 SOD1, 10 other) compared to 73 individuals from the same families (47% male, age 47.4 ± 12.9) without pathogenic mutations as controls. Bioimpedance analysis (BIA) and indirect calorimetry were performed, and Body Mass Index (BMI), Fat Mass (FM), Body Fat Percentage, Body Water (BW), Lean Body Mass (LBM), Extracellular Mass (ECM), Body Cell Mass (BCM), ECM/BCM ratio, Cells Percentage, Phase Angle, Resting Metabolic Rate (RMR), Metabolic Ratio (MR), and NfL were measured. Participants and evaluators were blinded regarding gene carrier status.Presymptomatic ALS gene carriers showed reduced LBM (p = 0.02), BCM (p = 0.004), Cells Percentage (p = 0.04), BW (p = 0.02), Phase Angle (p = 0.04), and increased ECM/BCM ratio (p = 0.04), consistently indicating a loss of metabolically active body cells. While in C9orf72 mutation carriers all tissue masses were reduced, only metabolically active tissue was affected in SOD1 mutation carriers. Unexpectedly, RMR (p = 0.009) and MR (p = 0.01) were lower in presymptomatic ALS gene carriers compared to non-carriers. NfL serum levels were similar in mutation carriers and non-carriers (p = 0.60).The observed metabolic phenomena might reflect reduced physical activity and/or preemptive, insufficient compensatory mechanisms to prepare for the later hypermetabolic state. As pre-symptomatic biomarkers we propose ECM/BCM ratio and Phase Angle for SOD1, and a 4-compartment affection in BIA for C9orf72 mutation carriers.This work was an investigator-initiated trial. On the German side, there was no institutional or industrial funding. On the Swedish side, this work was supported by grants from the Swedish Brain Foundation (grants nr. 2013-0279, 2016-0303, 2018-0310, 2020-0353), the Swedish Research Council (grants nr. 2012-3167, 2017-03100), the Knut and Alice Wallenberg Foundation (grants nr. 2012.0091, 2014.0305, 2020.0232), the Ulla-Carin Lindquist Foundation, Umeå University (223-2808-12, 223-1881-13, 2.1.12-1605-14) and the Västerbotten County Council (grants nr 56103-7002829), King Gustaf V:s and Queen Victoria's Freemason's Foundation.

Published
2023
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48. Impact of renal impairment on atrial fibrillation

Author

Ding W. Y., Potpara T. S., Blomstrom-Lundqvist C., Boriani G., Marin F., Fauchier L., Lip G. Y. H., Tavazzi L., Maggioni A. P., Dan G. -A., Potpara T., Nabauer M., Kalarus Z., Goda A., Mairesse G., Shalganov T., Antoniades L., Taborsky M., Riahi S., Muda P., Garcia Bolao I., Piot O., Etsadashvili K., Simantirakis E., Haim M., Azhari A., Najafian J., Santini M., Mirrakhimov E., Kulzida K., Erglis A., Poposka L., Burg M., Crijns H., Erkuner O., Atar D., Lenarczyk R., Martins Oliveira M., Shah D., Serdechnaya E., Diker E., Lane D., Zera E., Ekmekciu U., Paparisto V., Tase M., Gjergo H., Dragoti J., Ciutea M., Ahadi N., Husseini Z. E., Raepers M., Leroy J., Haushan P., Jourdan A., Lepiece C., Desteghe L., Vijgen J., Koopman P., Van Genechten G., Heidbuchel H., Boussy T., De Coninck M., Van Eeckhoutte H., Bouckaert N., Friart A., Boreux J., Arend C., Evrard P., Stefan L., Hoffer E., Herzet J., Massoz M., Celentano C., Sprynger M., Pierard L., Melon P., Van Hauwaert B., Kuppens C., Faes D., Van Lier D., Van Dorpe A., Gerardy A., Deceuninck O., Xhaet O., Dormal F., Ballant E., Blommaert D., Yakova D., Hristov M., Yncheva T., Stancheva N., Tisheva S., Tokmakova M., Nikolov F., Gencheva D., Kunev B., Stoyanov M., Marchov D., Gelev V., Traykov V., Kisheva A., Tsvyatkov H., Shtereva R., Bakalska-Georgieva S., Slavcheva S., Yotov Y., Kubickova M., Marni Joensen A., Gammelmark A., Hvilsted Rasmussen L., Dinesen P., Krogh Veno S., Sorensen B., Korsgaard A., Andersen K., Fragtrup Hellum C., Svenningsen A., Nyvad O., Wiggers P., May O., Aarup A., Graversen B., Jensen L., Andersen M., Svejgaard M., Vester S., Hansen S., Lynggaard V., Ciudad M., Vettus R., Maestre A., Castano S., Cheggour S., Poulard J., Mouquet V., Leparree S., Bouet J., Taieb J., Doucy A., Duquenne H., Furber A., Dupuis J., Rautureau J., Font M., Damiano P., Lacrimini M., Abalea J., Boismal S., Menez T., Mansourati J., Range G., Gorka H., Laure C., Vassaliere C., Elbaz N., Lellouche N., Djouadi K., Roubille F., Dietz D., Davy J., Granier M., Winum P., Leperchois-Jacquey C., Kassim H., Marijon E., Le Heuzey J., Fedida J., Maupain C., Himbert C., Gandjbakhch E., Hidden-Lucet F., Duthoit G., Badenco N., Chastre T., Waintraub X., Oudihat M., Lacoste J., Stephan C., Bader H., Delarche N., Giry L., Arnaud D., Lopez C., Boury F., Brunello I., Lefevre M., Mingam R., Haissaguerre M., Le Bidan M., Pavin D., Le Moal V., Leclercq C., Beitar T., Martel I., Schmid A., Sadki N., Romeyer-Bouchard C., Da Costa A., Arnault I., Boyer M., Piat C., Lozance N., Nastevska S., Doneva A., Fortomaroska Milevska B., Sheshoski B., Petroska K., Taneska N., Bakrecheski N., Lazarovska K., Jovevska S., Ristovski V., Antovski A., Lazarova E., Kotlar I., Taleski J., Kedev S., Zlatanovik N., Jordanova S., Bajraktarova Proseva T., Doncovska S., Maisuradze D., Esakia A., Sagirashvili E., Lartsuliani K., Natelashvili N., Gumberidze N., Gvenetadze R., Gotonelia N., Kuridze N., Papiashvili G., Menabde I., Gloggler S., Napp A., Lebherz C., Romero H., Schmitz K., Berger M., Zink M., Koster S., Sachse J., Vonderhagen E., Soiron G., Mischke K., Reith R., Schneider M., Rieker W., Boscher D., Taschareck A., Beer A., Oster D., Ritter O., Adamczewski J., Walter S., Frommhold A., Luckner E., Richter J., Schellner M., Landgraf S., Bartholome S., Naumann R., Schoeler J., Westermeier D., William F., Wilhelm K., Maerkl M., Oekinghaus R., Denart M., Kriete M., Tebbe U., Scheibner T., Gruber M., Gerlach A., Beckendorf C., Anneken L., Arnold M., Lengerer S., Bal Z., Uecker C., Fortsch H., Fechner S., Mages V., Martens E., Methe H., Schmidt T., Schaeffer B., Hoffmann B., Moser J., Heitmann K., Willems S., Klaus C., Lange I., Durak M., Esen E., Mibach F., Mibach H., Utech A., Gabelmann M., Stumm R., Landle V., Gartner C., Goerg C., Kaul N., Messer S., Burkhardt D., Sander C., Orthen R., Kaes S., Baumer A., Dodos F., Barth A., Schaeffer G., Gaertner J., Winkler J., Fahrig A., Aring J., Wenzel I., Steiner S., Kliesch A., Kratz E., Winter K., Schneider P., Haag A., Mutscher I., Bosch R., Taggeselle J., Meixner S., Schnabel A., Shamalla A., Hotz H., Korinth A., Rheinert C., Mehltretter G., Schon B., Schon N., Starflinger A., Englmann E., Baytok G., Laschinger T., Ritscher G., Gerth A., Dechering D., Eckardt L., Kuhlmann M., Proskynitopoulos N., Brunn J., Foth K., Axthelm C., Hohensee H., Eberhard K., Turbanisch S., Hassler N., Koestler A., Stenzel G., Kschiwan D., Schwefer M., Neiner S., Hettwer S., Haeussler-Schuchardt M., Degenhardt R., Sennhenn S., Brendel M., Stoehr A., Widjaja W., Loehndorf S., Logemann A., Hoskamp J., Grundt J., Block M., Ulrych R., Reithmeier A., Panagopoulos V., Martignani C., Bernucci D., Fantecchi E., Diemberger I., Ziacchi M., Biffi M., Cimaglia P., Frisoni J., Giannini I., Boni S., Fumagalli S., Pupo S., Di Chiara A., Mirone P., Pesce F., Zoccali C., Malavasi V. L., Mussagaliyeva A., Ahyt B., Salihova Z., Koshum-Bayeva K., Kerimkulova A., Bairamukova A., Lurina B., Zuzans R., Jegere S., Mintale I., Kupics K., Jubele K., Kalejs O., Vanhear K., Cachia M., Abela E., Warwicker S., Tabone T., Xuereb R., Asanovic D., Drakalovic D., Vukmirovic M., Pavlovic N., Music L., Bulatovic N., Boskovic A., Uiterwaal H., Bijsterveld N., De Groot J., Neefs J., van den Berg N., Piersma F., Wilde A., Hagens V., Van Es J., van Opstal J., Van Rennes B., Verheij H., Breukers W., Tjeerdsma G., Nijmeijer R., Wegink D., Binnema R., Said S., Philippens S., van Doorn W., Szili-Torok T., Bhagwandien R., Janse P., Muskens A., van Eck M., Gevers R., van der Ven N., Duygun A., Rahel B., Meeder J., Vold A., Holst Hansen C., Engset I., Dyduch-Fejklowicz B., Koba E., Cichocka M., Sokal A., Kubicius A., Pruchniewicz E., Kowalik-Sztylc A., Czapla W., Mroz I., Kozlowski M., Pawlowski T., Tendera M., Winiarska-Filipek A., Fidyk A., Slowikowski A., Haberka M., Lachor-Broda M., Biedron M., Gasior Z., Kolodziej M., Janion M., Gorczyca-Michta I., Wozakowska-Kaplon B., Stasiak M., Jakubowski P., Ciurus T., Drozdz J., Simiera M., Zajac P., Wcislo T., Zycinski P., Kasprzak J., Olejnik A., Harc-Dyl E., Miarka J., Pasieka M., Zieminska-Luc M., Bujak W., Sliwinski A., Grech A., Morka J., Petrykowska K., Prasal M., Hordynski G., Feusette P., Lipski P., Wester A., Streb W., Romanek J., Wozniak P., Chlebus M., Szafarz P., Stanik W., Zakrzewski M., Kazmierczak J., Przybylska A., Skorek E., Blaszczyk H., Stepien M., Szabowski S., Krysiak W., Szymanska M., Karasinski J., Blicharz J., Skura M., Halas K., Michalczyk L., Orski Z., Krzyzanowski K., Skrobowski A., Zielinski L., Tomaszewska-Kiecana M., Dluzniewski M., Kiliszek M., Peller M., Budnik M., Balsam P., Opolski G., Tyminska A., Ozieranski K., Wancerz A., Borowiec A., Majos E., Dabrowski R., Szwed H., Musialik-Lydka A., Leopold-Jadczyk A., Jedrzejczyk-Patej E., Koziel M., Mazurek M., Krzemien-Wolska K., Starosta P., Nowalany-Kozielska E., Orzechowska A., Szpot M., Staszel M., Almeida S., Pereira H., Brandao Alves L., Miranda R., Ribeiro L., Costa F., Morgado F., Carmo P., Galvao Santos P., Bernardo R., Adragao P., Ferreira da Silva G., Peres M., Alves M., Leal M., Cordeiro A., Magalhaes P., Fontes P., Leao S., Delgado A., Costa A., Marmelo B., Rodrigues B., Moreira D., Santos J., Santos L., Terchet A., Darabantiu D., Mercea S., Turcin Halka V., Pop Moldovan A., Gabor A., Doka B., Catanescu G., Rus H., Oboroceanu L., Bobescu E., Popescu R., Dan A., Buzea A., Daha I., Dan G., Neuhoff I., Baluta M., Ploesteanu R., Dumitrache N., Vintila M., Daraban A., Japie C., Badila E., Tewelde H., Hostiuc M., Frunza S., Tintea E., Bartos D., Ciobanu A., Popescu I., Toma N., Gherghinescu C., Cretu D., Patrascu N., Stoicescu C., Udroiu C., Bicescu G., Vintila V., Vinereanu D., Cinteza M., Rimbas R., Grecu M., Cozma A., Boros F., Ille M., Tica O., Tor R., Corina A., Jeewooth A., Maria B., Georgiana C., Natalia C., Alin D., Dinu-Andrei D., Livia M., Daniela R., Larisa R., Umaar S., Tamara T., Ioachim Popescu M., Nistor D., Sus I., Coborosanu O., Alina-Ramona N., Dan R., Petrescu L., Ionescu G., Vacarescu C., Goanta E., Mangea M., Ionac A., Mornos C., Cozma D., Pescariu S., Solodovnicova E., Soldatova I., Shutova J., Tjuleneva L., Zubova T., Uskov V., Obukhov D., Rusanova G., Isakova N., Odinsova S., Arhipova T., Kazakevich E., Zavyalova O., Novikova T., Riabaia I., Zhigalov S., Drozdova E., Luchkina I., Monogarova Y., Hegya D., Rodionova L., Nevzorova V., Lusanova O., Arandjelovic A., Toncev D., Vukmirovic L., Radisavljevic M., Milanov M., Sekularac N., Zdravkovic M., Hinic S., Dimkovic S., Acimovic T., Saric J., Radovanovic S., Kocijancic A., Obrenovic-Kircanski B., Kalimanovska Ostric D., Simic D., Jovanovic I., Petrovic I., Polovina M., Vukicevic M., Tomasevic M., Mujovic N., Radivojevic N., Petrovic O., Aleksandric S., Kovacevic V., Mijatovic Z., Ivanovic B., Tesic M., Ristic A., Vujisic-Tesic B., Nedeljkovic M., Karadzic A., Uscumlic A., Prodanovic M., Zlatar M., Asanin M., Bisenic B., Vasic V., Popovic Z., Djikic D., Sipic M., Peric V., Dejanovic B., Milosevic N., Backovic S., Stevanovic A., Andric A., Pencic B., Pavlovic-Kleut M., Celic V., Pavlovic M., Petrovic M., Vuleta M., Petrovic N., Simovic S., Savovic Z., Milanov S., Davidovic G., Iric-Cupic V., Djordjevic D., Damjanovic M., Zdravkovic S., Topic V., Stanojevic D., Randjelovic M., Jankovic-Tomasevic R., Atanaskovic V., Antic S., Simonovic D., Stojanovic M., Stojanovic S., Mitic V., Ilic V., Petrovic D., Deljanin Ilic M., Ilic S., Stoickov V., Markovic S., Mijatovic A., Tanasic D., Radakovic G., Peranovic J., Panic-Jelic N., Vujadinovic O., Pajic P., Bekic S., Kovacevic S., Garcia Fernandez A., Perez Cabeza A., Anguita M., Tercedor Sanchez L., Mau E., Loayssa J., Ayarra M., Carpintero M., Roldan Rabadan I., Gil Ortega M., Tello Montoliu A., Orenes Pinero E., Manzano Fernandez S., Romero Aniorte A., Veliz Martinez A., Quintana Giner M., Ballesteros G., Palacio M., Alcalde O., Garcia-Bolao I., Bertomeu Gonzalez V., Otero-Ravina F., Garcia Seara J., Gonzalez Juanatey J., Dayal N., Maziarski P., Gentil-Baron P., Koc M., Onrat E., Dural I. E., Yilmaz K., Ozin B., Tan Kurklu S., Atmaca Y., Canpolat U., Tokgozoglu L., Dolu A. K., Demirtas B., Sahin D., Ozcan Celebi O., Gagirci G., Turk U. O., Ari H., Polat N., Toprak N., Sucu M., Akin Serdar O., Taha Alper A., Kepez A., Yuksel Y., Uzunselvi A., Yuksel S., Sahin M., Kayapinar O., Ozcan T., Kaya H., Yilmaz M. B., Kutlu M., Demir M., Gibbs C., Kaminskiene S., Bryce M., Skinner A., Belcher G., Hunt J., Stancombe L., Holbrook B., Peters C., Tettersell S., Shantsila A., Senoo K., Proietti M., Russell K., Domingos P., Hussain S., Partridge J., Haynes R., Bahadur S., Brown R., McMahon S., McDonald J., Balachandran K., Singh R., Garg S., Desai H., Davies K., Goddard W., Galasko G., Rahman I., Chua Y., Payne O., Preston S., Brennan O., Pedley L., Whiteside C., Dickinson C., Brown J., Jones K., Benham L., Brady R., Buchanan L., Ashton A., Crowther H., Fairlamb H., Thornthwaite S., Relph C., McSkeane A., Poultney U., Kelsall N., Rice P., Wilson T., Wrigley M., Kaba R., Patel T., Young E., Law J., Runnett C., Thomas H., McKie H., Fuller J., Pick S., Sharp A., Hunt A., Thorpe K., Hardman C., Cusack E., Adams L., Hough M., Keenan S., Bowring A., Watts J., Zaman J., Goffin K., Nutt H., Beerachee Y., Featherstone J., Mills C., Pearson J., Stephenson L., Grant S., Wilson A., Hawksworth C., Alam I., 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Venn F., Mills H., Rewbury J., James K., Roberts K., Tonks L., Felmeden D., Taggu W., Summerhayes A., Hughes D., Sutton J., Felmeden L., Khan M., Walker E., Norris L., O'Donohoe L., Mozid A., Dymond H., Lloyd-Jones H., Saunders G., Simmons D., Coles D., Cotterill D., Beech S., Kidd S., Wrigley B., Petkar S., Smallwood A., Jones R., Radford E., Milgate S., Metherell S., Cottam V., Buckley C., Broadley A., Wood D., Allison J., Rennie K., Balian L., Howard L., Pippard L., Board S., Pitt-Kerby T., Pulmonary medicine, Rehabilitation medicine, Internal medicine, and Radiology and nuclear medicine

Subjects
Male, Medicin och hälsovetenskap, Clinical Biochemistry, Hemorrhage, Medical and Health Sciences, Biochemistry, Brain Ischemia, Risk Factors, Hemorrhage/chemically induced, death, Humans, Acute Coronary Syndrome/complications, atrial fibrillation, Renal Insufficiency, Registries, Acute Coronary Syndrome, Renal Insufficiency/chemically induced, Anticoagulants, General Medicine, thromboembolism, kidney failure, Stroke, Anticoagulants/therapeutic use, major bleeding, outcome, Female, Atrial Fibrillation/complications, chronic kidney disease, Stroke/complications
Abstract

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p 2 decrease), that was most notable in patients with eGFR 2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m 2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF.

Published
2022
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49. X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Author

Asano, Takaki, Boisson, Bertrand, Onodi, Fanny, Matuozzo, Daniela, Moncada-Velez, Marcela, Maglorius Renkilaraj, Majistor Raj Luxman, Zhang, Peng, Meertens, Laurent, Bolze, Alexandre, Materna, Marie, Korniotis, Sarantis, Gervais, Adrian, Talouarn, Estelle, Bigio, Benedetta, Seeleuthner, Yoann, Bilguvar, Kaya, Zhang, Yu, Neehus, Anna-Lena, Ogishi, Masato, Pelham, Simon J., Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Soler-Palacín, Pere, Colobran, Roger, Martin-Nalda, Andrea, Rivière, Jacques G., Tandjaoui-Lambiotte, Yacine, Chaïbi, Khalil, Shahrooei, Mohammad, Darazam, Ilad Alavi, Olyaei, Nasrin Alipour, Mansouri, Davood, Hatipoğlu, Nevin, Palabiyik, Figen, Ozcelik, Tayfun, Novelli, Giuseppe, Novelli, Antonio, Casari, Giorgio, Aiuti, Alessandro, Carrera, Paola, Bondesan, Simone, Barzaghi, Federica, Rovere-Querini, Patrizia, Tresoldi, Cristina, Franco, Jose Luis, Rojas, Julian, Reyes, Luis Felipe, Bustos, Ingrid G., Arias, Andres Augusto, Morelle, Guillaume, Kyheng, Christèle, Troya, Jesús, Planas-Serra, Laura, Schlüter, Agatha, Gut, Marta, Pujol, Aurora, Allende, Luis M., Rodriguez-Gallego, Carlos, Flores, Carlos, Cabrera-Marante, Oscar, Pleguezuelo, Daniel E., Pérez de Diego, Rebeca, Keles, Sevgi, Aytekin, Gokhan, Metin Akcan, Ozge, Bryceson, Yenan T., Bergman, Peter, Brodin, Petter, Smole, Daniel, Smith, C. I. Edvard, Norlin, Anna-Carin, Campbell, Tessa M., Covill, Laura E., Hammarström, Lennart, Pan-Hammarström, Qiang, Abolhassani, Hassan, Mane, Shrikant, Marr, Nico, Ata, Manar, Al Ali, Fatima, Khan, Taushif, Spaan, András N., Dalgard, Clifton L., Bonfanti, Paolo, Biondi, Andrea, Tubiana, Sarah, Burdet, Charles, Nussbaum, Robert, Kahn-Kirby, Amanda, Snow, Andrew L., Bustamante, Jacinta, Puel, Anne, Boisson-Dupuis, Stéphanie, Zhang, Shen-Ying, Béziat, Vivien, Lifton, Richard P., Bastard, Paul, Notarangelo, Luigi D., Abel, Laurent, Su, Helen C., Jouanguy, Emmanuelle, Amara, Ali, Soumelis, Vassili, Cobat, Aurélie, Zhang, Qian, Casanova, Jean-Laurent, Al-Muhsen, Saleh, Al-Mulla, Fahd, Anderson, Mark S., Andreakos, Evangelos, Arias, Andrés A., Feldman, Hagit Baris, Belot, Alexandre, Biggs, Catherine M., Bogunovic, Dusan, Bondarenko, Anastasiia, Bousfiha, Ahmed A., Bryceson, Yenan, Bustamante, Carlos D., Butte, Manish J., Chakravorty, Samya, Christodoulou, John, Condino-Neto, Antonio, Constantinescu, Stefan N., Cooper, Megan A., Desai, Murkesh, Drolet, Beth A., El Baghdadi, Jamila, Espinosa-Padilla, Sara, Fellay, Jacques, Franco, José Luis, Froidure, Antoine, Gregersen, Peter K., Haerynck, Filomeen, Hagin, David, Halwani, Rabih, Heath, James R., Henrickson, Sarah E., Hsieh, Elena W.Y., Husebye, Eystein, Imai, Kohsuke, Itan, Yuval, Jarvis, Erich D., Karamitros, Timokratis, Kisand, Kai, Ku, Cheng-Lung, Lau, Yu-Lung, Ling, Yun, Lucas, Carrie L., Maniatis, Tom, Maródi, László, Meyts, Isabelle, Milner, Joshua D., Mironska, Kristina, Mogensen, Trine H., Morio, Tomohiro, Ng, Lisa F.P., O'Farrelly, Cliona, Okada, Satoshi, de Diego, Rebeca Perez, Planas, Anna M., Prando, Carolina, Quintana-Murci, Lluis, Renia, Laurent, Resnick, Igor, Rodríguez-Gallego, Carlos, Sancho-Shimizu, Vanessa, Sediva, Anna, Seppänen, Mikko R.J., Shahrooei, Mohammed, Shcherbina, Anna, Slaby, Ondrej, Tancevski, Ivan, Tangye, Stuart G., Abou Tayoun, Ahmad, Ramaswamy, Sathishkumar, Turvey, Stuart E, Uddin, K M Furkan, Uddin, Mohammed J., van de Beek, Diederik, Vinh, Donald C., von Bernuth, Horst, Zatz, Mayana, Zawadzki, Pawel, Foti, Giuseppe, Bellani, Giacomo, Citerio, Giuseppe, Contro, Ernesto, Pesci, Alberto, Valsecchi, Maria Grazia, Cazzaniga, Marina, Abad, Jorge, Accordino, Giulia, Achille, Cristian, Aguilera-Albesa, Sergio, Aguiló-Cucurull, Aina, Özkan, Esra Akyüz, Roblero Albisures, Jonathan Antonio, Aldave, Juan C, Ramos, Miquel Alfonso, Khan, Taj Ali, Aliberti, Anna, Nadji, Seyed Alireza, Alkan, Gulsum, AlKhater, Suzan A., Allardet-Servent, Jerome, Allende, Luis M, Alonso-Arias, Rebeca, Alshahrani, Mohammed S, Alsina, Laia, Alyanakian, Marie-Alexandra, Borrero, Blanca Amador, Amoura, Zahir, Antolí, Arnau, Arrestier, Romain, Aubart, Mélodie, Auguet, Teresa, Avramenko, Iryna, Aytekin, Gökhan, Azot, Axelle, Bahram, Seiamak, Bajolle, Fanny, Baldanti, Fausto, Baldolli, Aurélie, Ballester, Maite, Barrou, Benoit, Barzagh, Federica, Basso, Sabrina, Bayhan, Gulsum Iclal, Bezrodnik, Liliana, Bilbao, Agurtzane, Blanchard-Rohner, Geraldine, Blanco, Ignacio, Blandinières, Adeline, Blázquez-Gamero, Daniel, Bleibtreu, Alexandre, Bloomfield, Marketa, Bolivar-Prados, Mireia, Borghesi, Alessandro, Borie, Raphael, Botdhlo-Nevers, Elisabeth, Bousfiha, Ahmed A, Bousquet, Aurore, Boutolleau, David, Bouvattier, Claire, Boyarchuk, Oksana, Bravais, Juliette, Briones, M. Luisa, Brunner, Marie-Eve, Bruno, Raffaele, Bueno, Maria Rita P, Bukhari, Huda, Cáceres Agra, Juan José, Capra, Ruggero, Carapito, Raphael, Carrabba, Maria, Casasnovas, Carlos, Caseris, Marion, Cassaniti, Irene, Castelle, Martin, Castelli, Francesco, de Vera, Martín Castillo, Castro, Mateus V, Catherinot, Emilie, Celik, Jale Bengi, Ceschi, Alessandro, Chalumeau, Martin, Charbit, Bruno, Cheng, Matthew P., Clavé, Père, Clotet, Bonaventura, Codina, Anna, Cohen, Yves, Comarmond, Cloé, Combes, Alain, Comoli, Patrizia, Corsico, Angelo G, Coşkuner, Taner, Cvetkovski, Aleksandar, Cyrus, Cyril, Dalmau, David, Danion, François, Darley, David Ross, Das, Vincent, Dauby, Nicolas, Dauger, Stéphane, De Munter, Paul, de Pontual, Loic, Dehban, Amin, Delplancq, Geoffroy, Demoule, Alexandre, Desguerre, Isabelle, Di Sabatino, Antonio, Diehl, Jean-Luc, Dobbelaere, Stephanie, Domínguez-Garrido, Elena, Dubost, Clément, Ekwall, Olov, Bozdemir, Şefika Elmas, Elnagdy, Marwa H, Emiroglu, Melike, Endo, Akifumi, Erdeniz, Emine Hafize, Aytekin, Selma Erol, Lasa, Maria Pilar Etxart, Euvrard, Romain, Fabio, Giovanna, Faivre, Laurence, Falck, Antonin, Fartoukh, Muriel, Faure, Morgane, Arquero, Miguel Fernandez, Ferrer, Ricard, Ferreres, Jose, Francois, Bruno, Fumadó, Victoria, Fung, Kitty S C, Fusco, Francesca, Gagro, Alenka, Solis, Blanca Garcia, Gaussem, Pascale, Gayretli, Zeynep, Gil-Herrera, Juana, Gilardin, Laurent, Gatineau, Audrey Giraud, Girona-Alarcón, Mònica, Cifuentes Godínez, Karen Alejandra, Goffard, Jean-Christophe, Gonzales, Nacho, Gonzalez-Granado, Luis I, González-Montelongo, Rafaela, Guerder, Antoine, Gülhan, Belgin, Gumucio, Victor Daniel, Hanitsch, Leif Gunnar, Gunst, Jan, Hadjadj, Jérôme, Hancerli, Selda, Hariyan, Tetyana, Hatipoglu, Nevin, Heppekcan, Deniz, Hernandez-Brito, Elisa, Ho, Po-ki, Holanda-Peña, María Soledad, Horcajada, Juan P, Hraiech, Sami, Humbert, Linda, Hung, Ivan F N, Iglesias, Alejandro D., Íñigo-Campos, Antonio, Jamme, Matthieu, Arranz, María Jesús, Jimeno, Marie-Thérèse, Jordan, Iolanda, Yüksek, Saliha Kanık, Kara, Yalcin Burak, Karahan, Aydın, Karbuz, Adem, Yasar, Kadriye Kart, Kasapcopur, Ozgur, Kashimada, Kenichi, Demirkol, Yasemin Kendir, Kido, Yasutoshi, Kizil, Can, Kılıç, Ahmet Osman, Klocperk, Adam, Koutsoukou, Antonia, Król, Zbigniew J., Ksouri, Hatem, Kuentz, Paul, Kwan, Arthur M C, Kwan, Yat Wah M, Kwok, Janette S Y, Lagier, Jean-Christophe, Lam, David S Y, Lampropoulou, Vicky, Lanternier, Fanny, LAU, Yu-Lung, Le Bourgeois, Fleur, Leo, Yee-Sin, Lopez, Rafael Leon, Leung, Daniel, Levin, Michael, Levy, Michael, Lévy, Romain, Li, Zhi, Lilleri, Daniele, Bolanos Lima, Edson Jose Adrian, Linglart, Agnes, López-Collazo, Eduardo, Lorenzo-Salazar, José M., Louapre, Céline, Lubetzki, Catherine, Lung, Kwok-Cheung, Luyt, Charles-Edouard, Lye, David C, Magnone, Cinthia, Marchioni, Enrico, Marioli, Carola, Marjani, Majid, Marques, Laura, Pereira, Jesus Marquez, Martín-Nalda, Andrea, Pueyo, David Martínez, Martinez-Picado, Javier, Marzana, Iciar, Mata-Martínez, Carmen, Mathian, Alexis, Matos, Larissa RB, Matthews, Gail V, Mayaux, Julien, McLaughlin-Garcia, Raquel, Meersseman, Philippe, Mège, Jean-Louis, Mekontso-Dessap, Armand, Melki, Isabelle, Meloni, Federica, Meritet, Jean-François, Merlani, Paolo, Akcan, Özge Metin, Mezidi, Mehdi, Migeotte, Isabelle, Millereux, Maude, Million, Matthieu, Mirault, Tristan, Mircher, Clotilde, Mirsaeidi, Mehdi, Mizoguchi, Yoko, Modi, Bhavi P, Mojoli, Francesco, Moncomble, Elsa, Melián, Abián Montesdeoca, Martinez, Antonio Morales, Morandeira, Francisco, Morange, Pierre-Emmanuel, Mordacq, Cléemence, Mouly, Stéphane J, Muñoz-Barrera, Adrián, Nafati, Cyril, Nagashima, Shintaro, Nakagama, Yu, Neven, Bénédicte, Neves, João Farela, Ng, Lisa FP, Ng, Yuk-Yung, Nielly, Hubert, Medina, Yeray Novoa, Cuadros, Esmeralda Nuñez, Ocejo-Vinyals, J. 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T Y, Tserel, Liina, Tso, Eugene Y K, Tucci, Alessandra, Tüter Öz, Şadiye Kübra, Ursini, Matilde Valeria, Utsumi, Takanori, Uzunhan, Yurdagul, Vabres, Pierre, Valencia-Ramos, Juan, Van Den Rym, Ana Maria, Vandernoot, Isabelle, Velez-Santamaria, Valentina, Zuniga Veliz, Silvia Patricia, Vidigal, Mateus C, Viel, Sébastien, Vilain, Cédric, Vilaire-Meunier, Marie E, Villar-García, Judit, Vincent, Audrey, Vogt, Guillaume, Voiriot, Guillaume, Volokha, Alla, Vuotto, Fanny, Wauters, Els, Wauters, Joost, Wu, Alan K L, Wu, Tak-Chiu, Yahşi, Aysun, Yesilbas, Osman, Yildiz, Mehmet, Young, Barnaby E, Yükselmiş, Ufuk, Zecca, Marco, Zuccaro, Valentina, Jens, Van Praet, Lambrecht, Bart N., Eva, Van Braeckel, Cédric, Bosteels, Levi, Hoste, Eric, Hoste, Bauters, Fré, De Clercq, Jozefien, Cathérine, Heijmans, Hans, Slabbynck, Leslie, Naesens, Florkin, Benoit, Boulanger, Cécile, Vanderlinden, Dimitri, Annereau, Jean-Philippe, Briseño-Roa, Luis, Gribouval, Olivier, Pelet, Anna, Andrejak, Claire, Angoulvant, 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H (Koos), Brouwer, Matthijs C., Wiersinga, W. 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R. L. M., Zhang, P., Meertens, L., Bolze, A., Materna, M., Korniotis, S., Gervais, A., Talouarn, E., Bigio, B., Seeleuthner, Y., Bilguvar, K., Zhang, Y., Neehus, A. -L., Ogishi, M., Pelham, S. J., Le Voyer, T., Rosain, J., Philippot, Q., Soler-Palacin, P., Colobran, R., Martin-Nalda, A., Riviere, J. G., Tandjaoui-Lambiotte, Y., Chaibi, K., Shahrooei, M., Darazam, I. A., Olyaei, N. A., Mansouri, D., Hatipoglu, N., Palabiyik, F., Ozcelik, T., Novelli, G., Novelli, A., Casari, G., Aiuti, A., Carrera, P., Bondesan, S., Barzaghi, F., Rovere-Querini, P., Tresoldi, C., Franco, J. L., Rojas, J., Reyes, L. F., Bustos, I. G., Arias, A. A., Morelle, G., Kyheng, C., Troya, J., Planas-Serra, L., Schluter, A., Gut, M., Pujol, A., Allende, L. M., Rodriguez-Gallego, C., Flores, C., Cabrera-Marante, O., Pleguezuelo, D. E., Diego, R. P. D., Keles, S., Aytekin, G., Akcan, O. M., Bryceson, Y. T., Bergman, P., Brodin, P., Smole, D., Smith, C. I. E., Norlin, A. -C., Campbell, T. M., Covill, L. E., Hammarstrom, L., Pan-Hammarstrom, Q., Abolhassani, H., Mane, S., Marr, N., Ata, M., Ali, F. A., Khan, T., Spaan, A. N., Dalgard, C. L., Bonfanti, P., Biondi, A., Tubiana, S., Burdet, C., Nussbaum, R., Kahn-Kirby, A., Snow, A. L., Bustamante, J., Puel, A., Boisson-Dupuis, S., Zhang, S. -Y., Beziat, V., Lifton, R. P., Bastard, P., Notarangelo, L. D., Abel, L., Su, H. C., Jouanguy, E., Amara, A., Soumelis, V., Cobat, A., Zhang, Q., Casanova, J. -L., Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Amiens-Picardie, French COVID cohort study group, The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, Rockefeller University, the St. Giles Foundation, the NIH (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at the George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01) and the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project, the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the European Union’s Horizon 2020 Research and Innovation Program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir–Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, Fondation du Souffle, Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, and the University of Paris. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (RECOVER WP 6). The Neurometabolic Diseases Laboratory received funding from the European Union’s Horizon 2020 Research and Innovation Program (EasiGenomics grant no. 824110 COVID-19/PID12342). A.P., R.P.d.D., C.R.-G., and C.F. were funded by Instituto de Salud Carlos III (COV20_01333 and COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1, AEI/FEDER, UE), Fundación DISA (OA18/017), and Cabildo Insular de Tenerife (CGIEU0000219140 and 'Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19'). The laboratories of G.N. and A.N. were supported by a grant awarded to Regione Lazio (PROGETTI DI GRUPPI DI RICERCA 2020) no. A0375-2020-36663, GecoBiomark. A. Amara’s laboratory was supported by ANR under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the FRM (EQU202003010193), ANR (ANR-20-COVI-000 project IDISCOVR and ANR-20-CO11-0004 project FISHBP), and the University of Paris (Plan de Soutien Covid-19: RACPL20FIR01-COVID-SOUL). This work was supported, in part, by the Division of Intramural Research, NIAID, NIH (grants 1ZIAAI001265 to H.C.S. and ZIA AI001270 to L.D.N.). The G.C. laboratory was supported by the Italian Ministry of Health (grant COVID-2020-12371617) and the intramural COVID Host Genetics program. The J.L.F. laboratory was supported, in part, by the Coopération Scientifique France-Colciencias (ECOS-Nord/COLCIENCIAS/MEN/ICETEX, 806-2018) and Colciencias contract 713-2016 (no. 111574455633). The V.S. laboratory was supported by ANR DENDRISEPSIS (ANR-17-CE15-0003) and ANR APCOD (ANR-17-CE15-0003-01), a Fast Grant from the Mercatus Center, FRM, University of Paris PLAN D’URGENCE COVID19. The N.M. laboratory was supported by Sidra Medicine (SDR400048) and the Qatar National Research Fund (grant No. NPRP9-251-3-045). A.-L.N. was supported by the Bettencourt Schueller Foundation and the International PhD program of the Imagine Institute. P. Bergman and C.I.E.S received support from the Center for Medical Innovation (CIMED), the Swedish Medical Research Council and the Stockholm County Council (ALF-project). Part of this work was generated within the European Reference Network for rare primary immunodeficiency, autoinflammatory and autoimmune diseases (RITA)., Members of French COVID Cohort Study Group: Laurent Abel1, Claire Andrejak2, François Angoulvant3, Delphine Bachelet4, Marie Bartoli5, Romain Basmaci6, Sylvie Behilill7, Marine Beluze8, Dehbia Benkerrou9, Krishna Bhavsar4, Lila Bouadma4, Sabelline Bouchez10, Maude Bouscambert11, Minerva Cervantes-Gonzalez4, Anissa Chair4, Catherine Chirouze12, Alexandra Coelho13, Camille Couffignal4, Sandrine Couffin-Cadiergues14, Eric d’Ortenzio5, Marie-Pierre Debray4, Lauren Deconinck4, Dominique Deplanque15, Diane Descamps4, Mathilde Desvallée16, Alpha Diallo5, Alphonsine Diouf13, Céline Dorival9, François Dubos17, Xavier Duval4, Brigitte Elharrar18, Philippine Eloy4, Vincent Enouf7, Hélène Esperou14, Marina Esposito-Farese4, Manuel Etienne19, Eglantine Ferrand Devouge19, Nathalie Gault4, Alexandre Gaymard11, Jade Ghosn4, Tristan Gigante20, Morgane Gilg20, Jérémie Guedj21, Alexandre Hoctin13, Isabelle Hoffmann4, Ikram Houas14, Jean-Sébastien Hulot22, Salma Jaafoura14, Ouifiya Kafif4, Florentia Kaguelidou23, Sabrina Kali4, Antoine Khalil4, Coralie Khan16, Cédric Laouénan4, Samira Laribi4, Minh Le4, Quentin Le Hingrat4, Soizic Le Mestre5, Hervé Le Nagard24, François-Xavier Lescure4, Sophie Letrou4, Yves Levy25, Bruno Lina11, Guillaume Lingas24, Jean Christophe Lucet4, Denis Malvy26, Marina Mambert13, France Mentré4, Amina Meziane9, Hugo Mouquet7, Jimmy Mullaert4, Nadège Neant24, Duc Nguyen26, Marion Noret27, Saad Nseir17, Aurélie Papadopoulos14, Christelle Paul5, Nathan Peiffer-Smadja4, Thomas Perpoint28, Ventzislava Petrov-Sanchez5, Gilles Peytavin4, Huong Pham4, Olivier Picone6, Valentine Piquard4, Oriane Puéchal29, Christian Rabaud30, Manuel Rosa-Calatrava11, Bénédicte Rossignol20, Patrick Rossignol30, Carine Roy4, Marion Schneider4, Richa Su4, Coralie Tardivon4, Marie-Capucine Tellier4, François Téoulé9, Olivier Terrier11, Jean-François Timsit4, Christelle Tual31, Sarah Tubiana4, Sylvie Van Der Werf7, Noémie Vanel32, Aurélie Veislinger31, Benoit Visseaux4, Aurélie Wiedemann25, Yazdan Yazdanpanah4, ANR-17-CE15-0003,DENDRISEPSIS,Analyse systémique des cellules présentatrices d'antigène dans le sepsis humain(2017), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), Asano, T, Boisson, B, Onodi, F, Matuozzo, D, Moncada-Velez, M, Maglorius Renkilaraj, M, Zhang, P, Meertens, L, Bolze, A, Materna, M, Korniotis, S, Gervais, A, Talouarn, E, Bigio, B, Seeleuthner, Y, Bilguvar, K, Zhang, Y, Neehus, A, Ogishi, M, Pelham, S, Le Voyer, T, Rosain, J, Philippot, Q, Soler-Palacín, P, Colobran, R, Martin-Nalda, A, Rivière, J, Tandjaoui-Lambiotte, Y, Chaïbi, K, Shahrooei, M, Darazam, I, Olyaei, N, Mansouri, D, Hatipoğlu, N, Palabiyik, F, Ozcelik, T, Novelli, G, Novelli, A, Casari, G, Aiuti, A, Carrera, P, Bondesan, S, Barzaghi, F, Rovere-Querini, P, Tresoldi, C, Franco, J, Rojas, J, Reyes, L, Bustos, I, Arias, A, Morelle, G, Christèle, K, Troya, J, Planas-Serra, L, Schlüter, A, Gut, M, Pujol, A, Allende, L, Rodriguez-Gallego, C, Flores, C, Cabrera-Marante, O, Pleguezuelo, D, de Diego, R, Keles, S, Aytekin, G, Akcan, O, Bryceson, Y, Bergman, P, Brodin, P, Smole, D, Smith, C, Norlin, A, Campbell, T, Covill, L, Hammarström, L, Pan-Hammarström, Q, Abolhassani, H, Mane, S, Marr, N, Ata, M, Al Ali, F, Khan, T, Spaan, A, Dalgard, C, Bonfanti, P, Biondi, A, Tubiana, S, Burdet, C, Nussbaum, R, Kahn-Kirby, A, Snow, A, Bustamante, J, Puel, A, Boisson-Dupuis, S, Zhang, S, Béziat, V, Lifton, R, Bastard, P, Notarangelo, L, Abel, L, Su, H, Jouanguy, E, Amara, A, Soumelis, V, Cobat, A, Zhang, Q, and Casanova, J

Subjects
Male, SUBSETS, [SDV]Life Sciences [q-bio], Penetrance, REDUNDANT, COVID-19 (Malaltia), 0302 clinical medicine, Resposta immunitària, 80 and over, Medicine and Health Sciences, Medicine, Young adult, Child, X-linked recessive inheritance, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, 0303 health sciences, education.field_of_study, PYOGENIC BACTERIAL-INFECTIONS, virus diseases, Genetic Diseases, X-Linked, HUMANS, General Medicine, Middle Aged, PROTECTIVE IMMUNITY, 3. Good health, Pedigree, Settore MED/03, Immune System Diseases, Genetic Diseases, Child, Preschool, Cohort, medicine.symptom, SINGLE-STRANDED RNA, Adult, Adolescent, Aged, Alleles, COVID-19, Humans, Infant, Toll-Like Receptor 7, Young Adult, Immunology, Population, Asymptomatic, Article, 03 medical and health sciences, HOST-DEFENSE, Immune response, Allele, Preschool, education, 030304 developmental biology, TOLL-LIKE RECEPTORS, business.industry, RECOGNITION, Proteins, X-Linked, medicine.disease, Pneumonia, 3121 General medicine, internal medicine and other clinical medicine, PLASMACYTOID DENDRITIC CELLS, business, Proteïnes, 030215 immunology
Abstract

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract. Funding: The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, Rockefeller University; the St. Giles Foundation; the NIH (R01AI088364), the National Center for Advancing Translational Sciences (NCATS); NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at the George Mason University; the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956); the Meyer Foundation; the JPB Foundation; the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01) and the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (EQU201903007798); the FRM and ANR GENCOVID project, the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AABIFNCOV (ANR-20-CO11-0001) projects; the European Union’s Horizon 2020 Research and Innovation Program under grant agreement no. 824110 (EASI-genomics). The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (RECOVER WP 6). The Neurometabolic Diseases Laboratory received funding from the European Union’s Horizon 2020 Research and Innovation Program (EasiGenomics grant no. 824110 COVID-19/PID12342). A.P., R.P.d.D., C.R.-G., and C.F. were funded by Instituto de Salud Carlos III (COV20_01333 and COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), Fundación DISA (OA18/017), and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). The laboratories of G.N. and A.N. were supported by a grant awarded to Regione Lazio (PROGETTI DI GRUPPI DI RICERCA 2020) no. A0375-2020-36663, GecoBiomark. A. Amara’s laboratory was supported by ANR under the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the FRM (EQU202003010193), ANR (ANR-20-COVI-000 project IDISCOVR and ANR-20-CO11-0004 project FISHBP), and the University of Paris (Plan de Soutien Covid-19: RACPL20FIR01-COVID-SOUL). This work was supported, in part, by the Division of Intramural Research, NIAID, NIH (grants 1ZIAAI001265 to H.C.S. and ZIA AI001270 to L.D.N.). The G.C. laboratory was supported by the Italian Ministry of Health (grant COVID-2020-12371617) and the intramural COVID Host Genetics program. The J.L.F. laboratory was supported, in part, by the Coopération Scientifique France-Colciencias (ECOS-Nord/COLCIENCIAS/MEN/ICETEX; 806-2018) and Colciencias contract 713-2016 (no. 111574455633). The V.S. laboratory was supported by ANR DENDRISEPSIS (ANR-17-CE15-0003) and ANR APCOD (ANR-17-CE15-0003-01), a Fast Grant from the Mercatus Center, FRM, University of Paris PLAN D’URGENCE COVID19. The N.M. laboratory was supported by Sidra Medicine (SDR400048) and the Qatar National Research Fund (grant No. NPRP9-251-3-045)

Published
2021
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50. Long-term overall survival and toxicities of ABVD vs BEACOPP in advanced Hodgkin lymphoma

Author

Pier Luigi Zinzani, Julien Depaus, P. Valagussa, Simonetta Viviani, Patrice Carde, Laurianne Clément-Filliatre, Jonathan Douxfils, Marc André, Olivier Casasnovas, Massimo Federico, Pauline Brice, Nicolas Mounier, Alessandro M. Gianni, Paolo G. Gobbi, Jehan Dupuis, Catherine Fortpied, Martin Hutchings, Emilio Iannitto, Monica Bellei, Marian Heczko, Alessandro Rambaldi, Josette Brière, Andre M.P.E., Carde P., Viviani S., Bellei M., Fortpied C., Hutchings M., Gianni A.M., Brice P., Casasnovas O., Gobbi P.G., Zinzani P.L., Dupuis J., Iannitto E., Rambaldi A., Briere J., Clement-Filliatre L., Heczko M., Valagussa P., Douxfils J., Depaus J., Federico M., Mounier N., UCL - (MGD) Service d'hématologie, and UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie

Subjects
0301 basic medicine, BEACOPP, Oncology, Male, Cancer Research, Time Factors, medicine.medical_treatment, Procarbazine, 0302 clinical medicine, International Prognostic Index, Risk Factors, Antineoplastic Combined Chemotherapy Protocols, Original Research, Etoposide, Randomized Controlled Trials as Topic, Hazard ratio, Neoplasms, Second Primary, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Hodgkin Disease, Dacarbazine, Vincristine, 030220 oncology & carcinogenesis, Disease Progression, secondary cancers, Female, medicine.drug, Adult, medicine.medical_specialty, ABVD, Hodgkin lymphoma, overall survival, progression-free survival, Adolescent, Vinblastine, Risk Assessment, Transplantation, Autologous, lcsh:RC254-282, 03 medical and health sciences, Bleomycin, Young Adult, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Progression-free survival, Cyclophosphamide, Aged, business.industry, Clinical Cancer Research, progression‐free survival, 030104 developmental biology, Clinical Trials, Phase III as Topic, Doxorubicin, Prednisone, business, Stem Cell Transplantation
Abstract

Purpose We explored the potential overall survival (OS) benefit of bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) over doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) in a pooled analysis of four randomized trials. Patients and methods Primary objective was to evaluate the OS impact of BEACOPP using individual patient data. Secondary objectives were progression‐free survival (PFS), secondary cancers, and use of autologous stem cell transplantation (ASCT). Results About 1227 patients were included. The 7‐year OS was 84.3% (95% CI 80.8‐87.2) for ABVD vs 87.7% (95% CI 84.5‐90.2) for BEACOPP. Two follow‐up periods were identified based on survival curves and hazard ratio (HR) over time. For the first 18 months, there was no difference. For the second period of ≥18 months, ABVD patients had a higher death risk (HRABVD vs BEACOPP = 1.59; 95% CI 1.09‐2.33). A Cox model stratified by trial and evaluating the effect of treatment and International Prognostic Index (IPI) score as fixed effects showed that both were statistically significant (treatment, P = .0185; IPI score, P = .0107). The 7‐year PFS was 71.1% (95% CI 67.1‐74.6) for ABVD vs 81.1% (95% CI 77.5‐84.2) for BEACOPP (P, Advanced Hodgkin lymphoma (HL) are treated with two different chemotherapy regimens (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine [ABVD] or bleomycin, etoposide, doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], procarbazine, and prednisone [BEACOPP]) that have two different toxicity profiles. In this pooled analysis of four randomized trials comparing these two regimens, and with a median follow‐up of 7 years, progression‐free survival is significantly superior with the BEACOPP regimen. The 7 years overall survival was 84.3% for ABVD and 87.7% for BEACOPP. The main cause of death after ABVD is HL, but second malignancy including 10 myeloid malignancies after BEACOPP.

Published
2020
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