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4. Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Author

Kariotis, S, Jammeh, E, Swietlik, EM, Pickworth, JA, Rhodes, CJ, Otero, P, Wharton, J, Iremonger, J, Dunning, MJ, Pandya, D, Mascarenhas, TS, Errington, N, Thompson, AAR, Romanoski, CE, Rischard, F, Garcia, JGN, Yuan, JX-J, An, T-HS, Desai, AA, Coghlan, G, Lordan, J, Corris, PA, Howard, LS, Condliffe, R, Kiely, DG, Church, C, Pepke-Zaba, J, Toshner, M, Wort, S, Gräf, S, Morrell, NW, Wilkins, MR, Lawrie, A, Wang, D, Bleda, M, Hadinnapola, C, Haimel, M, Auckland, K, Tilly, T, Martin, JM, Yates, K, Treacy, CM, Day, M, Greenhalgh, A, Shipley, D, Peacock, AJ, Irvine, V, Kennedy, F, Moledina, S, MacDonald, L, Tamvaki, E, Barnes, A, Cookson, V, Chentouf, L, Ali, S, Othman, S, Ranganathan, L, Gibbs, JSR, DaCosta, R, Pinguel, J, Dormand, N, Parker, A, Stokes, D, Ghedia, D, Tan, Y, Ngcozana, T, Wanjiku, I, Polwarth, G, Mackenzie Ross, RV, Suntharalingam, J, Grover, M, Kirby, A, Grove, A, White, K, Seatter, A, Creaser-Myers, A, Walker, S, Roney, S, Elliot, CA, Charalampopoulos, A, Sabroe, I, Hameed, A, Armstrong, I, Hamilton, N, Rothman, AMK, Swift, AJ, Wild, JM, Soubrier, F, Eyries, M, Humbert, M, Montani, D, Girerd, B, Scelsi, L, Ghio, S, Gall, H, Ghofrani, A, Bogaard, HJ, Noordegraaf, AV, Houweling, AC, Veld, AHI, and Schotte, G

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH.

Published
2021

7. Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Author

Kariotis, S, Jammeh, E, Swietlik, EM, Pickworth, JA, Rhodes, CJ, Otero, P, Wharton, J, Iremonger, J, Dunning, MJ, Pandya, D, Mascarenhas, TS, Errington, N, Thompson, AAR, Romanoski, CE, Rischard, F, Garcia, JGN, Yuan, JX-J, An, T-HS, Desai, AA, Coghlan, G, Lordan, J, Corris, PA, Howard, LS, Condliffe, R, Kiely, DG, Church, C, Pepke-Zaba, J, Toshner, M, Wort, S, Graf, S, Morrell, NW, Wilkins, MR, Lawrie, A, Wang, D, Bleda, M, Hadinnapola, C, Haimel, M, Auckland, K, Tilly, T, Martin, JM, Yates, K, Treacy, CM, Day, M, Greenhalgh, A, Shipley, D, Peacock, AJ, Irvine, V, Kennedy, F, Moledina, S, MacDonald, L, Tamvaki, E, Barnes, A, Cookson, V, Chentouf, L, Ali, S, Othman, S, Ranganathan, L, Gibbs, JSR, DaCosta, R, Pinguel, J, Dormand, N, Parker, A, Stokes, D, Ghedia, D, Tan, Y, Ngcozana, T, Wanjiku, I, Polwarth, G, Mackenzie Ross, RV, Suntharalingam, J, Grover, M, Kirby, A, Grove, A, White, K, Seatter, A, Creaser-Myers, A, Walker, S, Roney, S, Elliot, CA, Charalampopoulos, A, Sabroe, I, Hameed, A, Armstrong, I, Hamilton, N, Rothman, AMK, Swift, AJ, Wild, JM, Soubrier, F, Eyries, M, Humbert, M, Montani, D, Girerd, B, Scelsi, L, Ghio, S, Gall, H, Ghofrani, A, Bogaard, HJ, Noordegraaf, AV, Houweling, AC, Veld, AHI, Schotte, G, Kariotis, Sokratis [0000-0001-9993-6017], Pickworth, Josephine A [0000-0002-7199-364X], Rhodes, Christopher J [0000-0002-4962-3204], Wharton, John [0000-0001-8110-2575], Iremonger, James [0000-0003-3953-8812], Dunning, Mark J [0000-0002-8853-9435], Errington, Niamh [0000-0001-6768-7394], Thompson, AA Roger [0000-0002-0717-4551], Howard, Luke S [0000-0003-2822-210X], Graf, Stefan [0000-0002-1315-8873], Wilkins, Martin R [0000-0003-3926-1171], Lawrie, Allan [0000-0003-4192-9505], Wang, Dennis [0000-0003-0068-1005], Apollo - University of Cambridge Repository, Gräf, Stefan [0000-0002-1315-8873], Pickworth, Josephine A. [0000-0002-7199-364X], Rhodes, Christopher J. [0000-0002-4962-3204], Dunning, Mark J. [0000-0002-8853-9435], Thompson, A. A. Roger [0000-0002-0717-4551], Howard, Luke S. [0000-0003-2822-210X], Wilkins, Martin R. [0000-0003-3926-1171], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, and ACS - Atherosclerosis & ischemic syndromes

Subjects
HYPOXIA-INDUCED PROLIFERATION, OPERATED CALCIUM-ENTRY, Classification and taxonomy, Science, PROGNOSTIC IMPACT, General Physics and Astronomy, Down-Regulation, 631/114/2404, General Biochemistry, Genetics and Molecular Biology, 38/91, Functional clustering, Genomic analysis, 631/114/1386, 631/1647/2217, Humans, Familial Primary Pulmonary Hypertension, HLA-DP beta-Chains, RISK SCORE CALCULATOR, OUTCOMES, Pulmonary Arterial Hypertension, Science & Technology, Multidisciplinary, Gene Expression Profiling, 692/4019/592/75, article, 49/39, General Chemistry, Multidisciplinary Sciences, IRON-DEFICIENCY, Cardiovascular diseases, UK National PAH Cohort Study Consortium, REGISTRY, ASSESSMENTS, SURVIVAL, Science & Technology - Other Topics, Transcriptome, 5-Aminolevulinate Synthetase
Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH., Idiopathic pulmonary arterial hypertension is a rare and fatal disease with a heterogeneous treatment response. Here the authors show that unsupervised machine learning of whole blood transcriptomes from 359 patients with idiopathic pulmonary arterial hypertension identifies 3 subgroups (endophenotypes) that improve risk stratification and provide new molecular insights.

Published
2020

8. Whole-Blood RNA Profiles Associated with Pulmonary Arterial Hypertension and Clinical Outcome

Author

Rhodes, CJ, Otero-Núñez, P, Wharton, J, Swietlik, EM, Kariotis, S, Harbaum, L, Dunning, MJ, Elinoff, JM, Errington, N, Thompson, AAR, Iremonger, J, Coghlan, JG, Corris, PA, Howard, LS, Kiely, DG, Church, C, Pepke-Zaba, J, Toshner, M, Wort, SJ, Desai, AA, Humbert, M, Nichols, WC, Southgate, L, Trégouët, D-A, Trembath, RC, Prokopenko, I, Gräf, S, Morrell, NW, Wang, D, Lawrie, A, and Wilkins, MR

Abstract

Rationale: Idiopathic and heritable pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signaling pathways and stratify patients more robustly according to clinical risk.Objectives: To use a three-stage design of RNA discovery, RNA validation and model construction, and model validation to define a set of PAH-associated RNAs and a single summarizing RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomization (MR) analysis.Methods: RNA sequencing was performed on whole-blood samples from 359 patients with idiopathic, heritable, and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known expression quantitative trait loci and summary statistics from a PAH genome-wide association study.Measurements and Main Results: We identified 507 genes with differential RNA expression in patients with PAH compared with control subjects. A model of 25 RNAs distinguished PAH with 87% accuracy (area under the curve 95% confidence interval: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (P = 4.66 × 10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (odds ratio, 0.317; 95% confidence interval, 0.129-0.776; P = 0.012).Conclusions: A whole-blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.

Published
2020

9. Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension

Author

Ulrich, A, Wharton, J, Thayer, TE, Swietlik, EM, Assad, TR, Desai, AA, Gräf, S, Harbaum, L, Humbert, M, Morrell, NW, Nichols, WC, Soubrier, F, Southgate, L, Trégouët, D-A, Trembath, RC, Brittain, EL, Wilkins, MR, Prokopenko, I, Rhodes, CJ, NIHR BioResource – Rare Diseases Consortium, UK PAH Cohort Study Consortium, and US PAH Biobank Consortium

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early stage iron deficiency or iron deficiency anaemia. This study investigated if elevated RDW is causally associated with PAH.A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively.We confirmed the observed association between RDW and PAH (OR=1.90, 95% CI=1.80-2.01) in a multi-centre case-control study (N cases=642, N disease controls=15 889). The primary MR analysis was adequately powered to detect a causal effect (OR) from between 1.25 and 1.52 or greater based on estimates reported in the RDW GWAS or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (ORcausal=1.07, 95% CI=0.92-1.24) or the secondary (ORcausal=1.09, 95% CI=0.77-1.54) MR analysis.The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution as any improvements observed may not be mechanistically linked to the development of PAH.

Published
2020

10. S91 Patterns of cytokines and growth factors in pulmonary arterial hypertension patients with BMPR2 mutations and PAH patients without driving mutations and their influence on survival

Author

Schwiening, M, primary, Pandya, D, additional, Swietlik, EM, additional, Burling, KA, additional, Barker, P, additional, Treacy, CM, additional, Wort, SJ, additional, Pepke-Zaba, J, additional, Graf, S, additional, Marciniak, SJ, additional, Morrell, NW, additional, and Soon, E, additional

Published
2021
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11. Germline selection shapes human mitochondrial DNA diversity

Author

Wei, W, Tuna, S, Keogh, MJ, Smith, KR, Aitman, TJ, Beales, PL, Bennett, DL, Gale, DP, Bitner-Glindzicz, MAK, Black, GC, Brennan, P, Elliott, P, Flinter, FA, Floto, RA, Houlden, H, Irving, M, Koziell, A, Maher, ER, Markus, HS, Morrell, NW, Newman, WG, Roberts, I, Sayer, JA, Smith, KGC, Taylor, JC, Watkins, H, Webster, AR, Wilkie, AOM, Williamson, C, Attwood, A, Brown, M, Brod, NC, Crisp-Hihn, A, Davis, J, Deevi, SVV, Dewhurst, EF, Edwards, K, Erwood, M, Fox, J, Frary, AJ, Hu, F, Jolley, J, Kingston, N, Linger, R, Mapeta, R, Martin, J, Meacham, S, Papadia, S, Rayner-Matthews, PJ, Samarghitean, C, Shamardina, O, Simeoni, I, Staines, S, Staples, E, Stark, H, Stephens, J, Titterton, C, Von Ziegenweidt, J, Watt, C, Whitehorn, D, Wood, Y, Yates, K, Yu, P, James, R, Ashford, S, Penkett, CJ, Stirrups, KE, Bariana, T, Lentaigne, C, Sivapalaratnam, S, Westbury, SK, Allsup, DJ, Bakchoul, T, Biss, T, Boyce, S, Collins, J, Collins, PW, Curry, NS, Downes, K, Dutt, T, Erber, WN, Evans, G, Everington, T, Favier, R, Gomez, K, Greene, D, Gresele, P, Hart, D, Kazmi, R, Kelly, AM, Lambert, M, Madan, B, Mangles, S, Mathias, M, Millar, C, Obaji, S, Peerlinck, K, Roughley, C, Schulman, S, Scully, M, Shapiro, SE, Sibson, K, Sims, MC, Tait, RC, Talks, K, Thys, C, Toh, C-H, Van Geet, C, Westwood, J-P, Mumford, AD, Ouwehand, WH, Freson, K, Laffan, MA, Tan, RYY, Harkness, K, Mehta, S, Muir, KW, Hassan, A, Traylor, M, Drazyk, AM, Parry, D, Ahmed, M, Kazkaz, H, Vandersteen, AM, Ormondroyd, E, Thomson, K, Dent, T, Buchan, RJ, Bueser, T, Carr-White, G, Cook, S, Daniels, MJ, Harper, AR, Ware, JS, Dixon, PH, Chambers, J, Cheng, F, Estiu, MC, Hague, WM, Marschall, H-U, Vazquez-Lopez, M, Arno, G, French, CE, Michaelides, M, Moore, AT, Sanchis-Juan, A, Carss, K, Raymond, FL, Chinnery, PF, Griffiths, P, Horvath, R, Hudson, G, Jurkute, N, Pyle, A, Yu-Wai-Man, P, Whitworth, J, Adlard, J, Armstrong, R, Brewer, C, Casey, R, Cole, TRP, Evans, DG, Greenhalgh, L, Hanson, HL, Hoffman, J, Izatt, L, Kumar, A, Lalloo, F, Ong, KR, Park, S-M, Searle, C, Side, L, Snape, K, Woodward, E, Tischkowitz, M, Grozeva, D, Kurian, MA, Themistocleous, AC, Gosal, D, Marshall, A, Matthews, E, McCarthy, MI, Renton, T, Rice, ASC, Vale, T, Walker, SM, Woods, CG, Thaventhiran, JE, Allen, HL, Savic, S, Alachkar, H, Antrobus, R, Baxendale, HE, Browning, MJ, Buckland, MS, Cooper, N, Edgar, JDM, Egner, W, Gilmour, KC, Goddard, S, Gordins, P, Grigoriadou, S, Hackett, S, Hague, R, Hayman, G, Herwadkar, A, Huissoon, AP, Jolles, S, Kelleher, P, Kumararatne, D, Longhurst, H, Lorenzo, LE, Lyons, PA, Maimaris, J, Noorani, S, Richter, A, Sargur, RB, Sewell, WAC, Thomas, D, Thomas, MJ, Worth, A, Yong, PFK, Kuijpers, TW, Thrasher, AJ, Levine, AP, Sadeghi-Alavijeh, O, Wong, EKS, Cook, HT, Chan, MMY, Hall, M, Harris, C, McAlinden, P, Marchbank, KJ, Marks, S, Maxwell, H, Mozere, M, Wessels, J, Johnson, SA, Bleda, M, Hadinnapola, C, Haimel, M, Swietlik, E, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, P, Danesino, C, Eyries, M, Gall, H, Ghofrani, H-A, Gibbs, JSR, Girerd, B, Holden, S, Houweling, A, Howard, LS, Humbert, M, Kiely, DG, Kovacs, G, Lawrie, A, Ross, RVM, Moledina, S, Montani, D, Newnham, M, Olschewski, A, Olschewski, H, Peacock, A, Pepke-Zaba, J, Scelsi, L, Seeger, W, Soubrier, F, Suntharalingam, J, Toshner, M, Treacy, C, Trembath, R, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Wilkins, MR, Wort, SJ, Graf, S, Louka, E, Roy, NB, Rao, A, Ancliff, P, Babbs, C, Layton, DM, Mead, AJ, O'Sullivan, J, Okoli, S, Saleem, M, Bierzynska, A, Diz, CB, Colby, E, Ekani, MN, Satchell, S, Fowler, T, Rendon, A, Scott, R, Smedley, D, Thomas, E, Caulfield, M, Abbs, S, Burrows, N, Chitre, M, Gattens, M, Gurnell, M, Kelsall, W, Poole, KES, Ross-Russell, R, Spasic-Boskovic, O, Twiss, P, Wagner, A, Banka, S, Clayton-Smith, J, Douzgou, S, Abulhoul, L, Aurora, P, Bockenhauer, D, Cleary, M, Dattani, M, Ganesan, V, Pilkington, C, Rahman, S, Shah, N, Wedderburn, L, Compton, CJ, Deshpande, C, Fassihi, H, Haque, E, Josifova, D, Mohammed, SN, Robert, L, Rose, SJ, Ruddy, DM, Sarkany, RN, Sayer, G, Shaw, AC, Campbell, C, Gibson, K, Koelling, N, Lester, T, Nemeth, AH, Palles, C, Patel, S, Sen, A, Taylor, J, Tomlinson, IP, Malka, S, Browning, AC, Burn, J, De Soyza, A, Graham, J, Pearce, S, Quinton, R, Schaefer, AM, Wilson, BT, Wright, M, Simpson, M, Syrris, P, Bradley, JR, Turro, E, ARD - Amsterdam Reproduction and Development, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Medical Research Council (MRC), Wellcome Trust, Wei, Wei [0000-0002-2945-3543], Tuna, Salih [0000-0003-3606-4367], Smith, Katherine R [0000-0002-0329-5938], Beales, Phil L [0000-0002-9164-9782], Bennett, David L [0000-0002-7996-2696], Gale, Daniel P [0000-0002-9170-1579], Brennan, Paul [0000-0003-1128-6254], Elliott, Perry [0000-0003-3383-3984], Floto, R Andres [0000-0002-2188-5659], Houlden, Henry [0000-0002-2866-7777], Koziell, Ania [0000-0003-4882-0246], Maher, Eamonn R [0000-0002-6226-6918], Markus, Hugh S [0000-0002-9794-5996], Morrell, Nicholas W [0000-0001-5700-9792], Newman, William G [0000-0002-6382-4678], Sayer, John A [0000-0003-1881-3782], Smith, Kenneth GC [0000-0003-3829-4326], Taylor, Jenny C [0000-0003-3602-5704], Watkins, Hugh [0000-0002-5287-9016], Webster, Andrew R [0000-0001-6915-9560], Wilkie, Andrew OM [0000-0002-2972-5481], Penkett, Christopher J [0000-0003-4006-7261], Stirrups, Kathleen E [0000-0002-6823-3252], Rendon, Augusto [0000-0001-8994-0039], Bradley, John R [0000-0002-7774-8805], Turro, Ernest [0000-0002-1820-6563], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Non-Mendelian inheritance, Genome, Mitochondrial/genetics, DNA, Mitochondrial/genetics, 0302 clinical medicine, Ovum/growth & development, MTDNA, TRANSCRIPTION, Genetics, education.field_of_study, Multidisciplinary, NIHR BioResource–Rare Diseases, ASSOCIATION, Heteroplasmy, Mitochondrial, Multidisciplinary Sciences, GENOME, REPLACEMENT, Science & Technology - Other Topics, Female, Maternal Inheritance, Mitochondrial DNA, General Science & Technology, Genetic genealogy, Population, Biology, Human mitochondrial genetics, SEQUENCE, DNA, Mitochondrial, 03 medical and health sciences, Genetic, 100,000 Genomes Project–Rare Diseases Pilot, Genetic variation, MD Multidisciplinary, Humans, Selection, Genetic, education, Selection, Ovum, Science & Technology, MUTATIONS, Genetic Variation, DNA, LEIGH-DISEASE, 030104 developmental biology, REPLICATION, Genome, Mitochondrial, HETEROPLASMY, 030217 neurology & neurosurgery
Abstract

INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.

Published
2019
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12. Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children

Author

French, CE, Delon, I, Dolling, H, Sanchis-Juan, A, Shamardina, O, Mégy, K, Abbs, S, Austin, T, Bowdin, S, Branco, RG, Firth, H, Tuna, S, Aitman, TJ, Ashford, S, Astle, WJ, Bennet, DL, Bleda, M, Carss, KJ, Chinnery, PF, Deevi, SVV, Fletcher, D, Gale, DP, Gräf, SF, Hu, F, James, R, Kasanicki, MA, Kingston, N, Koziell, AB, Allen, HL, Maher, ER, Markus, HS, Meacham, S, Morrell, NW, Penkett, CJ, Roberts, I, Smith, KGC, Stark, H, Stirrups, KE, Turro, E, Watkins, H, Williamson, C, Young, T, Bradley, JR, Ouwehand, WH, Raymond, FL, Agrawal, S, Armstrong, R, Beardsall, K, Belteki, G, Bohatschek, M, Broster, S, Campbell, R, Chaudhary, R, Costa, C, D’Amore, A, Fitzsimmons, A, Hague, J, Harley, J, Hoodbhoy, S, Kayani, R, Kelsall, W, Mehta, SG, O’Donnell, R, O’Hare, S, Ogilvy-Stuart, A, Papakostas, S, Park, SM, Parker, A, Pathan, N, Prapa, M, Sammut, A, Sandford, R, Schon, K, Singh, Y, Spike, K, Tavares, ALT, Wari-Pepple, D, Wong, HS, Woods, CG, Rowitch, DH, Raymond, F Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository

Subjects
Male, NICU, medicine.medical_specialty, Palliative care, Adolescent, PICU, Original, Critical Illness, Critically ill children, Genomics, Critical Care and Intensive Care Medicine, Intensive Care Units, Pediatric, State Medicine, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Anesthesiology, Intensive care, Intensive Care Units, Neonatal, Genetics, Medicine, Humans, Prospective Studies, Medical diagnosis, Intensive care medicine, Prospective cohort study, Child, Whole genome sequencing, Whole Genome Sequencing, business.industry, Genetic Diseases, Inborn, Infant, Newborn, Infant, 030208 emergency & critical care medicine, 030228 respiratory system, England, FOS: Biological sciences, Child, Preschool, Female, business, Genetic Background, Cohort study
Abstract

Purpose With growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations. Methods We performed trio whole genome sequence (WGS) analysis on a prospective cohort of families recruited in NICU and PICU at a single site in the UK. We developed a research pipeline in collaboration with the National Health Service to deliver validated pertinent pathogenic findings within 2–3 weeks of recruitment. Results A total of 195 families had whole genome analysis performed (567 samples) and 21% received a molecular diagnosis for the underlying genetic condition in the child. The phenotypic description of the child was a poor predictor of the gene identified in 90% of cases, arguing for gene agnostic testing in NICU/PICU. The diagnosis affected clinical management in more than 65% of cases (83% in neonates) including modification of treatments and care pathways and/or informing palliative care decisions. A 2–3 week turnaround was sufficient to impact most clinical decision-making. Conclusions The use of WGS in intensively ill children is acceptable and trio analysis facilitates diagnoses. A gene agnostic approach was effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. WGS analysis has the potential to be a first-line diagnostic tool for a subset of intensively ill children. Electronic supplementary material The online version of this article (10.1007/s00134-019-05552-x) contains supplementary material, which is available to authorized users.

Published
2019

13. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author

Rhodes, CJ, Batai, K, Bleda, M, Haimel, M, Southgate, L, Germain, M, Pauciulo, MW, Hadinnapola, C, Aman, J, Girerd, B, Arora, A, Knight, J, Hanscombe, KB, Karnes, JH, Kaakinen, M, Gall, H, Ulrich, A, Harbaum, L, Cebola, I, Ferrer, J, Lutz, K, Swietlik, EM, Ahmad, F, Amouyel, P, Archer, SL, Argula, R, Austin, ED, Badesch, D, Bakshi, S, Barnett, C, Benza, R, Bhatt, N, Bogaard, HJ, Burger, CD, Chakinala, M, Church, C, Coghlan, JG, Condliffe, R, Corris, PA, Danesino, C, Debette, S, Elliott, CG, Elwing, J, Eyries, M, Fortin, T, Franke, A, Frantz, RP, Frost, A, Garcia, JGN, Ghio, S, Ghofrani, H-A, Gibbs, JSR, Harley, J, He, H, Hill, NS, Hirsch, R, Houweling, AC, Howard, LS, Ivy, D, Kiely, DG, Klinger, J, Kovacs, G, Lahm, T, Laudes, M, Machado, RD, Ross, RV, Marsolo, K, Martin, LJ, Moledina, S, Montani, D, Nathan, SD, Newnham, M, Olschewski, A, Olschewski, H, Oudiz, RJ, Ouwehand, WH, Peacock, AJ, Pepke-Zaba, J, Rehman, Z, Robbins, I, Roden, DM, Rosenzweig, EB, Saydain, G, Scelsi, L, Schilz, R, Seeger, W, Shaffer, CM, Simms, RW, Simon, M, Sitbon, O, Suntharalingam, J, Tang, H, Tchourbanov, AY, Thenappan, T, Torres, F, Toshner, MR, Treacy, CM, Noordegraaf, A, Waisfisz, Q, Walsworth, AK, Walter, RE, Wharton, J, White, RJ, Wilt, J, Wort, SJ, Yung, D, Lawrie, A, Humbert, M, Soubrier, F, Trégouët, D-A, Prokopenko, I, Kittles, R, Gräf, S, Nichols, WC, Trembath, RC, Desai, AA, Morrell, NW, Wilkins, MR, Consortium, UK NIHR Bioresource Rare Diseases, Consortium, UK PAH Cohort Study, Consortium, US PAH Biobank, McCarthy, M, Sorbonne Université (SU), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, APH - Quality of Care, and ACS - Microcirculation

Subjects
Male, Pulmonary Arterial Hypertension, Genotyping Techniques, [SDV]Life Sciences [q-bio], Genetic Variation, HLA-DP alpha-Chains, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Survival Analysis, Article, SOXF Transcription Factors, Humans, Female, Genetic Predisposition to Disease, HLA-DP beta-Chains, Genome-Wide Association Study, Signal Transduction
Abstract

Background Raregenetic variantscause pulmonary arterial hypertension, but the contribution of commongenetic variationto disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS usedgenotypesfrom 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals.Cross-validationof loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration ofsurvival.All-cause mortalitywas the primary endpoint in survival analyses. Findings A locus nearSOX17(rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus inHLA-DPA1andHLA-DPB1(collectively referred to asHLA-DPA1/DPB1here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. TheSOX17locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional andepigenomicdata indicate that the risk variants nearSOX17altergene regulationvia anenhanceractive inendothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reducedSOX17expression. TheHLA-DPA1/DPB1rs2856830 genotype was strongly associated with survival. Median survival fromdiagnosisin patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baselinedisease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer nearSOX17and inHLA-DPA1/DPB1is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by raremutationsinSOX17. Further studies are needed to confirm the association betweenHLA typingor rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improvesrisk stratificationin clinical practice or trials.

Published
2019

27. Genetic determinants of risk in pulmonary arterial hypertension: international case-control studies and meta-analysis

Author

Rhodes, CJ, Batai, K, Bleda, M, Haimel, M, Southgate, L, Germain, M, Pauciulo, MW, Hadinnapola, C, Aman, J, Girerd, B, Arora, A, Robbins, I, Roden, DM, Rosenzweig, EB, Saydain, G, Scelsi, L, Schilz, R, Seeger, W, Shaffer, CM, Simms, RW, Simon, M, Walter, RE, Sitbon, O, Suntharalingam, J, Tang, H, Tchourbanov, AY, Thenappan, T, Torres, F, Toshner, MR, Treacy, CM, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Walsworth, AK, White, RJ, Wilt, J, Wort, SJ, Yung, D, Lawrie, A, Humbert, M, Soubrier, F, Trégouët, D-A, Knight, J, Prokopenko, I, Kittles, R, Gräf, S, Nichols, WC, Trembath, RC, Desai, AA, Morrell, NW, Wilkins, MR, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, Hanscombe, KB, US PAH Biobank Consortium, Karnes, JH, Kaakinen, M, Gall, H, Ulrich, A, Harbaum, L, Cebola, I, Ferrer, J, Lutz, K, Swietlik, EM, Ahmad, F, Amouyel, P, Archer, SL, Argula, R, Austin, ED, Badesch, D, Bakshi, S, Barnett, C, Benza, R, Bhatt, N, Bogaard, HJ, Burger, CD, Chakinala, M, Church, C, Coghlan, JG, Condliffe, R, Corris, PA, Danesino, C, Debette, S, Elliott, CG, Elwing, J, Eyries, M, Fortin, T, Franke, A, Frantz, RP, Frost, A, Garcia, JGN, Ghio, S, Ghofrani, H-A, Gibbs, JSR, Harley, J, He, H, Hill, NS, Hirsch, R, Houweling, AC, Howard, LS, Ivy, D, Kiely, DG, Klinger, J, Kovacs, G, Lahm, T, Laudes, M, Machado, RD, Ross, RVM, Marsolo, K, Martin, LJ, Moledina, S, Montani, D, Nathan, SD, Newnham, M, Olschewski, A, Olschewski, H, Oudiz, RJ, Ouwehand, WH, Peacock, AJ, Pepke-Zaba, J, Rehman, Z, British Heart Foundation, Wellcome Trust, and Medical Research Council (MRC)

Subjects
ALPHA, Science & Technology, US PAH Biobank Consortium, Critical Care Medicine, ENDODERM FORMATION, General & Internal Medicine, UK NIHR BioResource Rare Diseases Consortium, Respiratory System, UK PAH Cohort Study Consortium, SUSCEPTIBILITY, SOX17, Life Sciences & Biomedicine, DISEASE
Abstract

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.

Published
2018

28. Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data

Author

Farmery, JHR, Smith, ML, Lynch, AG, Huissoon, A, Furnell, A, Mead, A, Levine, AP, Manzur, A, Thrasher, A, Greenhalgh, A, Parker, A, Sanchis-Juan, A, Richter, A, Gardham, A, Lawrie, A, Sohal, A, Creaser-Myers, A, Frary, A, Greinacher, A, Themistocleous, A, Peacock, AJ, Marshall, A, Mumford, A, Rice, A, Webster, A, Brady, A, Koziell, A, Manson, A, Chandra, A, Hensiek, A, In't Veld, AH, Maw, A, Kelly, AM, Moore, A, Noordegraaf, AV, Attwood, A, Herwadkar, A, Ghofrani, A, Houweling, AC, Girerd, B, Furie, B, Treacy, CM, Millar, CM, Sewell, C, Roughley, C, Titterton, C, Williamson, C, Hadinnapola, C, Deshpande, C, Toh, C-H, Bacchelli, C, Patch, C, Van Geet, C, Babbs, C, Bryson, C, Penkett, CJ, Rhodes, CJ, Watt, C, Bethune, C, Booth, C, Lentaigne, C, McJannet, C, Church, C, French, C, Samarghitean, C, Halmagyi, C, Gale, D, Greene, D, Hart, D, Allsup, D, Bennett, D, Edgar, D, Kiely, DG, Gosal, D, Perry, DJ, Keeling, D, Montani, D, Shipley, D, Whitehorn, D, Fletcher, D, Krishnakumar, D, Grozeva, D, Kumararatne, D, Thompson, D, Josifova, D, Maher, E, Wong, EKS, Murphy, E, Dewhurst, E, Louka, E, Rosser, E, Chalmers, E, Colby, E, Drewe, E, McDermott, E, Thomas, E, Staples, E, Clement, E, Matthews, E, Wakeling, E, Oksenhendler, E, Turro, E, Reid, E, Wassmer, E, Raymond, FL, Hu, F, Kennedy, F, Soubrier, F, Flinter, F, Kovacs, G, Polwarth, G, Ambegaonkar, G, Arno, G, Hudson, G, Woods, G, Coghlan, G, Hayman, G, Arumugakani, G, Schotte, G, Cook, HT, Alachkar, H, Allen, HL, Lango-Allen, H, Stark, H, Stauss, H, Schulze, H, Boggard, HJ, Baxendale, H, Dolling, H, Firth, H, Gall, H, Watson, H, Longhurst, H, Markus, HS, Watkins, H, Simeoni, I, Emmerson, I, Roberts, I, Quinti, I, Wanjiku, I, Gibbs, JSR, Thaventhiran, J, Whitworth, J, Hurst, J, Collins, J, Suntharalingam, J, Payne, J, Thachil, J, Martin, JM, Martin, J, Carmichael, J, Maimaris, J, Paterson, J, Pepke-Zaba, J, Heemskerk, JWM, Gebhart, J, Davis, J, Pasi, J, Bradley, JR, Wharton, J, Stephens, J, Rankin, J, Anderson, J, Vogt, J, Von Ziegenweldt, J, Rehnstrom, K, Megy, K, Talks, K, Peerlinck, K, Yates, K, Freson, K, Stirrups, K, Gomez, K, Smith, KGC, Carss, K, Rue-Albrecht, K, Gilmour, K, Masati, L, Scelsi, L, Southgate, L, Ranganathan, L, Ginsberg, L, Devlin, L, Willcocks, L, Ormondroyd, L, Lorenzo, L, Harper, L, Allen, L, Daugherty, L, Chitre, M, Kurian, M, Humbert, M, Tischkowitz, M, Bitner-Glindzicz, M, Erwood, M, Scully, M, Veltman, M, Caulfield, M, Layton, M, McCarthy, M, Ponsford, M, Toshner, M, Bleda, M, Wilkins, M, Mathias, M, Reilly, M, Afzal, M, Brown, M, Rondina, M, Stubbs, M, Haimel, M, Lees, M, Laffan, MA, Browning, M, Gattens, M, Richards, M, Michaelides, M, Lambert, MP, Makris, M, De Vries, M, Mahdi-Rogers, M, Saleem, M, Thomas, M, Holder, M, Eyries, M, Clements-Brod, N, Canham, N, Dormand, N, Van Zuydam, N, Kingston, N, Ghali, N, Cooper, N, Morrell, NW, Yeatman, N, Roy, N, Shamardina, O, Alavijeh, OS, Gresele, P, Nurden, P, Chinnery, P, Deegan, P, Yong, P, Yu-Wai-Man, P, Corris, PA, Calleja, P, Gissen, P, Bolton-Maggs, P, Rayner-Matthews, P, Ghataorhe, PK, Gordins, P, Stein, P, Collins, P, Dixon, P, Kelleher, P, Ancliff, P, Yu, P, Tait, RC, Linger, R, Doffinger, R, Machado, R, Kazmi, R, Sargur, R, Favier, R, Tan, R, Liesner, R, Antrobus, R, Sandford, R, Scott, R, Trembath, R, Horvath, R, Hadden, R, MackenzieRoss, RV, Henderson, R, MacLaren, R, James, R, Ghurye, R, DaCosta, R, Hague, R, Mapeta, R, Armstrong, R, Noorani, S, Murng, S, Santra, S, Tuna, S, Johnson, S, Chong, S, Lear, S, Walker, S, Goddard, S, Mangles, S, Westbury, S, Mehta, S, Hackett, S, Nejentsev, S, Moledina, S, Bibi, S, Meehan, S, Othman, S, Revel-Vilk, S, Holden, S, McGowan, S, Staines, S, Savic, S, Burns, S, Grigoriadou, S, Papadia, S, Ashford, S, Schulman, S, Ali, S, Park, S-M, Davies, S, Stock, S, Deevi, SVV, Graf, S, Ghio, S, Wort, SJ, Jolles, S, Austin, S, Welch, S, Meacham, S, Rankin, S, Seneviratne, S, Holder, S, Sivapalaratnam, S, Richardson, S, Kuijpers, T, Kuijpers, TW, Bariana, TK, Bakchoul, T, Everington, T, Renton, T, Young, T, Aitman, T, Warner, TQ, Vale, T, Hammerton, T, Pollock, V, Matser, V, Cookson, V, Clowes, V, Qasim, W, Wei, W, Erber, WN, Ouwehand, WH, Astle, W, Egner, W, Turek, W, Henskens, Y, Tan, Y, Lynch, Andy G [0000-0002-7876-7338], Apollo - University of Cambridge Repository, Medical Research Council (MRC), and British Heart Foundation

Subjects
Whole genome sequencing, 0303 health sciences, Multidisciplinary, Science & Technology, lcsh:R, lcsh:Medicine, Computational biology, Biology, Telomere, Multidisciplinary Sciences, 03 medical and health sciences, 0302 clinical medicine, NIHR BioResource - Rare Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, lcsh:Q, Ploidy, lcsh:Science, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Correction to: Scientific Reports https://doi.org/10.1038/s41598-017-14403-y, published online 22 January 2018 The original version of this Article contained a typographical error in the spelling of the consortium member Patrick Yu-Wai-Man which was incorrectly given as Patrick Yu Wai Man. In addition, a supplementary file containing additional algorithms and analysis was omitted from the original version of this Article. These errors have now been corrected in the HTML and PDF versions of the Article.

Published
2018

29. Transforming growth factor-beta signaling via ALK1 and ALK5 regulates distinct functional pathways in vein graft intimal hyperplasia

Author

Low, EL, primary, Schwartze, JT, additional, Kurkiewicz, A, additional, Pek, M, additional, Kelly, DJ, additional, Shaw, AS, additional, Thorikay, M, additional, McClure, J, additional, McBride, M, additional, Arias-Rivas, S, additional, Francis, SE, additional, Morrell, NW, additional, Delles, C, additional, Herzyk, P, additional, Havenga, MJ, additional, Nicklin, SA, additional, Ten Dijke, P, additional, Baker, AH, additional, and Bradshaw, AC, additional

Published
2019
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31. S40 Phenotypic characterisation of GDF2 mutation carriers in a large cohort of patients with pulmonary arterial hypertension

Author

Swietlik, EM, primary, Hodgson, J, additional, Hadinnapola, C, additional, Bleda, M, additional, Haimel, M, additional, Church, C, additional, Coghlan, G, additional, Condliffe, R, additional, Corris, PA, additional, Gibbs, JSR, additional, Holden, S, additional, Howard, L, additional, Humbert, M, additional, Jonson, M, additional, Kiely, DG, additional, Lawrie, A, additional, Lordan, J, additional, MacKenzie Ross, RV, additional, Olschewski, H, additional, Moledina, S, additional, Peacock, AJ, additional, Pepke-Zaba, J, additional, Suntharalingam, J, additional, Seeger, W, additional, Toshner, MR, additional, Trembath, RC, additional, Vonk Noordegraaf, A, additional, Wharton, J, additional, Wilkins, MR, additional, Wort, SJ, additional, Upton, PD, additional, Gräf, S, additional, and Morrell, NW, additional

Published
2018
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33. S41 Characterisation of mutations in the gene encoding growth and differentiation factor 2 (GDF2) in patients with pulmonary arterial hypertension

Author

Hodgson, J, primary, Swietlik, E, additional, Salmon, RM, additional, Hadinnapola, C, additional, Wharton, J, additional, Haimel, M, additional, Bleda, M, additional, Lawera, A, additional, Li, W, additional, Wilkins, M, additional, Gräf, S, additional, Upton, PD, additional, and Morrell, NW, additional

Published
2018
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35. Elabela/Toddler is an Endogenous Agonist of the Apelin APJ Receptor in the Adult Cardiovascular System, and Exogenous Administration of the Peptide Compensates for the Downregulation of its Expression in Pulmonary Arterial Hypertension

Author

Yang, P, Read, C, Kuc, RE, Buonincontri, G, Southwood, M, Torella, R, Upton, PD, Crosby, A, Sawiak, SJ, Carpenter, TA, Glen, RC, Morrell, NW, Maguire, JJ, Davenport, AP, Upton, Paul [0000-0003-2716-4921], Sawiak, Stephen [0000-0003-4210-9816], Carpenter, Adrian [0000-0002-2939-8222], Glen, Robert [0000-0003-1759-2914], Morrell, Nicholas [0000-0001-5700-9792], Maguire, Janet [0000-0002-9254-7040], Davenport, Anthony [0000-0002-2096-3117], and Apollo - University of Cambridge Repository

Subjects
receptors, G-protein-coupled, Male, Cardiac & Cardiovascular Systems, Toddler, cardiopulmonary, Heart Ventricles, Hypertension, Pulmonary, Peptide Hormones, receptor, Down-Regulation, Molecular Dynamics Simulation, IMMUNOCYTOCHEMICAL LOCALIZATION, DISEASE, Catheterization, 1117 Public Health and Health Services, PATHWAY, Rats, Sprague-Dawley, GPCR, pulmonary hypertension, Animals, Humans, Amino Acid Sequence, 1102 Cardiorespiratory Medicine and Haematology, IN-VIVO, Science & Technology, Binding Sites, Monocrotaline, APELA, 1103 Clinical Sciences, ENDOTHELIAL-CELLS, peptide, Protein Structure, Tertiary, Rats, Disease Models, Animal, Peripheral Vascular Disease, Cardiovascular System & Hematology, apelin, Elabela/Toddler, Cardiovascular System & Cardiology, HEART, Intercellular Signaling Peptides and Proteins, Elabela, Endothelium, Vascular, LIGAND, Life Sciences & Biomedicine, CARDIAC CONTRACTILITY
Abstract

BACKGROUND: -Elabela/Toddler (ELA) is a critical cardiac developmental peptide that acts through the G protein-coupled apelin receptor, despite lack of sequence similarity to the established ligand apelin. Our aim was to investigate the receptor pharmacology, expression pattern and in vivo function of ELA peptides in the adult cardiovascular system, to seek evidence for alteration in pulmonary arterial hypertension (PAH) in which apelin signaling is down-regulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model. METHODS: -In silico docking analysis, competition binding experiments and down-stream assays were used to characterize ELA receptor binding in human heart and signaling in cells expressing the apelin receptor. ELA expression in human cardiovascular tissues and plasma was determined using RT-qPCR, dual-labelling immunofluorescent staining and immunoassays. Acute cardiac effects of ELA-32 and [Pyr(1)]apelin-13 were assessed by magnet resonance imaging and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline (MCT) and Sugen/hypoxia exposed rats were used to show changes in ELA expression in PAH. The effect of ELA treatment on cardiopulmonary remodeling in PAH was investigated in the MCT rat model. RESULTS: -ELA competed for binding of apelin in human heart with overlap for the two peptides indicated by in silico modeling. ELA activated G protein- and Β-arrestin-dependent pathways. We detected ELA expression in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, cardiac output and elicited vasodilatation in rat in vivo ELA expression was reduced in cardiopulmonary tissues from PAH patients and PAH rat models, respectively. ELA treatment significantly attenuated elevation of right ventricular systolic pressure and right ventricular hypertrophy and pulmonary vascular remodeling in MCT exposed rats. CONCLUSIONS: -These results show ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin, is down-regulated in human disease and rodent PAH models and exogenous peptide can reduce the severity of cardiopulmonary remodeling and function in PAH in rats. This study provides additional proof of principle that an apelin receptor agonist may be of therapeutic use in PAH in man.

Published
2017

36. Plasma metabolomics implicates modified transfer RNAs and altered bioenergetics in the outcomes of pulmonary arterial hypertension

Author

Rhodes, CJ, Ghataorhe, P, Wharton, J, Rue-Albrecht, KC, Hadinnapola, C, Watson, G, Bleda, M, Haimel, M, Coghlan, G, Corris, PA, Howard, LS, Kiely, DG, Peacock, AJ, Pepke-Zaba, J, Toshner, MR, Wort, SJ, Gibbs, JSR, Lawrie, A, Gräf, S, Morrell, NW, Wilkins, MR, Hadinnapola, Charaka [0000-0002-7794-3432], Haimel, Matthias [0000-0002-0320-0214], Toshner, Mark [0000-0002-3969-6143], Graf, Stefan [0000-0002-1315-8873], Morrell, Nicholas [0000-0001-5700-9792], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Hypertension, Pulmonary, Middle Aged, Prognosis, metabolomics, Young Adult, Treatment Outcome, RNA, Transfer, pulmonary circulation, Original Research Articles, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Humans, metabolome, Female, Energy Metabolism, metabolism, Aged
Abstract

Supplemental Digital Content is available in the text., Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. Methods: We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis. Results: Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P

Published
2016

37. S108 Genome-wide association study in chronic thromboembolic pulmonary hypertension reveals new insights into aetiology

Author

Newnham, M, primary, Toshner, M, additional, Bleda, M, additional, Auger, WR, additional, Barberà, JA, additional, Bogaard, HJ, additional, Cannon, J, additional, Coghlan, G, additional, Corris, PA, additional, Delcroix, M, additional, Dunning, J, additional, Elding, H, additional, Gibbs, S, additional, Hadinnapola, C, additional, Jenkins, D, additional, Kiely, D, additional, Lang, I, additional, Maher, E, additional, Ng, C, additional, Peacock, A, additional, Screaton, N, additional, Sheares, K, additional, Simpson, M, additional, Soranzo, N, additional, Taboada, D, additional, Trembath, R, additional, Tsui, S, additional, Wilkins, MR, additional, Wort, SJ, additional, Gräf, S, additional, Pepke-Zaba, J, additional, and Morrell, NW, additional

Published
2017
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38. S109 Adamts13 protein levels are decreased in chronic thromboembolic pulmonary hypertension and implicated in its pathobiology

Author

Newnham, M, primary, South, K, additional, Bleda, M, additional, Cannon, J, additional, Gräf, S, additional, Hadinnapola, C, additional, Sheares, K, additional, Taboada, D, additional, Wilkins, MR, additional, Wharton, J, additional, Pepke-Zaba, J, additional, Laffan, M, additional, Lane, DA, additional, Toshner, M, additional, and Morrell, NW, additional

Published
2017
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40. S84 Identification of MIR-124a as a major regulator of enhanced endothelial cell glycolysis in pulmonary arterial hypertension

Author

Caruso, P, primary, Dunmore, BJ, additional, Schlosser, K, additional, Schoors, S, additional, Santos, C Dos, additional, Perez-Iratxeta, C, additional, Lavoie, JR, additional, Long, L, additional, Hurst, L, additional, Ormiston, ML, additional, Hata, A, additional, Carmeliet, P, additional, Stewart, DJ, additional, and Morrell, NW, additional

Published
2016
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45. Intersegmental vessel formation in zebrafish: requirement for VEGF but not BMP signalling revealed by selective and non-selective BMP antagonists

Author

Cannon, JE, Upton, PD, Smith, JC, and Morrell, NW

Subjects
Vascular Endothelial Growth Factor A, Endothelial Cells, Neovascularization, Physiologic, Zebrafish Proteins, Research Papers, Animals, Genetically Modified, Pyrimidines, Bone Morphogenetic Proteins, Animals, Humans, Pyrazoles, Enzyme Inhibitors, Cells, Cultured, Zebrafish, Body Patterning, Signal Transduction
Abstract

Bone morphogenetic proteins (BMPs) were first identified through their role in inducing bone and cartilage formation, but many other important functions have since been ascribed to BMPs, including dorsoventral patterning, angiogenesis and tissue homeostasis. Using dorsomorphin and LDN193189, selective small molecule inhibitors of BMP signalling, we investigated the role of BMP signalling in early vascular patterning in zebrafish.The effects of dorsomorphin and LDN193189 on vascular endothelial growth factor-a (VEGF) and BMP signalling in developing zebrafish and in human pulmonary artery endothelial cells were determined using confocal microscopy, Western blotting and quantitative PCR.We showed that dorsomorphin, similar to the VEGF inhibitor SU5416, strongly inhibits intersegmental vessel formation in zebrafish and that this is due to inhibition of VEGF activation of VEGF receptor 2 (VEGFR2), leading to reduced VEGF-induced phospho-ERK (extracellular regulated kinase) 1/2 and VEGF target gene transcription. These effects occurred at concentrations of dorsomorphin that block BMP signalling. We also showed that LDN193189, an analogue of dorsomorphin, more potently blocks BMP signalling but has no effect on VEGF signalling in zebrafish and does not disrupt early vascular patterning.Dorsomorphin inhibits both BMP and VEGF signalling, whereas LDN193189 is a more selective BMP antagonist. Results obtained in cardiovascular studies using dorsomorphin need to be interpreted with caution, and use of LDN193189 would be preferable due to its selectivity. Our data also suggest that BMP signalling is dispensable for early patterning of intersegmental vessels in zebrafish.

Published
2010

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