Imperial College London

ProfessorStuartCook

Faculty of MedicineInstitute of Clinical Sciences

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 3313 1346stuart.cook

 
 
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Location

 

RF 16Sydney StreetRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

424 results found

Owen R, Buchan R, Frenneaux M, Jarman JWE, Baruah R, Lota AS, Halliday BP, Roberts AM, Izgi C, Van Spall H, Michos ED, McMurray J, Januzzi JL, Pennell DJ, Cook SA, Ware JS, Barton PJ, Gregson J, Prasad SK, Tayal Uet al., 2024, Sex differences in the clinical presentation and natural history of dilated cardiomyopathy, JACC: Heart Failure, Vol: 12, Pages: 352-363, ISSN: 2213-1787

Background: Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved.Objective: To investigate sex-specific differences in DCM presentation, natural history, and prognostic factors.Methods We conducted a prospective observational cohort study of DCM patients, assessing baseline characteristics, CMR-imaging, biomarkers and genotype. The composite outcome was cardiovascular mortality or major heart-failure (HF) events. Results: Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline female patients had higher left ventricular ejection fraction (LVEF), smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%) and lower high sensitivity cardiac troponin (hs-cTnI) than males (all p<0.05), with no difference in time from diagnosis, age at enrollment, NT-proBNP levels, pathogenic DCM genetic variants, myocardial fibrosis extent or medications used for HF. Despite a more favourable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted hazard ratio 3.14, 95% CI 1.55 to 6.35, p=0.001). Between 2-5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, LVEF, left atrial volume, NT-proBNP, hs-cTnI, left bundle branch block and NYHA class were not sex specific prognostic factors. Conclusions: We identify a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences.

Journal article

Widjaja AA, Cook SA, 2024, Nonspecific Inhibition of IL6 Family Cytokine Signalling by Soluble gp130., Int J Mol Sci, Vol: 25

IL6 is a proinflammatory cytokine that binds to membrane-bound IL6 receptor (IL6R) or soluble IL6R to signal via gp130 in cis or trans, respectively. We tested the hypothesis that sgp130Fc, which is believed to be a selective IL6 trans-signalling inhibitor, is in fact a non-specific inhibitor of gp130 signalling. In human cancer and primary cells, sgp130Fc inhibited IL6, IL11, OSM and CT1 cis-signalling. The IC50 values of sgp130Fc for IL6 and OSM cis-signalling were markedly (20- to 200-fold) lower than the concentrations of sgp130Fc used in mouse studies and clinical trials. sgp130 inhibited IL6 and OSM signalling in the presence of an ADAM10/17 inhibitor and the absence of soluble IL6R or OSMR, with effects that were indistinguishable from those of a gp130 neutralising antibody. These data show that sgp130Fc does not exclusively block IL6 trans-signalling and reveal instead that broad inhibition of gp130 signalling likely underlies its therapeutic effects. This proposes global or modular inhibition of gp130 as a therapeutic approach for treating human disease.

Journal article

Cook SA, 2023, Understanding interleukin 11 as a disease gene and therapeutic target, Biochemical Journal, Vol: 480, Pages: 1987-2008, ISSN: 0264-6021

Interleukin 11 (IL11) is an elusive member of the IL6 family of cytokines. While initially thought to be a haematopoietic and cytoprotective factor, more recent data show instead that IL11 is redundant for haematopoiesis and toxic. In this review, the reasons that led to the original misunderstandings of IL11 biology, which are now understandable, are explained with particular attention on the use of recombinant human IL11 in mice and humans. Following tissue injury, as part of an evolutionary ancient homeostatic response, IL11 is secreted from damaged mammalian cells to signal via JAK/STAT3, ERK/P90RSK, LKB1/mTOR and GSK3β/SNAI1 in autocrine and paracrine. This activates a program of mesenchymal transition of epithelial, stromal, and endothelial cells to cause inflammation, fibrosis, and stalled endogenous tissue repair, leading to organ failure. The role of IL11 signalling in cell- and organ-specific pathobiology is described, the large unknowns about IL11 biology are discussed and the promise of targeting IL11 signalling as a therapeutic approach is reviewed.

Journal article

Curran L, Simoes Monteiro de Marvao A, Inglese P, McGurk K, Schiratti P-R, Clement A, Zheng S, Li S, Pua CJ, Shah M, Jafari M, Theotokis P, Buchan R, Jurgens S, Raphael C, Baksi A, Pantazis A, Halliday B, Pennell D, Bai W, Chin C, Tadros R, Bezzina C, Watkins H, Cook S, Prasad S, Ware J, O'Regan Det al., 2023, Genotype-phenotype taxonomy of hypertrophic cardiomyopathy, Circulation: Genomic and Precision Medicine, Vol: 16, Pages: 559-570, ISSN: 2574-8300

Background:Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes but there is no systematic framework for classifying morphology or assessing associated risks. Here we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression.Methods:We enrolled 436 HCM patients (median age 60 years; 28.8% women) with clinical, genetic and imaging data. Anindependent cohort of 60 HCM patients from Singapore (median age 59 years; 11% women) and a reference population from UK Biobank (n = 16,691, mean age 55 years; 52.5% women) were also recruited. We used machine learning to analyse the three-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree.Results:Carriers of pathogenic or likely pathogenic variants (P/LP) for HCM had lower left ventricular mass, but greater basalseptal hypertrophy, with reduced lifespan (mean follow-up 9.9 years) compared to genotype negative individuals(hazard ratio: 2.66; 95% confidence interval [CI]: 1.42-4.96; P < 0.002). Four main phenotypic branches were identified using unsupervised learning of three-dimensional shape: 1) non-sarcomeric hypertrophy with co-existing hypertension; 2) diffuse and basal asymmetric hypertrophy associated with outflow tract obstruction; 3) isolated basal hypertrophy; 4) milder non-obstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for P/LP variants: 2.18 [95% CI: 1.93-2.28, P = 0.0001]). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalisable to an independent cohort (trustworthiness M1: 0.86-0.88).Conclusions:We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severi

Journal article

Widjaja AA, Cook SA, 2023, The pathobiology of IL-11 in kidney disease: from epithelial cell to fibroblast and back again, American Journal of Pathology, Vol: 193, Pages: 1910-1912, ISSN: 0002-9440

Up to 25% of adults >60 years of age have chronic kidney disease (CKD), which represents a growing global health challenge. Some progress has been made in treating kidney diseases in recent years, but CKD for the most part remains progressive and leads to end-stage kidney disease, with the subsequent need for renal replacement therapy (life-long dialysis or renal transplantation). Although CKD can arise from a multitude of factors, including infections, obstructions, toxins, genetics, hemodynamics, and metabolic issues, renal fibrosis emerges as a common consequence of each of these triggers. Of all the CKD pathologies, extent of fibrosis most accurately predicts progression to end-stage kidney disease and poor clinical outcomes.

Journal article

McGurk K, Zhang X, Theotokis P, Thomson K, Harper A, Buchan R, Mazaika E, Ormondroyd E, Wright W, Macaya D, Chee Jian P, Funke B, MacArthur D, Prasad S, Cook S, Allouba M, Aguib Y, Yacoub M, O'Regan D, Barton P, Watkins H, Bottolo L, Ware Jet al., 2023, The penetrance of rare variants in cardiomyopathy-associated genes: a cross-sectional approach to estimate penetrance for secondary findings, American Journal of Human Genetics, Vol: 110, Pages: 1482-1495, ISSN: 0002-9297

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.

Journal article

Lee V, Zheng Q, Toh D-F, Pua CJ, Bryant JA, Lee C-H, Cook SA, Butler J, Diez J, Richards AM, Le T-T, Chin CWLet al., 2023, Sacubitril/valsartan versus valsartan in regressing myocardial fibrosis in hypertension: a prospective, randomized, open-label, blinded endpoint clinical trial protocol, Frontiers in Cardiovascular Medicine, Vol: 10, ISSN: 2297-055X

Background: Diffuse interstitial myocardial fibrosis is a key common pathological manifestation in hypertensive heart disease (HHD) progressing to heart failure (HF). Angiotensin receptor–neprilysin inhibitors (ARNi), now a front-line treatment for HF, confer benefits independent of blood pressure, signifying a multifactorial mode of action beyond hemodynamic regulation. We aim to test the hypothesis that compared with angiotensin II receptor blockade (ARB) alone, ARNi is more effective in regressing diffuse interstitial myocardial fibrosis in HHD.Methods: Role of ARNi in Ventricular Remodeling in Hypertensive LVH (REVERSE-LVH) is a prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial. Adults with hypertension and left ventricular hypertrophy (LVH) according to Asian sex- and age-specific thresholds on cardiovascular magnetic resonance (CMR) imaging are randomized to treatment with either sacubitril/valsartan (an ARNi) or valsartan (an ARB) in 1:1 ratio for a duration of 52 weeks, at the end of which a repeat CMR is performed to assess differential changes from baseline between the two groups. The primary endpoint is the change in CMR-derived diffuse interstitial fibrosis volume. Secondary endpoints include changes in CMR-derived left ventricular mass, volumes, and functional parameters. Serum samples are collected and stored to assess the effects of ARNi, compared with ARB, on circulating biomarkers of cardiac remodeling. The endpoints will be analyzed with reference to the corresponding baseline parameters to evaluate the therapeutic effect of sacubitril/valsartan vs. valsartan.Discussion: REVERSE-LVH will examine the anti-fibrotic potential of sacubitril/valsartan and will offer mechanistic insights into the clinical benefits of sacubitril/valsartan in hypertension in relation to cardiac remodeling. Advancing the knowledge of the pathophysiology of HHD will consolidate effective risk stratification and personalized treatment through

Journal article

Sweeney M, O'Fee K, Villanueva-Hayes C, Rahman E, Lee M, Vanezis K, Andrew I, Lim W-W, Widjaja A, Barton P, Cook Set al., 2023, Cardiomyocyte-restricted expression of IL11 causes cardiac fibrosis, inflammation, and dysfunction, International Journal of Molecular Sciences, Vol: 24, Pages: 1-14, ISSN: 1422-0067

Cardiac fibrosis is a common pathological process in heart disease, representing a therapeutic target. Transforming growth factor β (TGFβ) is the canonical driver of cardiac fibrosis and was recently shown to be dependent on interleukin 11 (IL11) for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and anti-inflammatory in the mouse heart. In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murine Il11 expression. Using protein assays, bulk RNA-sequencing, and in vivo imaging, we analyzed the effects of IL11 on myocardial fibrosis, inflammation, and cardiac function, challenging previous reports suggesting the cardioprotective potential of IL11. TGFβ stimulation of cardiomyocytes caused Il11 upregulation. Compared to wild-type controls, Il11-expressing hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors, and increased inflammatory cells. IL11 expression also activated a program of endothelial-to-mesenchymal transition and resulted in left ventricular dysfunction. Our data define species-matched IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes and further establish IL11 as a disease factor.

Journal article

Cook SA, 2023, The pathobiology of interleukin 11 in mammalian disease is likely explained by its essential evolutionary role for Fin regeneration, Journal of Cardiovascular Translational Research, Vol: 16, Pages: 755-757, ISSN: 1937-5395

Recent studies have shown IL11 to be pro-fibrotic, pro-inflammatory and anti-regenerative in heart, liver, lung and kidney disease in mice and humans. However, data also show that IL11 is specifically required for appendage regeneration following trauma in some species. In fish, tadpoles and axolotl, IL11 is uniquely upregulated in the regenerative organ, the blastema, following loss of fin, tail or limb. In this short essay I suggest that the pathobiology of IL11 in mammals is rooted in its deep evolutionary role for epimorphic appendage regeneration. In both blastema formation and mammalian disease there is robust IL11-driven fibroblast activation, extracellular matrix production, inflammation and epithelial cell dedifferentiation. While these cellular processes are critical for regeneration in lower species they cause organ failure in mammals. This hypothesis, if correct, may explain the apparent redundancy of IL11 for human health and suggest IL11 as a therapeutic target.

Journal article

Pua CJ, Loo G, Kui M, Moy WL, Hii A-A, Lee V, Chin C-T, Bryant JA, Toh D-F, Lee C-H, Cook SA, Richards AM, Le T-T, Chin CWLet al., 2023, Impact of diabetes on myocardial fibrosis in patients with hypertension: the REMODEL study, Circulation: Cardiovascular Imaging, Vol: 16, Pages: 545-553, ISSN: 1941-9651

BACKGROUND:Compared with patients with hypertension only, those with hypertension and diabetes (HTN/DM) have worse prognosis. We aimed to characterize morphological differences between hypertension and HTN/DM using cardiovascular magnetic resonance; and compare differentially expressed proteins associated with myocardial fibrosis using high throughput multiplex assays.METHODS:Asymptomatic patients underwent cardiovascular magnetic resonance: 438 patients with hypertension (60±8 years; 59% males) and 167 age- and sex-matched patients with HTN/DM (60±10 years; 64% males). Replacement myocardial fibrosis was defined as nonischemic late gadolinium enhancement on cardiovascular magnetic resonance. Extracellular volume fraction was used as a marker of diffuse myocardial fibrosis. A total of 184 serum proteins (Olink Target Cardiovascular Disease II and III panels) were measured to identify unique signatures associated with myocardial fibrosis in all patients.RESULTS:Despite similar left ventricular mass (P=0.344) and systolic blood pressure (P=0.086), patients with HTN/DM had increased concentricity and worse multidirectional strain (P<0.001 for comparison of all strain measures) compared to hypertension only. Replacement myocardial fibrosis was present in 28% of patients with HTN/DM compared to 16% of those with hypertension (P<0.001). NT-proBNP (N-terminal pro-B-type natriuretic peptide) was the only protein differentially upregulated in hypertension patients with replacement myocardial fibrosis and independently associated with extracellular volume. In patients with HTN/DM, GDF-15 (growth differentiation factor 15) was independently associated with replacement myocardial fibrosis and extracellular volume. Ingenuity Pathway Analysis demonstrated a strong association between increased inflammatory response/immune cell trafficking and myocardial fibrosis in patients with HTN/DM.CONCLUSIONS:Adverse cardiac remodeling was observed in patients with HTN/DM

Journal article

Ng B, Xie C, Su L, Kuthubudeen FF, Kwek X-Y, Yeong D, Pua CJ, Cook SA, Lim W-Wet al., 2023, IL11 (Interleukin-11) causes emphysematous lung disease in a mouse model of marfan syndrome., Arteriosclerosis, Thrombosis and Vascular Biology, Vol: 43, Pages: 739-754, ISSN: 1079-5642

BACKGROUND: Marfan Syndrome (MFS) is an inherited connective tissue disorder caused by mutations in the FBN1 (fibrillin-1) gene. Lung abnormalities are common in MFS, but their pathogenesis is poorly understood. IL11 (interleukin-11) causes aortic disease in a mouse model of MFS and was studied here in the lung. METHODS: We examined histological and molecular phenotypes in the lungs of Fbn1C1041G/+ mice (mouse model of Marfan Syndrome [mMFS]), an established mouse model of MFS. To identify IL11-expressing cells, we used immunohistochemistry on lungs of 4- and 16-week-old Fbn1C1041G/+:Il11EGFP/+ reporter mice. We studied the effects of IL11 inhibition by RT-qPCR, immunoblots and histopathology in lungs from genetic or pharmacologic models: (1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice (Fbn1C1041G/+:Il11ra1-/- mice) and (2) in mMFS mice administered IgG control or interleukin-11 receptor antibodies twice weekly from 4 to 24 weeks of age. RESULTS: mMFS lungs showed progressive loss and enlargement of distal airspaces associated with increased proinflammatory and profibrotic gene expression as well as matrix metalloproteinases 2, 9, and 12. IL11 was increased in mMFS lungs and localized to smooth muscle and endothelial cells in young mMFS mice in the Fbn1C1041G/+:Il11EGFP/+ reporter strain and in fibroblasts, in older mice. In mMFS mice, genetic (Fbn1C1041G/+:Il11ra1-/-) or pharmacologic (anti-interleukin-11 receptor) inhibition of IL11 signaling reduced lung emphysema, fibrosis, and inflammation. This protective effect was associated with reduced pathogenic ERK1/2 signaling and lower metalloproteinase 2, 9, and 12 expression. CONCLUSIONS: IL11 causes lung disease in mMFS. This reveals a shared IL11-driven disease mechanism in lung and aorta in MFS and suggests inhibition of IL11 signaling as a holistic approach for treating multiorgan morbidity in MFS.

Journal article

Sweeney M, Cook SA, Gil J, 2023, Therapeutic opportunities for senolysis in cardiovascular disease, The Federation of European Biochemical Societies (FEBS) Journal, Vol: 290, Pages: 1235-1255, ISSN: 1742-464X

Cellular senescence within the cardiovascular system has, until recently, been understudied and unappreciated as a factor in the development of age-related cardiovascular diseases such as heart failure, myocardial infarction and atherosclerosis. This is in part due to challenges with defining senescence within post-mitotic cells such as cardiomyocytes. However, recent evidence has demonstrated senescent-like changes, including a senescence-associated secretory phenotype (SASP), in cardiomyocytes in response to ageing and cell stress. Other replicating cells, including fibroblasts and vascular smooth muscle cells, within the cardiovascular system have also been shown to undergo senescence and contribute to disease pathogenesis. These findings coupled with the emergence of senolytic therapies, to target and eliminate senescent cells, have provided fascinating new avenues for management of several age-related cardiovascular diseases with high prevalence. In this review, we discuss the role of senescent cells within the cardiovascular system and highlight the contribution of senescence cells to common cardiovascular diseases. We discuss the emerging role for senolytics in cardiovascular disease management while highlighting important aspects of senescence biology which must be clarified before the potential of senolytics can be fully realized.

Journal article

Tadros R, Zheng SL, Grace C, Jordà P, Francis C, Jurgens SJ, Thomson KL, Harper AR, Ormondroyd E, West DM, Xu X, Theotokis PI, Buchan RJ, McGurk KA, Mazzarotto F, Boschi B, Pelo E, Lee M, Noseda M, Varnava A, Vermeer AM, Walsh R, Amin AS, van Slegtenhorst MA, Roslin N, Strug LJ, Salvi E, Lanzani C, de Marvao A, Hypergenes InterOmics Collaborators, Roberts JD, Tremblay-Gravel M, Giraldeau G, Cadrin-Tourigny J, L'Allier PL, Garceau P, Talajic M, Pinto YM, Rakowski H, Pantazis A, Baksi J, Halliday BP, Prasad SK, Barton PJ, O'Regan DP, Cook SA, de Boer RA, Christiaans I, Michels M, Kramer CM, Ho CY, Neubauer S, HCMR Investigators, Matthews PM, Wilde AA, Tardif J-C, Olivotto I, Adler A, Goel A, Ware JS, Bezzina CR, Watkins Het al., 2023, Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy., medRxiv

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.

Journal article

Quaife NM, Chothani S, Schulz JF, Lindberg EL, Vanezis K, Adami E, O'Fee K, Greiner J, Litviňuková M, van Heesch S, Whiffin N, Hubner N, Schafer S, Rackham O, Cook SA, Barton PJRet al., 2023, LINC01013 is a determinant of fibroblast activation and encodes a novel fibroblast-activating micropeptide, Journal of Cardiovascular Translational Research, Vol: 16, Pages: 77-85, ISSN: 1937-5387

Myocardial fibrosis confers an almost threefold mortality risk in heart disease. There are no prognostic therapies and novel therapeutic targets are needed. Many thousands of unannotated small open reading frames (smORFs) have been identified across the genome with potential to produce micropeptides (< 100 amino acids). We sought to investigate the role of smORFs in myocardial fibroblast activation.Analysis of human cardiac atrial fibroblasts (HCFs) stimulated with profibrotic TGFβ1 using RNA sequencing (RNA-Seq) and ribosome profiling (Ribo-Seq) identified long intergenic non-coding RNA LINC01013 as TGFβ1 responsive and containing an actively translated smORF. Knockdown of LINC01013 using siRNA reduced expression of profibrotic markers at baseline and blunted their response to TGFβ1. In contrast, overexpression of a codon-optimised smORF invoked a profibrotic response comparable to that seen with TGFβ1 treatment, whilst FLAG-tagged peptide associated with the mitochondria.Together, these data support a novel LINC01013 smORF micropeptide-mediated mechanism of fibroblast activation.

Journal article

Wong E, Bertin N, Hebrard M, Tirado-Magallanes R, Bellis C, Lim WK, Chua CY, Tong PML, Chua R, Mak K, Lim TM, Cheong WY, Thien KE, Goh KT, Chai J-F, Lee J, Sung JJ-Y, Wong TY, Chin CWLD, Gluckman P, Goh LL, Ban KHK, Tan TWM, Van Dam RM, Teo YY, Loh M, Eillot P, Lee ES, Ngeow J, Riboli E, Dalan R, Kassam I, Lakshmanan LN, Lim TH, Ng HK, Mina T, Tay D, Sabanayagam C, Tham YC, Rim T, Aung T, Chee ML, Li H, Chee ML, Yeo KK, Cook SA, Pua CJ, Yang C, Chong YS, Eriksson JG, Tan KH, Yap F, Lim CW, Tsai PK, Chew WJ, Sim WC, Toh L-XG, Lin CB, Sia YY, Koh TH, Meah WY, Tan JHJ, Jeyakani J, Ow J, Ang S, Malik AJ, Kenanov D, Sim X, Cheng C-Y, Davila S, Karnani N, Leong KP, Liu J, Prabhakar S, Maurer-Stroh S, Verma CS, Krishnaswamy P, Goh RSM, Chia I, Ho C, Low D, Virabhak S, Yong J, Zheng W, Seow SW, Seck YK, Koh M, Chambers JC, Tai ES, Tan Pet al., 2023, The Singapore National Precision Medicine Strategy, NATURE GENETICS, Vol: 55, Pages: 178-+, ISSN: 1061-4036

Journal article

Effenberger M, Widjaja AA, Grabherr F, Schaefer B, Grander C, Mayr L, Schwaerzler J, Enrich B, Moser P, Fink J, Pedrini A, Jaschke N, Kirchmair A, Pfister A, Hausmann B, Bale R, Putzer D, Zoller H, Schafer S, Pjevac P, Trajanoski Z, Oberhuber G, Adolph T, Cook S, Tilg Het al., 2023, Interleukin-11 drives human and mouse alcohol-related liver disease, GUT, Vol: 72, Pages: 168-179, ISSN: 0017-5749

Journal article

Widjaja AA, Viswanathan S, Shekeran SG, Adami E, Lim W-W, Chothani S, Tan J, Goh JWT, Chen HM, Lim SY, Boustany-Kari CM, Hawkins J, Petretto E, Huebner N, Schafer S, Coffman TM, Cook SAet al., 2022, Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease, Nature Communications, Vol: 13, Pages: 1-18, ISSN: 2041-1723

The kidney has large regenerative capacity, but this is compromised when kidney damage is excessive and renal tubular epithelial cells (TECs) undergo SNAI1-driven growth arrest. Here we investigate the role of IL11 in TECs, kidney injury and renal repair. IL11 stimulation of TECs induces ERK- and p90RSK-mediated GSK3β inactivation, SNAI1 upregulation and pro-inflammatory gene expression. Mice with acute kidney injury upregulate IL11 in TECs leading to SNAI1 expression and kidney dysfunction, which is not seen in Il11 deleted mice or in mice administered a neutralizing IL11 antibody in either preemptive or treatment modes. In acute kidney injury, anti-TGFβ reduces renal fibrosis but exacerbates inflammation and tubule damage whereas anti-IL11 reduces all pathologies. Mice with TEC-specific deletion of Il11ra1 have reduced pathogenic signaling and are protected from renal injury-induced inflammation, fibrosis, and failure. In a model of chronic kidney disease, anti-IL11 therapy promotes TEC proliferation and parenchymal regeneration, reverses fibroinflammation and restores renal mass and function. These data highlight IL11-induced mesenchymal transition of injured TECs as an important renal pathology and suggest IL11 as a therapeutic target for restoring stalled endogenous regeneration in the diseased kidney.

Journal article

Sweeney M, O'Fee K, Villanueva-Hayes C, Vanezis K, Rahman E, Widjaja A, Hausenloy D, Barton PJ, Cook SAet al., 2022, Dissection of Cardiomyocyte versus Fibroblast Effects of Interleukin-11 in Heart Failure, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Ng B, Xie C, Su L, Kuthubudeen FFF, Kwek X, Yeong D, Schafer S, Cook S, Lim W-Wet al., 2022, Il11 Causes Pulmonary Tissue Remodeling and Emphysematous Lung Disease in the Fbn1<SUP>C1041G/+</SUP> Mouse Model of Marfan Syndrome, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Chan SH, Bylstra Y, Teo JX, Kuan JL, Bertin N, Gonzalez-Porta M, Hebrard M, Tirado-Magallanes R, Tan JHJ, Jeyakani J, Li Z, Chai JF, Chong YS, Davila S, Goh LL, Lee ES, Wong E, Wong TY, Prabhakar S, Liu J, Cheng C-Y, Eisenhaber B, Karnani N, Leong KP, Sim X, Yeo KK, Chambers JC, Tai E-S, Tan P, Jamuar SS, Ngeow J, Lim WKet al., 2022, Analysis of clinically relevant variants from ancestrally diverse Asian genomes, Nature Communications, Vol: 13, ISSN: 2041-1723

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population.

Journal article

Tripathi M, Singh BK, Zhou J, Tikno K, Widjaja A, Sandireddy R, Arul K, Ghani SABA, Bee GGB, Wong KA, Pei HJ, Shekeran SG, Sinha RA, Singh MK, Cook SA, Suzuki A, Lim TR, Cheah C-C, Wang J, Xiao R-P, Zhang X, Chow PKH, Yen PMet al., 2022, Vitamin B₁₂ and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation, Journal of Hepatology, Vol: 77, Pages: 1246-1255, ISSN: 0168-8278

Background & AimsSeveral recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B12 (B12) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it is not known whether hyperhomocysteinemia (HHcy) plays a pathogenic role in NASH.MethodsWe examined the effects of HHcy on NASH progression, metabolism, and autophagy in dietary and genetic mouse models, patients, and primates. We employed vitamin B12 (B12) and folate (Fol) to reverse NASH features in mice and cell culture.ResultsSerum Hcy correlated with hepatic inflammation and fibrosis in NASH. Elevated hepatic Hcy induced and exacerbated NASH. Gene expression of hepatic Hcy-metabolizing enzymes was downregulated in NASH. Surprisingly, we found increased homocysteinylation (Hcy-lation) and ubiquitination of multiple hepatic proteins in NASH including the key autophagosome/lysosome fusion protein, Syntaxin 17 (Stx17). This protein was Hcy-lated and ubiquitinated, and its degradation led to a block in autophagy. Genetic manipulation of Stx17 revealed its critical role in regulating autophagy, inflammation and fibrosis during HHcy. Remarkably, dietary B12/Fol, which promotes enzymatic conversion of Hcy to methionine, decreased HHcy and hepatic Hcy-lated protein levels, restored Stx17 expression and autophagy, stimulated β -oxidation of fatty acids, and improved hepatic histology in mice with pre-established NASH.ConclusionsHHcy plays a key role in the pathogenesis of NASH via Stx17 homocysteinylation. B12/folate also may represent a novel first-line therapy for NASH.Lay summaryThe incidence of non-alcoholic steatohepatitis, for which there are no approved pharmacological therapies, is increasing, posing a significant healthcare challenge. Herein, based on studies in mice, primates and humans, we found that dietary supplementation with vitamin B12 and folate could have therapeutic potential for the preventio

Journal article

Lota A, Hazebroek M, Theotokis P, Wassall R, Salmi S, Halliday B, Tayal U, Verdonschot J, Meena D, Owen R, de Marvao A, Iacob A, Yazdani M, Hammersley D, Jones R, Wage R, Buchan R, Vivian F, Hafouda Y, Noseda M, Gregson J, Mittal T, Wong J, Robertus JL, Baksi AJ, Vassiliou V, Tzoulaki I, Pantazis A, Cleland J, Barton P, Cook S, Pennell D, Cooper L, Garcia-Pavia P, Heymans S, Ware J, Prasad Set al., 2022, Genetic architecture of acute myocarditis and the overlap with inherited cardiomyopathy, Circulation, Vol: 146, Pages: 1123-1134, ISSN: 0009-7322

Background: Acute myocarditis is an inflammatory condition that may herald the onset of dilated (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. Methods: Population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA-sequencing for well-characterised cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Results: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared to <1% of healthy controls (p=0.0097). In the London cohort (n=230; median age 33years; 84% men), patients were representative of national myocarditis admissions (median age 32years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% cases vs 0.4% controls; odds ratio 8.2; p=0.001). This was driven predominantly by desmoplakin (DSP)-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age 54years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv found in 7% (all with LVEF<50%) compared to 1% in controls (OR 3.6; p=0.0116). Across both cohorts over a median of 5.0 years (IQR 3.9-7.8), all-cause mortality was 5.4%. Two thirds of deaths were cardiovascular, due to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype negative patients versus 11.1% for genotype positive patients (Padjusted=0.08). Conclusions: We identified DCM- or ACM-associated genetic variants in 8% of patients wit

Journal article

Zhou J, Pang J, Tripathi M, Ho JP, Widjaja AA, Shekeran SG, Cook SA, Suzuki A, Diehl AM, Petretto E, Singh BK, Yen PMet al., 2022, Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression, Nature Communications, Vol: 13, Pages: 1-14, ISSN: 2041-1723

Spermidine is a natural polyamine that has health benefits and extends life span in several species. Deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) are key enzymes that utilize spermidine to catalyze the post-translational hypusination of the translation factor EIF5A (EIF5AH). Here, we have found that hepatic DOHH mRNA expression is decreased in patients and mice with non-alcoholic steatohepatitis (NASH), and hepatic cells treated with fatty acids. The mouse and cell culture models of NASH have concomitant decreases in Eif5aH and mitochondrial protein synthesis which leads to lower mitochondrial activity and fatty acid β-oxidation. Spermidine treatment restores EIF5AH, partially restores protein synthesis and mitochondrial function in NASH, and prevents NASH progression in vivo. Thus, the disrupted DHPS-DOHH-EIF5AH pathway during NASH represents a therapeutic target to increase hepatic protein synthesis and mitochondrial fatty acid oxidation (FAO) and prevent NASH progression.

Journal article

Widjaja AA, Viswanathan S, Wei Ting JG, Tan J, Shekeran SG, Carling D, Lim W-W, Cook SAet al., 2022, IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR initiating a mesenchymal program in stromal, epithelial, and cancer cells, iScience, Vol: 25, ISSN: 2589-0042

IL11 initiates fibroblast activation but also causes epithelial cell dysfunction. The mechanisms underlying these processes are not known. We report that IL11-stimulated ERK/P90RSK activity causes the phosphorylation of LKB1 at S325 and S428, leading to its inactivation. This inhibits AMPK and activates mTOR across cell types. In stromal cells, IL11-stimulated ERK activity inhibits LKB1/AMPK which is associated with mTOR activation, ⍺SMA expression, and myofibroblast transformation. In hepatocytes and epithelial cells, IL11/ERK activity inhibits LKB1/AMPK leading to mTOR activation, SNAI1 expression, and cell dysfunction. Across cells, IL11-induced phenotypes were inhibited by metformin stimulated AMPK activation. In mice, genetic or pharmacologic manipulation of IL11 activity revealed a critical role of IL11/ERK signaling for LKB1/AMPK inhibition and mTOR activation in fatty liver disease. These data identify the IL11/mTOR axis as a signaling commonality in stromal, epithelial, and cancer cells and reveal a shared IL11-driven mesenchymal program across cell types.

Journal article

Dixon PH, Levine AP, Cebola I, Chan MMY, Amin AS, Aich A, Mozere M, Maude H, Mitchell AL, Zhang J, NIHR BioResource, Genomics England Research Consortium Collaborators, Chambers J, Syngelaki A, Donnelly J, Cooley S, Geary M, Nicolaides K, Thorsell M, Hague WM, Estiu MC, Marschall H-U, Gale DP, Williamson Cet al., 2022, GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements, Nature Communications, Vol: 13, ISSN: 2041-1723

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1,138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility.

Journal article

Widjaja AA, Chothani S, Viswanathan S, Goh JWT, Lim W-W, Cook SAet al., 2022, IL11 stimulates IL33 expression and proinflammatory fibroblast activation across tissues, International Journal of Molecular Sciences, Vol: 23, ISSN: 1422-0067

Interleukin 11 (IL11) is upregulated in inflammatory conditions, where it is mostly believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 promotes inflammation by activating fibroblasts. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in the transient phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the sustained activation of extracellular signal-regulated protein kinases (ERK). RNA sequencing over a time course of IL11 stimulation revealed a robust but short-lived transcriptional response that was enriched for gene set hallmarks of inflammation and characterized by the upregulation of SERPINB2, TNFRSF18, Interleukin 33 (IL33), CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, p = 9.8 × 10-5), and IL1RL1, its cognate receptor, was similarly increased (18-fold, p = 1.1 × 10-34). In proteomic studies, IL11 triggered a proinflammatory secretome with the notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes, and lymphocytes. IL11 induced IL33 expression across fibroblast types, and the inhibition of STAT3 but not of MEK/ERK prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts across tissues.

Journal article

Chothani SP, Adami E, Widjaja AA, Langley SR, Viswanathan S, Pua CJ, Zhihao NT, Harmston N, D'Agostino G, Whiffin N, Mao W, Ouyang JF, Lim WW, Lim S, Lee CQE, Grubman A, Chen J, Kovalik JP, Tryggvason K, Polo JM, Ho L, Cook SA, Rackham OJL, Schafer Set al., 2022, A high-resolution map of human RNA translation, Molecular Cell, Vol: 82, Pages: 2885-2899, ISSN: 1097-2765

Translated small open reading frames (smORFs) can have important regulatory roles and encode microproteins, yet their genome-wide identification has been challenging. We determined the ribosome locationsacross six primary human cell types and five tissues and detected 7,767 smORFs with translational profilesmatching those of known proteins. The human genome was found to contain highly cell-type- and tissuespecific smORFs and a subset that encodes highly conserved amino acid sequences. Changes in the translational efficiency of upstream-encoded smORFs (uORFs) and the corresponding main ORFs predominantlyoccur in the same direction. Integration with 456 mass-spectrometry datasets confirms the presence of 603small peptides at the protein level in humans and provides insights into the subcellular localization of thesesmall proteins. This study provides a comprehensive atlas of high-confidence translated smORFs derivedfrom primary human cells and tissues in order to provide a more complete understanding of the translatedhuman genome.

Journal article

Iyer NR, Le T-T, Kui MSL, Tang H-C, Chin C-T, Phua S-K, Bryant JA, Pua C-J, Ang B, Toh D-F, Aw T-C, Lee C-H, Cook SA, Ugander M, Chin CWLet al., 2022, Markers of focal and diffuse nonischemic myocardial fibrosis are associated with adverse cardiac remodeling and prognosis in patients with hypertension: the REMODEL study, Hypertension, Vol: 79, Pages: 1804-1813, ISSN: 0194-911X

Background:The prognostic significance of focal and diffuse myocardial fibrosis in patients with cardiovascular risk factors is unclear.Methods:REMODEL (Response of the Myocardium to Hypertrophic Conditions in the Adult Population) is an observational cohort of asymptomatic patients with essential hypertension. All participants underwent cardiovascular magnetic resonance to assess for myocardial fibrosis: nonischemic late gadolinium enhancement (LGE), native myocardial T1, postcontrast myocardial T1, extracellular volume fraction including/excluding LGE regions, interstitial volume (extracellular volume×myocardial volume), and interstitial/myocyte ratio. Primary outcome was a composite of first occurrence acute coronary syndrome, heart failure hospitalization, strokes, and cardiovascular mortality. Patients were recruited from February 2016 and followed until June 2021.Results:Of the 786 patients with hypertension (58±11 years; 39% women; systolic blood pressure, 130±14 mm Hg), 145 (18%) had nonischemic LGE. Patients with nonischemic LGE were more likely to be men, have diabetes, be current smokers, and have higher blood pressure (P<0.05 for all). Compared with those without LGE, patients with nonischemic LGE had greater left ventricular mass (66±22 versus 49±9 g/m2; P<0.001), worse multidirectional strain (P<0.001 for all measures), and elevated circulating markers of myocardial wall stress and myocardial injury, adjusted for potential confounders. Twenty-four patients had primary outcome over 39 (30–50) months of follow-up. Of all the cardiovascular magnetic resonance markers of myocardial fibrosis assessed, only nonischemic LGE (hazard ratio, 6.69 [95% CI, 2.54–17.60]; P<0.001) and indexed interstitial volume (hazard ratio, 1.11 [95% CI, 1.04–1.19]; P=0.002) demonstrated independent association with primary outcome.Conclusions:In patients with hypertension, myocardial fibrosis on cardiovascula

Journal article

Zhou W, Chan YE, Foo CS, Zhang J, Teo JX, Davila S, Huang W, Yap J, Cook S, Tan P, Chin CW-L, Yeo KK, Lim WK, Krishnaswamy Pet al., 2022, High-resolution digital phenotypes from consumer wearables and their applications in machine learning of cardiometabolic risk markers: cohort study, Journal of Medical Internet Research, Vol: 24, ISSN: 1438-8871

Background:Consumer-grade wearable devices enable detailed recordings of heart rate and step counts in free-living conditions. Recent studies have shown that summary statistics from these wearable recordings have potential uses for longitudinal monitoring of health and disease states. However, the relationship between higher resolution physiological dynamics from wearables and known markers of health and disease remains largely uncharacterized.Objective:We aimed to derive high-resolution digital phenotypes from observational wearable recordings and to examine their associations with modifiable and inherent markers of cardiometabolic disease risk.Methods:We introduced a principled framework to extract interpretable high-resolution phenotypes from wearable data recorded in free-living conditions. The proposed framework standardizes the handling of data irregularities; encodes contextual information regarding the underlying physiological state at any given time; and generates a set of 66 minimally redundant features across active, sedentary, and sleep states. We applied our approach to a multimodal data set, from the SingHEART study (NCT02791152), which comprises heart rate and step count time series from wearables, clinical screening profiles, and whole genome sequences from 692 healthy volunteers. We used machine learning to model nonlinear relationships between the high-resolution phenotypes on the one hand and clinical or genomic risk markers for blood pressure, lipid, weight and sugar abnormalities on the other. For each risk type, we performed model comparisons based on Brier scores to assess the predictive value of high-resolution features over and beyond typical baselines. We also qualitatively characterized the wearable phenotypes for participants who had actualized clinical events.Results:We found that the high-resolution features have higher predictive value than typical baselines for clinical markers of cardiometabolic disease risk: the best models based on

Journal article

Quaife NM, Chothani S, Schulz JF, Lindberg EL, Vanezis K, Adami E, O'Fee K, Greiner J, Litvinukova M, van Heesch S, Whiffin N, Hubner N, Schafer S, Rackham O, Cook SA, Barton PJRet al., 2022, LINC01013 Is a determinant of fibroblast activation and encodes a novel fibroblast-activating micropeptide (Jun, 10.1007/s12265-022-10288-z, 2022), Journal of Cardiovascular Translational Research, Vol: 16, Pages: 1-1, ISSN: 1937-5395

Journal article

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