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101. Early life socioeconomic adversity is associated in adult life with chronic inflammation, carotid atherosclerosis, poorer lung function and decreased cognitive performance: a cross-sectional, population-based study

Author

Sattar Naveed, McGinty Agnes, Millar Keith, Henderson Marion, Deans Kevin A, Cavanagh Jonathan, Burns Harry, Ford Ian, Batty G David, McLean Jennifer S, Bezlyak Vladimir, Packard Chris J, Shiels Paul G, Velupillai Yoga N, and Tannahill Carol

Subjects
Public aspects of medicine, RA1-1270
Abstract

Abstract Background Socioeconomic gradients in health persist despite public health campaigns and improvements in healthcare. The Psychosocial and Biological Determinants of Ill-health (pSoBid) study was designed to uncover novel biomarkers of chronic disease that may help explain pathways between socioeconomic adversity and poorer physical and mental health. Methods We examined links between indicators of early life adversity, possible intermediary phenotypes, and markers of ill health in adult subjects (n = 666) recruited from affluent and deprived areas. Classical and novel risk factors for chronic disease (lung function and atherosclerosis) and for cognitive performance were assessed, and associations sought with early life variables including conditions in the parental home, family size and leg length. Results Associations were observed between father's occupation, childhood home status (owner-occupier; overcrowding) and biomarkers of chronic inflammation and endothelial activation in adults (C reactive protein, interleukin 6, intercellular adhesion molecule; P < 0.0001) but not number of siblings and leg length. Lung function (forced expiratory volume in 1 second) and cognition (Choice Reaction Time, the Stroop test, Auditory Verbal Learning Test) were likewise related to early life conditions (P < 0.001). In multivariate models inclusion of inflammatory variables reduced the impact and independence of early life conditions on lung function and measures of cognitive ability. Including variables of adult socioeconomic status attenuated the early life associations with disease biomarkers. Conclusions Adverse levels of biomarkers of ill health in adults appear to be influenced by father's occupation and childhood home conditions. Chronic inflammation and endothelial activation may in part act as intermediary phenotypes in this complex relationship. Reducing the 'health divide' requires that these life course determinants are taken into account.

Published
2011
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102. A biomimetic natural sciences approach to understanding the mechanisms of ageing in burden of lifestyle diseases.

Author

Lu Dai, Schurgers, Leon, Shiels, Paul G., and Stenvinkel, Peter

Subjects
AGING, AGE factors in disease, LABORATORY animals, MEDICAL research, ANIMAL species
Abstract

The worldwide landscape of an ageing population and age-related disease brings with it huge socio-economic and public healthcare concerns across nations. Correspondingly, monumental human and financial resources have been invested in biomedical research, with a mission to decode the mechanisms of ageing and how these contribute to age-related disease. Multiple hallmarks of ageing have been identified that are common across taxa, highlighting their fundamental importance. These include dysregulated mitochondrial metabolism and telomeres biology, epigenetic modifications, cell-matrix interactions, proteostasis, dysregulated nutrient sensing, stem cell exhaustion, inflammageing and immuno-senescence. While our understanding of the molecular basis of ageing is improving, it remains a complex and multifactorial process that remains to be fully understood. A key aspect of the shortfall in our understanding of the ageing process lies in translating data from standard animal models to humans. Consequently, we suggest that a 'biomimetic' and comparative approach, integrating knowledge from species in the wild, as opposed to inbred genetically homogenous laboratory animals, can provide powerful insights into human ageing processes. Here we discuss some particularities and comparative patterns among several species from the animal kingdom, endowed with longevity or short lifespans and unique metabolic profiles that could be potentially exploited to the understanding of ageing and age-related diseases. Based upon lessons from nature, we also highlight several avenues for renewed focus in the pathophysiology of ageing and age-related disease (i.e. diet-microbiome-health axis, oxidative protein damage, adaptive homoeostasis and planetary health). We propose that a biomimetic alliance with collaborative research from different disciplines can improve our understanding of ageing and age-related diseases with long-term sustainable utility. [ABSTRACT FROM AUTHOR]

Published
2021
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103. The oxygen cascade in patients treated with hemodialysis and native high-altitude dwellers: lessons from extreme physiology to benefit patients with end-stage renal disease.

Author

Kooman, Jeroen P., Stenvinkel, Peter, Shiels, Paul G., Feelisch, Martin, Canaud, Bernard, and Kotanko, Peter

Subjects
CHRONIC kidney failure, PULMONARY gas exchange, HEMODIALYSIS patients, FETAL anoxia, TREATMENT effectiveness, PHYSIOLOGY, KIDNEY diseases
Abstract

Patients treated with hemodialysis (HD) repeatedly undergo intradialytic low arterial oxygen saturation and low central venous oxygen saturation, reflecting an imbalance between upper body systemic oxygen supply and demand, which are associated with increased mortality. Abnormalities along the entire oxygen cascade, with impaired diffusive and convective oxygen transport, contribute to the reduced tissue oxygen supply. HD treatment impairs pulmonary gas exchange and reduces ventilatory drive, whereas ultrafiltration can reduce tissue perfusion due to a decline in cardiac output. In addition to these factors, capillary rarefaction and reduced mitochondrial efficacy can further affect the balance between cellular oxygen supply and demand. Whereas it has been convincingly demonstrated that a reduced perfusion of heart and brain during HD contributes to organ damage, the significance of systemic hypoxia remains uncertain, although it may contribute to oxidative stress, systemic inflammation, and accelerated senescence. These abnormalities along the oxygen cascade of patients treated with HD appear to be diametrically opposite to the situation in Tibetan highlanders and Sherpa, whose physiology adapted to the inescapable hypobaric hypoxia of their living environment over many generations. Their adaptation includes pulmonary, vascular, and metabolic alterations with enhanced capillary density, nitric oxide production, and mitochondrial efficacy without oxidative stress. Improving the tissue oxygen supply in patients treated with HD depends primarily on preventing hemodynamic instability by increasing dialysis time/frequency or prescribing cool dialysis. Whether dietary or pharmacological interventions, such as the administration of L-arginine, fermented food, nitrate, nuclear factor erythroid 2-related factor 2 agonists, or prolyl hydroxylase 2 inhibitors, improve clinical outcome in patients treated with HD warrants future research. [ABSTRACT FROM AUTHOR]

Published
2021
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104. Understanding the role of the cytoprotective transcription factor nuclear factor erythroid 2-related factor 2—lessons from evolution, the animal kingdom and rare progeroid syndromes.

Author

Stenvinkel, Peter, Meyer, Colin J, Block, Geoffrey A, Chertow, Glenn M, and Shiels, Paul G

Subjects
REACTIVE oxygen species, TRANSCRIPTION factors, DEEP diving, BIOLOGICAL evolution, PROTHROMBIN
Abstract

The cytoprotective transcriptor factor nuclear factor erythroid 2– related factor 2 (NRF2) is part of a complex regulatory network that responds to environmental cues. To better understand its role in a cluster of inflammatory and pro-oxidative burden of lifestyle diseases that accumulate with age, lessons can be learned from evolution, the animal kingdom and progeroid syndromes. When levels of oxygen increased in the atmosphere, mammals required ways to protect themselves from the metabolic toxicity that arose from the production of reactive oxygen species. The evolutionary origin of the NRF2–Kelch-like ECH-associated protein 1 (KEAP1) signalling pathway from primitive origins has been a prerequisite for a successful life on earth, with checkpoints in antioxidant gene expression, inflammation, detoxification and protein homoeostasis. Examples from the animal kingdom suggest that superior antioxidant defense mechanisms with enhanced NRF2 expression have been developed during evolution to protect animals during extreme environmental conditions, such as deep sea diving, hibernation and habitual hypoxia. The NRF2–KEAP1 signalling pathway is repressed in progeroid (accelerated ageing) syndromes and a cluster of burden of lifestyle disorders that accumulate with age. Compelling links exist between tissue hypoxia, senescence and a repressed NRF2 system. Effects of interventions that activate NRF2, including nutrients, and more potent (semi)synthetic NRF2 agonists on clinical outcomes are of major interest. Given the broad-ranging actions of NRF2, we need to better understand the mechanisms of activation, biological function and regulation of NRF2 and its inhibitor, KEAP1, in different clinical conditions to ensure that modulation of this thiol-based system will not result in major adverse effects. Lessons from evolution, the animal kingdom and conditions of accelerated ageing clarify a major role of a controlled NRF2–KEAP1 system in healthy ageing and well-being. [ABSTRACT FROM AUTHOR]

Published
2020
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105. Increased telomere attrition following renal transplantation: impact of anti-metabolite therapy

Author

Luttropp, Karin, Nordfors, Louise, McGuinness, Dagmara, Wennberg, Lars, Curley, Hannah, Quasim, Tara, Genberg, Helena, Sönnerborg, Isabella, Sandberg, John, Schalling, Martin, Qureshi, Abdul Rashid, Bárány, Peter, Shiels, Paul G., and Stenvinkel, Peter

Abstract

Background: The uremic milieu exposes chronic kidney disease (CKD) patients to premature ageing processes. The impact of renal replacement therapy (dialysis and renal transplantation [RTx]) or immunosuppressive treatment regimens on ageing biomarkers has scarcely been studied.\ud \ud Methods: In this study telomere length in whole blood cells was measured in 49 dialysis patients and 47 RTx patients close to therapy initiation and again after 12 months. Forty-three non-CKD patients were included as controls.\ud \ud Results: Non-CKD patients had significantly (P

Published
2016

106. Adverse childhood experiences, epigenetics and telomere length variation in childhood and beyond: a systematic review of the literature.

Author

Lang, Jason, McKie, Judith, Smith, Helen, McLaughlin, Angela, Gillberg, Christopher, Shiels, Paul G., and Minnis, Helen

Subjects
BIOMARKERS, CHILD abuse, TELOMERES, SYSTEMATIC reviews, DNA methylation, DESCRIPTIVE statistics, EPIGENOMICS, ADVERSE childhood experiences
Abstract

A systematic review following PRISMA guidelines was conducted to answer the question: What epigenetic, telomeric and associated biological changes are associated with exposure to adverse childhood experiences (ACEs) in the under 12s? Using PRISMA guidelines, appropriate databases were searched. 190 papers were returned with 38 articles fully reviewed. Articles were each independently quality rated by two authors using the Crowe Critical Appraisal Tool and data were extracted. Of the 38 articles, 23 were rated as very high quality. Most study participants were adults (n = 7769) with n = 727 child participants. Only seven of the very/high-quality studies were prospective and involved children. Methylation was the most studied method of epigenetic modification. There is some evidence supporting epigenetic modification of certain markers in participants exposed to ACEs measured in adulthood. Research is lacking on non-coding aspects of the epigenome and on coding aspects other than DNA methylation. There is some evidence of a more powerful effect on telomere length if physical neglect was involved. Much further work is required to model biological and psychological effects of epigenetic changes during childhood using prospective study designs. The effect of ACEs on the cellular ageing process during childhood is inadequately investigated and relies solely on measure of telomere length. Future research suggestions are proposed. [ABSTRACT FROM AUTHOR]

Published
2020
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107. A molecular signature for delayed graft function

Author

McGuinness, Dagmara, primary, Mohammed, Suhaib, additional, Monaghan, Laura, additional, Wilson, Paul A., additional, Kingsmore, David B., additional, Shapter, Oliver, additional, Stevenson, Karen S., additional, Coley, Shana M., additional, Devey, Luke, additional, Kirkpatrick, Robert B., additional, and Shiels, Paul G., additional

Published
2018
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110. An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis

Author

Martín, J. [0000-0002-2202-0622], Bossini-Castillo, L., Campillo-Davó, D., López-Isac, Elena, Carmona, F.D., Simeón, Carmen P., Carreira, P., Callejas-Rubio, J. L., Castellví, I., Fernández-Nebro, Antonio, Rodríguez-Rodríguez, Luis, Rubio-Rivas, M., García-Hernández, Francisco José, Madroñero, A.B., Beretta, L., Santaniello, Alessandro, Lunardi, C., Airó, Paolo, Hoffmann-Vold, A. M., Kreuter, A., Riemekasten, G., Witte, Torsten, Hunzelmann, Nicolas, Vonk, Madelon C., Voskuyl, Alexandre E., de Vries-Bouwstra, Jeska, Shiels, Paul G., Herrick, A., Worthington, J., Radstake, T. R., Martín, J., Spanish Scleroderma Group, Martín, J. [0000-0002-2202-0622], Bossini-Castillo, L., Campillo-Davó, D., López-Isac, Elena, Carmona, F.D., Simeón, Carmen P., Carreira, P., Callejas-Rubio, J. L., Castellví, I., Fernández-Nebro, Antonio, Rodríguez-Rodríguez, Luis, Rubio-Rivas, M., García-Hernández, Francisco José, Madroñero, A.B., Beretta, L., Santaniello, Alessandro, Lunardi, C., Airó, Paolo, Hoffmann-Vold, A. M., Kreuter, A., Riemekasten, G., Witte, Torsten, Hunzelmann, Nicolas, Vonk, Madelon C., Voskuyl, Alexandre E., de Vries-Bouwstra, Jeska, Shiels, Paul G., Herrick, A., Worthington, J., Radstake, T. R., Martín, J., and Spanish Scleroderma Group

Abstract

OBJECTIVE: Systemic sclerosis (SSc) is a fibrotic immune-mediated disease of unknown etiology. Among its clinical manifestations, pulmonary involvement is the leading cause of mortality in patients with SSc. However, the genetic factors involved in lung complication are not well defined. We aimed to review the association of the MIF gene, which encodes a cytokine implicated in idiopathic pulmonary hypertension among other diseases, with the susceptibility and clinical expression of SSc, in addition to testing the association of this polymorphism with SSc-related pulmonary involvement. METHODS: A total of 4392 patients with SSc and 16,591 unaffected controls from 6 cohorts of European origin were genotyped for the MIF promoter variant rs755622. An inverse variance method was used to metaanalyze the data. RESULTS: A statistically significant increase of the MIF rs755622*C allele frequency compared with controls was observed in the subgroups of patients with diffuse cutaneous SSc (dcSSc) and with pulmonary arterial hypertension (PAH) independently (dcSSc: p = 3.20E-2, OR 1.13; PAH: p = 2.19E-02, OR 1.32). However, our data revealed a stronger effect size with the subset of patients with SSc showing both clinical manifestations (dcSSc with PAH: p = 6.91E-3, OR 2.05). CONCLUSION: We reviewed the association of the MIF rs755622*C allele with SSc and described a phenotype-specific association of this variant with the susceptibility to develop PAH in patients with dcSSc.

Published
2017

111. Identification of molecular markers of delayed graft function based on the regulation of biological ageing

Author

McGuinness, Dagmara, Leierer, Johannes, Shapter, Olivier, Mohammed, Suhaib, Gingell-Littlejohn, Marc, Kingsmore, David B., Little, Ann-Margaret, Kerschbaum, Julia, Schneeberger, Stefan, Maglione, Manuel, Nadalin, Silvio, Wagner, Sylvia, Königsrainer, Alfred, Aitken, Emma, Whalen, Henry, Clancy, Marc, McConnachie, Alex, Koppelstaetter, Christian, Stevenson, Karen S., and Shiels, Paul G.

Subjects
surgical procedures, operative, lcsh:R, lcsh:Medicine, lcsh:Q, lcsh:Science, Research Article
Abstract

Introduction:\ud \ud Delayed graft function is a prevalent clinical problem in renal transplantation for which there is no objective system to predict occurrence in advance. It can result in a significant increase in the necessity for hospitalisation post-transplant and is a significant risk factor for other post-transplant complications.\ud \ud Methodology:\ud \ud The importance of microRNAs (miRNAs), a specific subclass of small RNA, have been clearly demonstrated to influence many pathways in health and disease. To investigate the influence of miRNAs on renal allograft performance post-transplant, the expression of a panel of miRNAs in pre-transplant renal biopsies was measured using qPCR. Expression was then related to clinical parameters and outcomes in two independent renal transplant cohorts.\ud \ud Results:\ud \ud Here we demonstrate, in two independent cohorts of pre-implantation human renal allograft biopsies, that a novel pre-transplant renal performance scoring system (GRPSS), can determine the occurrence of DGF with a high sensitivity (>90%) and specificity (>60%) for donor allografts pre-transplant, using just three senescence associated microRNAs combined with donor age and type of organ donation.\ud \ud Conclusion:\ud \ud These results demonstrate a relationship between pre-transplant microRNA expression levels, cellular biological ageing pathways and clinical outcomes for renal transplantation. They provide for a simple, rapid quantitative molecular pre-transplant assay to determine post-transplant allograft function and scope for future intervention. Furthermore, these results demonstrate the involvement of senescence pathways in ischaemic injury during the organ transplantation process and an indication of accelerated bio-ageing as a consequence of both warm and cold ischaemia.

Published
2016

116. CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

Author

Stenvinkel, Peter, primary, Luttropp, Karin, additional, McGuinness, Dagmara, additional, Witasp, Anna, additional, Qureshi, Abdul Rashid, additional, Wernerson, Annika, additional, Nordfors, Louise, additional, Schalling, Martin, additional, Ripsweden, Jonaz, additional, Wennberg, Lars, additional, Söderberg, Magnus, additional, Bárány, Peter, additional, Olauson, Hannes, additional, and Shiels, Paul G, additional

Published
2017
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117. Increased Telomere Attrition After Renal Transplantation—Impact of Antimetabolite Therapy

Author

Luttropp, Karin, primary, Nordfors, Louise, additional, McGuinness, Dagmara, additional, Wennberg, Lars, additional, Curley, Hannah, additional, Quasim, Tara, additional, Genberg, Helena, additional, Sandberg, John, additional, Sönnerborg, Isabella, additional, Schalling, Martin, additional, Qureshi, Abdul Rashid, additional, Bárány, Peter, additional, Shiels, Paul G., additional, and Stenvinkel, Peter, additional

Published
2016
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118. Gender and telomere length: Systematic review and meta-analysis

Author

Gardner, Michael, Bann, Daniel, Wiley, Laura, Cooper, Rachel, Hardy, Rebecca, Nitsch, Dorothea, Martin-Ruiz, Carmen, Shiels, Paul G, Sayer, Avan Aihie, Barbieri, Michelangela, Bekaert, Sofie, Bischoff, Claus, Brooks-Wilson, Angela, Chen, Wei, and Robertson, Tony

Subjects
Telomere length, Measurement methods, Epidemiology, Systematic review and meta-analysis, Gender
Abstract

Background: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. Methods: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. Results: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p = 1.00) or cell type (p = 0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. Conclusions: Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.

Published
2014

119. A genome wide association study follow-up suggests a possible role of PPARG in systemic esclerosis susceptiblity

Author

López Isac, Elena, Bossini Castillo, Lara, Simeón Aznar, Carmen Pilar, Egurbide Arberas, María Victoria, Alegre-Sancho, Juan José, Callejas Rubio, José Luis, Román-Ivorra, José Andrés, Freire, Mayka, Beretta, Lorenzo, Santaniello, Alessandro, Airó, Paolo, Lunardi, Claudio, Hunzelmann, Nicolas, Riemestaken, Gabriela, Witte, Torsten, Kreuter, Alexander, Distler, Jörg H.V., Schuerwegh, Annemie J., Vonk, Madelon C., Voskuyl, Alexandre E., Shiels, Paul G., van Laar, Jacob M., Fonseca, Carmen, Denton, Christopher P., Herrick, Ariane L., Worthington, Jane, Assassi, Shervin, Koeleman, Bobby P. C., Mayes, Maureen D., Radstake, Timothy R.D.J., Martín, Javier, Espinosa Garriga, Gerard, Spanish Scleroderma Study Group (SSSG), Narváez García, Francisco Javier, Universidad de Cantabria, Rheumatology, CCA - Disease profiling, Sociedad Española de Reumatología, Ministerio de Economía y Competitividad (España), Junta de Andalucía, European League Against Rheumatism, Ministerio de Educación, Cultura y Deporte (España), Netherlands Organization for Scientific Research, Dutch Arthritis Foundation, National Institutes of Health (US), National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), Congressionally Directed Medical Research Programs (US), and Universitat de Barcelona

Subjects
Adult, Male, Peroxisome proliferator-activated receptor gamma, Genotype, Autoimmune diseases, Immunology, Genome-wide association study, Single-nucleotide polymorphism, Bioinformatics, Genoma humà, Polymorphism, Single Nucleotide, PPARG gene, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, GWAS, Humans, Immunology and Allergy, Medicine, Genetic Predisposition to Disease, Genotyping, 030304 developmental biology, 030203 arthritis & rheumatology, 0303 health sciences, Scleroderma, Systemic, Malalties autoimmunitàries, Human genome, business.industry, Middle Aged, 3. Good health, SNP genotyping, PPAR gamma, Scleroderma (Disease), SYSTEMIC SCLEROSIS, Cohort, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Female, SNPs, Esclerodèrmia, business, Genome-Wide Association Study, Research Article, Cohort study
Abstract

[Introduction] A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy., [Methods] Sixty-six non-HLA SNPs showing a P value, [Results] We observed nominal associations for both PPARG rs310746 (P MH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (P MH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (P MH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis., [Conclusion] Our results suggest a role of PPARG gene in the development of SSc., This work was supported by the following grants: JM was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 and SAF2012-34435 from the Spanish Ministry of Economy and Competitiveness, CTS-4977, and CTS-180 from Junta de Andalucía, and is sponsored by the Orphan Disease Program grant from the European League Against Rheumatism (EULAR). This study was also funded by PI-0590-2010, from Consejería de Salud y Bienestar Social, Junta de Andalucía, Spain. JLCR and JM are funded by Consejería de Salud, Junta de Andalucía, through PI-0590-2010. ELI was supported by Ministerio de Educación, Cultura y Deporte through the program FPU. TRDJR was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). TW was granted by DFG WI 1031/6.1. Study on USA samples were supported by US National Institutes of Health and National Institute of Arthritis and Musculoskeletal Diseases (NIH-NIAMS) R01-AR-055258, Two-Stage Genome Wide Association Study in Systemic Sclerosis (MDM) and by the NIH-NIAMS Center of Research Translation (CORT) in SSc (P50AR054144) (MDM, FCA, FKT), the NIH-NIAMS SSc Family Registry and DNA Repository (N01-AR-0-2251) (MDM), NIH-KL2RR024149 (SA), K23AR061436 (SA), and the Department of Defense Congressionally Directed Medical Research Programs (W81XWH-07-01-0111) (MDM).

Published
2014

122. Correction: Identification of Molecular Markers of Delayed Graft Function Based on the Regulation of Biological Ageing

Author

McGuinness, Dagmara, primary, Leierer, Johannes, additional, Shapter, Olivier, additional, Mohammed, Suhaib, additional, Gingell-Littlejohn, Marc, additional, Kingsmore, David B., additional, Little, Ann-Margaret, additional, Kerschbaum, Julia, additional, Schneeberger, Stefan, additional, Maglione, Manuel, additional, Nadalin, Silvio, additional, Wagner, Sylvia, additional, Königsrainer, Alfred, additional, Aitken, Emma, additional, Whalen, Henry, additional, Clancy, Marc, additional, McConnachie, Alex, additional, Koppelstaetter, Christian, additional, Stevenson, Karen S., additional, and Shiels, Paul G., additional

Published
2016
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124. Reproducibility of telomere length assessment : an international collaborative study

Author

Martin-Ruiz, Carmen M, Baird, Duncan, Roger, Laureline, Boukamp, Petra, Krunic, Damir, Cawthon, Richard, Dokter, Martin M, van der Harst, Pim, Bekaert, Sofie, de Meyer, Tim, Roos, Göran, Svenson, Ulrika, Codd, Veryan, Samani, Nilesh J, McGlynn, Liane, Shiels, Paul G, Pooley, Karen A, Dunning, Alison M, Cooper, Rachel, Wong, Andrew, Kingston, Andrew, von Zglinicki, Thomas, Martin-Ruiz, Carmen M, Baird, Duncan, Roger, Laureline, Boukamp, Petra, Krunic, Damir, Cawthon, Richard, Dokter, Martin M, van der Harst, Pim, Bekaert, Sofie, de Meyer, Tim, Roos, Göran, Svenson, Ulrika, Codd, Veryan, Samani, Nilesh J, McGlynn, Liane, Shiels, Paul G, Pooley, Karen A, Dunning, Alison M, Cooper, Rachel, Wong, Andrew, Kingston, Andrew, and von Zglinicki, Thomas

Abstract

Background: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories. Methods: We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra- and inter-batch variation between laboratories and techniques. Results: Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63-0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However, inter-laboratory coefficients of variation (CVs) averaged about 10% for Southern blotting and STELA and more than 20% for qPCR. This difference was compensated for by a higher dynamic range for the qPCR method as shown by equal variance after z-scoring. Technical variation per laboratory, measured as median of intra- and inter-batch CVs, ranged from 1.4% to 9.5%, with differences between laboratories only marginally significant (P = 0.06). Gel-based and PCR-based techniques were not different in accuracy. Conclusions: Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories. We propose to establish a common set of physical telomere length standards to improve comparability of telomere length estimates between laboratories.

Published
2015
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125. Is Southern blotting necessary to measure telomere length reproducibly? : Authors' Response to: Commentary: The reliability of telomere length measurements

Author

Martin-Ruiz, Carmen M, Baird, Duncan, Roger, Laureline, Boukamp, Petra, Krunic, Damir, Cawthon, Richard, Dokter, Martin M, Van Der Harst, Pim, Bekaert, Sofie, De Meyer, Tim, Roos, Göran, Svenson, Ulrika, Codd, Veryan, Samani, Nilesh J, Mcglynn, Liane, Shiels, Paul G, Pooley, Karen A, Dunning, Alison M, Cooper, Rachel, Wong, Andrew, Kingston, Andrew, Von Zglinicki, Thomas, Martin-Ruiz, Carmen M, Baird, Duncan, Roger, Laureline, Boukamp, Petra, Krunic, Damir, Cawthon, Richard, Dokter, Martin M, Van Der Harst, Pim, Bekaert, Sofie, De Meyer, Tim, Roos, Göran, Svenson, Ulrika, Codd, Veryan, Samani, Nilesh J, Mcglynn, Liane, Shiels, Paul G, Pooley, Karen A, Dunning, Alison M, Cooper, Rachel, Wong, Andrew, Kingston, Andrew, and Von Zglinicki, Thomas

Published
2015
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126. Reproducibility of telomere length assessment : Authors' Response to Damjan Krstajic and Ljubomir Buturovic

Author

Martin-Ruiz, Carmen M, Baird, Duncan, Roger, Laureline, Boukamp, Petra, Krunic, Damir, Cawthon, Richard, Dokter, Martin M, Van der Harst, Pim, Bekaert, Sofie, De Meyer, Tim, Roos, Göran, Svenson, Ulrika, Codd, Veryan, Samani, Nilesh J, Mcglynn, Liane, Shiels, Paul G, Pooley, Karen A, Dunning, Alison M, Cooper, Rachel, Wong, Andrew, Kingston, Andrew, Von Zglinicki, Thomas, Martin-Ruiz, Carmen M, Baird, Duncan, Roger, Laureline, Boukamp, Petra, Krunic, Damir, Cawthon, Richard, Dokter, Martin M, Van der Harst, Pim, Bekaert, Sofie, De Meyer, Tim, Roos, Göran, Svenson, Ulrika, Codd, Veryan, Samani, Nilesh J, Mcglynn, Liane, Shiels, Paul G, Pooley, Karen A, Dunning, Alison M, Cooper, Rachel, Wong, Andrew, Kingston, Andrew, and Von Zglinicki, Thomas

Published
2015
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128. The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis

Author

Carmona, F.D., Martín, J. E., Beretta, L., Simeón, Carmen P., Carreira, P., Callejas-Rubio, J. L., Fernández-Castro, Monica, Sáez-Comet, L., Beltrán, E., Camps, M. T., Egurbide, M. V., Airó, Paolo, Scorza, R., Lunardi, C., Hunzelmann, Nicolas, Riemekasten, G., Witte, Torsten, Kreuter, A., Distler, J. H., Madhok, R., Shiels, Paul G., Laar, Jacob M. van, Fonseca, C., Denton, C., Herrick, A., Worthington, J., Schuerwegh, A. J., Vonk, Madelon C., Voskuyl, Alexandre E., Radstake, T. R., and Martín, J.

Abstract

Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34×10-8, OR = 1.22, CI 95% = 1.14-1.30; rs2004640: P = 4.60×10-7, OR = 0.84, CI 95% = 0.78-0.90; rs10488631: P = 7.53×10-20, OR = 1.63, CI 95% = 1.47-1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P = 9.04×10-22, OR = 1.75, CI 95% = 1.56-1.97) better explained the observed association (likelihood P-value = 1.48×10-4), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific. © 2013 Carmona et al.

Published
2013

129. Telomere Homeostasis: Interplay with Magnesium.

Author

Maguire, Donogh, Neytchev, Ognian, Talwar, Dinesh, McMillan, Donald, and Shiels, Paul G.

Subjects
TELOMERES, HOMEOSTASIS, CELLULAR aging, MAGNESIUM, MITOCHONDRIA, CIRCADIAN rhythms
Abstract

Telomere biology, a key component of the hallmarks of ageing, offers insight into dysregulation of normative ageing processes that accompany age-related diseases such as cancer. Telomere homeostasis is tightly linked to cellular metabolism, and in particular with mitochondrial physiology, which is also diminished during cellular senescence and normative physiological ageing. Inherent in the biochemistry of these processes is the role of magnesium, one of the main cellular ions and an essential cofactor in all reactions that use ATP. Magnesium plays an important role in many of the processes involved in regulating telomere structure, integrity and function. This review explores themechanisms thatmaintain telomere structure and function, their influence on circadian rhythms and their impact on health and age-related disease. The pervasive role of magnesium in telomere homeostasis is also highlighted. [ABSTRACT FROM AUTHOR]

Published
2018
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132. Reproducibility of Telomere Length Assessment - An International Collaborative Study

Author

Martin-Ruiz, Carmen M., primary, Baird, Duncan, additional, Roger, Laureline, additional, Boukamp, Petra, additional, Krunic, Damir, additional, Cawthon, Richard, additional, Dokter, Martin M, additional, van der Harst, Pim, additional, Bekaert, Sofie, additional, de Meyer, Tim, additional, Roos, Goran, additional, Svenson, Ulrika, additional, Codd, Veryan, additional, Samani, Nilesh J, additional, McGlynn, Liane, additional, Shiels, Paul G, additional, Pooley, Karen A, additional, Dunning, Alison M, additional, Cooper, Rachel, additional, Wong, Andrew, additional, Kingston, Andrew, additional, and von Zglinicki, Thomas, additional

Published
2015
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133. Reproducibility of telomere length assessment: Authors’ Response to Damjan Krstajic and Ljubomir Buturovic

Author

Martin-Ruiz, Carmen M, primary, Baird, Duncan, additional, Roger, Laureline, additional, Boukamp, Petra, additional, Krunic, Damir, additional, Cawthon, Richard, additional, Dokter, Martin M, additional, Van Der Harst, Pim, additional, Bekaert, Sofie, additional, De Meyer, Tim, additional, Roos, Goran, additional, Svenson, Ulrika, additional, Codd, Veryan, additional, Samani, Nilesh J, additional, Mcglynn, Liane, additional, Shiels, Paul G, additional, Pooley, Karen A, additional, Dunning, Alison M, additional, Cooper, Rachel, additional, Wong, Andrew, additional, Kingston, Andrew, additional, and Von Zglinicki, Thomas, additional

Published
2015
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134. Is Southern blotting necessary to measure telomere length reproducibly? Authors’ Response to: Commentary: The reliability of telomere length measurements

Author

Martin-Ruiz, Carmen M, primary, Baird, Duncan, additional, Roger, Laureline, additional, Boukamp, Petra, additional, Krunic, Damir, additional, Cawthon, Richard, additional, Dokter, Martin M, additional, Van Der Harst, Pim, additional, Bekaert, Sofie, additional, De Meyer, Tim, additional, Roos, Goran, additional, Svenson, Ulrika, additional, Codd, Veryan, additional, Samani, Nilesh J, additional, Mcglynn, Liane, additional, Shiels, Paul G, additional, Pooley, Karen A, additional, Dunning, Alison M, additional, Cooper, Rachel, additional, Wong, Andrew, additional, Kingston, Andrew, additional, and Von Zglinicki, Thomas, additional

Published
2015
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137. Corrigendum to “Cardio-metabolic risk factors and cortical thickness in a neurologically healthy male population: Results from the psychological, social and biological determinants of ill health (pSoBid) study” [Neuroimage Clin. 2 (2013) 646–57]

Author

Krishnadas, Rajeev, primary, McLean, John, additional, Batty, G. David, additional, Burns, Harry, additional, Deans, Kevin A., additional, Ford, Ian, additional, McConnachie, Alex, additional, McGinty, Agnes, additional, McLean, Jennifer S., additional, Millar, Keith, additional, Sattar, Naveed, additional, Shiels, Paul G., additional, Velupillai, Yoga N., additional, Packard, Chris J., additional, and Cavanagh, Jonathan, additional

Published
2015
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138. The Histone Deacetylase SIRT6 Is a Tumor Suppressor that Controls Cancer Metabolism

Author

Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Gymrek, Melissa A., Bernstein, Bradley E., Regev, Aviv, Zwaans, Bernadette M.M., Silberman, Dafne M., Goren, Alon, Zhong, Lei, Ram, Oren, Truelove, Jessica, Guimaraes, Alexander R., Toiber, Debra, Cosentino, Claudia, Greenson, Joel K., MacDonald, Alasdair I., McGlynn, Liane, Maxwell, Fraser, Edwards, Joanne, Giacosa, Sofia, Guccione, Ernesto, Weissleder, Ralph, Shiels, Paul G., Lombard, David B., Mostoslavsky, Raul, Sebastian, Carlos, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Gymrek, Melissa A., Bernstein, Bradley E., Regev, Aviv, Zwaans, Bernadette M.M., Silberman, Dafne M., Goren, Alon, Zhong, Lei, Ram, Oren, Truelove, Jessica, Guimaraes, Alexander R., Toiber, Debra, Cosentino, Claudia, Greenson, Joel K., MacDonald, Alasdair I., McGlynn, Liane, Maxwell, Fraser, Edwards, Joanne, Giacosa, Sofia, Guccione, Ernesto, Weissleder, Ralph, Shiels, Paul G., Lombard, David B., Mostoslavsky, Raul, and Sebastian, Carlos

Abstract

Reprogramming of cellular metabolism is a key event during tumorigenesis. Despite being known for decades (Warburg effect), the molecular mechanisms regulating this switch remained unexplored. Here, we identify SIRT6 as a tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of SIRT6 leads to tumor formation without activation of known oncogenes, whereas transformed SIRT6-deficient cells display increased glycolysis and tumor growth, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. By using a conditional SIRT6 allele, we show that SIRT6 deletion in vivo increases the number, size, and aggressiveness of tumors. SIRT6 also functions as a regulator of ribosome metabolism by corepressing MYC transcriptional activity. Lastly, Sirt6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism., American Society for Engineering Education. National Defense Science and Engineering Graduate Fellowship, National Human Genome Research Institute (U.S.). Center of Excellence in Genome Science (Grant P50HG006193)

Published
2014

139. A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Author

Lopez-Isac, Elena, Bossini-Castillo, Lara, Simeon, Carmen P., Victoria Egurbide, Maria, Jose Alegre-Sancho, Juan, Luis Callejas, Jose, Andres Roman-Ivorra, Jose, Freire, Mayka, Beretta, Lorenzo, Santaniello, Alessandro, Airo, Paolo, Lunardi, Claudio, Hunzelmann, Nicolas, Riemekasten, Gabriela, Witte, Torsten, Kreuter, Alexander, Distler, Joerg H. W., Schuerwegh, Annemie J., Vonk, Madelon C., Voskuyl, Alexandre E., Shiels, Paul G., van Laar, Jacob M., Fonseca, Carmen, Denton, Christopher, Herrick, Ariane, Worthington, Jane, Assassi, Shervin, Koeleman, Bobby P., Mayes, Maureen D., Radstake, Timothy R. D. J., Martin, Javier, Lopez-Isac, Elena, Bossini-Castillo, Lara, Simeon, Carmen P., Victoria Egurbide, Maria, Jose Alegre-Sancho, Juan, Luis Callejas, Jose, Andres Roman-Ivorra, Jose, Freire, Mayka, Beretta, Lorenzo, Santaniello, Alessandro, Airo, Paolo, Lunardi, Claudio, Hunzelmann, Nicolas, Riemekasten, Gabriela, Witte, Torsten, Kreuter, Alexander, Distler, Joerg H. W., Schuerwegh, Annemie J., Vonk, Madelon C., Voskuyl, Alexandre E., Shiels, Paul G., van Laar, Jacob M., Fonseca, Carmen, Denton, Christopher, Herrick, Ariane, Worthington, Jane, Assassi, Shervin, Koeleman, Bobby P., Mayes, Maureen D., Radstake, Timothy R. D. J., and Martin, Javier

Abstract

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy. Methods: Sixty-six non-HLA SNPs showing a P value < 10(-4) in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (P-MH = 1.90 x 10(-6), OR, 1.28) and CHRNA9 rs6832151 (P-MH = 4.30 x 10(-6), OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (P-MH = 5.00 x 10(-7); OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis. Conclusion: Our results suggest a role of PPARG gene in the development of SSc.

Published
2014

140. Inflammation and premature aging in advanced chronic kidney disease.

Author

Kooman, Jeroen P., Dekker, Marijke J., Usvyat, Len A., Kotanko, Peter, van der Sande, Frank M., Schalkwijk, Casper G., Shiels, Paul G., and Stenvinkel, Peter

Subjects
KIDNEY disease risk factors, AGING, INFLAMMATION, PROGNOSIS
Abstract

Systemic inflammation in end-stage renal disease is an established risk factor for mortality and a catalyst for other complications, which are related to a premature aging phenotype, including muscle wasting, vascular calcification, and other forms of premature vascular disease, depression, osteoporosis, and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have a direct effect on cellular and tissue function. In addition to uremia-specific causes, such as abnormalities in the phosphate-Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called "inflammaging" in the general population. Potentially relevant, but still somewhat unexplored in this respect, are abnormal or misplaced protein structures, as well as abnormalities in tissue homeostasis, which evoke danger signals through damage-associated molecular patterns, as well as the senescenceassociated secretory phenotype. Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserves, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relationship between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences, are discussed. [ABSTRACT FROM AUTHOR]

Published
2017
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141. Segmental Aging Underlies the Development of a Parkinson Phenotype in the AS/AGU Rat.

Author

Khojah, Sohair M., Payne, Anthony P., McGuinness, Dagmara, and Shiels, Paul G.

Subjects
PARKINSON'S disease, MOLECULAR biology, AGING, BRAIN, GENETIC mutation, LABORATORY rats
Abstract

There is a paucity of information on the molecular biology of aging processes in the brain. We have used biomarkers of aging (SA β-Gal, p16Ink4a, Sirt5, Sirt6, and Sirt7) to demonstrate the presence of an accelerated aging phenotype across different brain regions in the AS/AGU rat, a spontaneous Parkinsonian mutant of PKC derived from a parental AS strain. P16INK4a expression was significantly higher in AS/AGU animals compared to age-matched AS controls (p < 0.001) and displayed segmental expression across various brain regions. The age-related expression of sirtuins similarly showed differences between strains and between brain regions. Our data clearly show segmental aging processes within the rat brain, and that these are accelerated in the AS/AGU mutant. The accelerated aging, Parkinsonian phenotype, and disruption to dopamine signalling in the basal ganglia in AS/AGU rats, suggests that this rat strain represents a useful model for studies of development and progression of Parkinson's disease in the context of biological aging and may offer unique mechanistic insights into the biology of aging. [ABSTRACT FROM AUTHOR]

Published
2016
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143. Reproducibility of telomere length assessment: an international collaborative study

Author

Martin-Ruiz, Carmen M, primary, Baird, Duncan, additional, Roger, Laureline, additional, Boukamp, Petra, additional, Krunic, Damir, additional, Cawthon, Richard, additional, Dokter, Martin M, additional, van der Harst, Pim, additional, Bekaert, Sofie, additional, de Meyer, Tim, additional, Roos, Goran, additional, Svenson, Ulrika, additional, Codd, Veryan, additional, Samani, Nilesh J, additional, McGlynn, Liane, additional, Shiels, Paul G, additional, Pooley, Karen A, additional, Dunning, Alison M, additional, Cooper, Rachel, additional, Wong, Andrew, additional, Kingston, Andrew, additional, and von Zglinicki, Thomas, additional

Published
2014
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144. SIRT2: Tumour suppressor or tumour promoter in operable breast cancer?

Author

McGlynn, Liane M., primary, Zino, Samer, additional, MacDonald, Alasdair I., additional, Curle, Jennifer, additional, Reilly, Justice E., additional, Mohammed, Zahra M.A., additional, McMillan, Donald C., additional, Mallon, Elizabeth, additional, Payne, Anthony P., additional, Edwards, Joanne, additional, and Shiels, Paul G., additional

Published
2014
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145. Analysis fo telomere lengths in cloned sheep

Author

Shiels, Paul G., KInd, Alexander J., Campbell, Keith H.S., Waddington, David, Wilmut, Ian, Colman, alan, and Schnieke, Angelika E.

Subjects
Telomeres -- Research, Genetic research -- Observations, Cloning -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Animals can be produced without involving germline cells, with the development of nuclear-transfer technology using cultured somatic cells. The telomere lengths of animals 6LL3 (Dolly), 6LL6 and 6LL7 have been compared with age-matched control sheep, donor mammary gland tissue and donor cells before and after culturing, to examine whether telomere erosion is repaired following nuclear transfer. The mean terminal restriction fragment (TRF) sizes were smaller in each of the nuclear-transfer animals than the controls, with DNA in 6LL3 showing the highest diminution of mean TRF. There were no major differences in the DNA of the six year old progenitor mammary tissue and age-matched control DNA from fresh blood.

Published
1999

146. KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor

Author

Bossini-Castillo, L., Simeón, Carmen P., Beretta, L., Broen, Jasper C., Vonk, Madelon C., Callejas-Rubio, J. L., Carreira, P., Rodríguez-Rodríguez, Luis, García-Portales, Rosa, González-Gay, M. A., Castellví, I., Camps, M. T., Tolosa, Carlos, Vicente, Esther, Egurbide, M. V., Spanish Scleroderma Group, Schuerwegh, A. J., Hesselstrand, R., Lunardi, C., Laar, Jacob M. van, Shiels, Paul G., Herrick, A., Worthington, J., Denton, C., Radstake, T. R., Fonseca, C., Martín, J., Bossini-Castillo, L., Simeón, Carmen P., Beretta, L., Broen, Jasper C., Vonk, Madelon C., Callejas-Rubio, J. L., Carreira, P., Rodríguez-Rodríguez, Luis, García-Portales, Rosa, González-Gay, M. A., Castellví, I., Camps, M. T., Tolosa, Carlos, Vicente, Esther, Egurbide, M. V., Spanish Scleroderma Group, Schuerwegh, A. J., Hesselstrand, R., Lunardi, C., Laar, Jacob M. van, Shiels, Paul G., Herrick, A., Worthington, J., Denton, C., Radstake, T. R., Fonseca, C., and Martín, J.

Abstract

Introduction Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort. Methods The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay. Results Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients. Conclusions Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients.

Published
2012

147. A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations

Author

Bossini-Castillo, L., Martín, J. E., Broen, Jasper C., Gorlova, Olga, Simeón, Carmen P., Beretta, L., Vonk, Madelon C., Callejas-Rubio, J. L., Castellví, I., Carreira, P., García-Hernández, Francisco José, Castro, M. F., Coenen, M. J., Riemekasten, G., Witte, Torsten, Hunzelmann, Nicolas, Kreuter, A., Distler, J. H., Koeleman, B. P., Voskuyl, Alexandre E., Schuerwegh, A. J., Palm, Øyvind, Hesselstrand, R., Nordin, A., Airó, Paolo, Lunardi, C., Scorza, R., Shiels, Paul G., Laar, Jacob M. van, Herrick, A., Worthington, J., Denton, C., Tan, Filemon K., Arnett, F. C., Agarwal, S. K., Assassi, S., Fonseca, C., Mayes, Maureen D., Radstake, T. R., Martín, J., Bossini-Castillo, L., Martín, J. E., Broen, Jasper C., Gorlova, Olga, Simeón, Carmen P., Beretta, L., Vonk, Madelon C., Callejas-Rubio, J. L., Castellví, I., Carreira, P., García-Hernández, Francisco José, Castro, M. F., Coenen, M. J., Riemekasten, G., Witte, Torsten, Hunzelmann, Nicolas, Kreuter, A., Distler, J. H., Koeleman, B. P., Voskuyl, Alexandre E., Schuerwegh, A. J., Palm, Øyvind, Hesselstrand, R., Nordin, A., Airó, Paolo, Lunardi, C., Scorza, R., Shiels, Paul G., Laar, Jacob M. van, Herrick, A., Worthington, J., Denton, C., Tan, Filemon K., Arnett, F. C., Agarwal, S. K., Assassi, S., Fonseca, C., Mayes, Maureen D., Radstake, T. R., and Martín, J.

Abstract

A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [PMH5 1.92 3 10 -5 odds ratio (OR) 5 1.19] as the genetic variant with the firmest independent association observed in the analyzedGWASpeak of association. After the first follow-up phase, only the association of rs3790567 was consistent (PMH5 4.84 3 10 -3OR 5 1.12). The second follow-up phase confirmed this finding (Px2 5 2.82 3 10 -4 OR 5 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (PMH5 2.82 3 10 -9 OR 5 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis. © The Author 2011. Published by Oxford University Press. All rights reserved.

Published
2012

148. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.

Author

Gorlova, Olga, Gorlova, Olga, Martin, Jose-Ezequiel, Rueda, Blanca, Koeleman, Bobby PC, Ying, Jun, Teruel, Maria, Diaz-Gallo, Lina-Marcela, Broen, Jasper C, Vonk, Madelon C, Simeon, Carmen P, Alizadeh, Behrooz Z, Coenen, Marieke JH, Voskuyl, Alexandre E, Schuerwegh, Annemie J, van Riel, Piet LCM, Vanthuyne, Marie, van 't Slot, Ruben, Italiaander, Annet, Ophoff, Roel A, Hunzelmann, Nicolas, Fonollosa, Vicente, Ortego-Centeno, Norberto, González-Gay, Miguel A, García-Hernández, Francisco J, González-Escribano, María F, Airo, Paolo, van Laar, Jacob, Worthington, Jane, Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul G, Westhovens, Rene, Kreuter, Alexander, de Baere, Elfride, Witte, Torsten, Padyukov, Leonid, Nordin, Annika, Scorza, Raffaella, Lunardi, Claudio, Lie, Benedicte A, Hoffmann-Vold, Anna-Maria, Palm, Oyvind, García de la Peña, Paloma, Carreira, Patricia, Spanish Scleroderma Group, Varga, John, Hinchcliff, Monique, Lee, Annette T, Gourh, Pravitt, Amos, Christopher I, Wigley, Frederick M, Hummers, Laura K, Nelson, J Lee, Riemekasten, Gabriella, Herrick, Ariane, Beretta, Lorenzo, Fonseca, Carmen, Denton, Christopher P, Gregersen, Peter K, Agarwal, Sandeep, Assassi, Shervin, Tan, Filemon K, Arnett, Frank C, Radstake, Timothy RDJ, Mayes, Maureen D, Martin, Javier, Gorlova, Olga, Gorlova, Olga, Martin, Jose-Ezequiel, Rueda, Blanca, Koeleman, Bobby PC, Ying, Jun, Teruel, Maria, Diaz-Gallo, Lina-Marcela, Broen, Jasper C, Vonk, Madelon C, Simeon, Carmen P, Alizadeh, Behrooz Z, Coenen, Marieke JH, Voskuyl, Alexandre E, Schuerwegh, Annemie J, van Riel, Piet LCM, Vanthuyne, Marie, van 't Slot, Ruben, Italiaander, Annet, Ophoff, Roel A, Hunzelmann, Nicolas, Fonollosa, Vicente, Ortego-Centeno, Norberto, González-Gay, Miguel A, García-Hernández, Francisco J, González-Escribano, María F, Airo, Paolo, van Laar, Jacob, Worthington, Jane, Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul G, Westhovens, Rene, Kreuter, Alexander, de Baere, Elfride, Witte, Torsten, Padyukov, Leonid, Nordin, Annika, Scorza, Raffaella, Lunardi, Claudio, Lie, Benedicte A, Hoffmann-Vold, Anna-Maria, Palm, Oyvind, García de la Peña, Paloma, Carreira, Patricia, Spanish Scleroderma Group, Varga, John, Hinchcliff, Monique, Lee, Annette T, Gourh, Pravitt, Amos, Christopher I, Wigley, Frederick M, Hummers, Laura K, Nelson, J Lee, Riemekasten, Gabriella, Herrick, Ariane, Beretta, Lorenzo, Fonseca, Carmen, Denton, Christopher P, Gregersen, Peter K, Agarwal, Sandeep, Assassi, Shervin, Tan, Filemon K, Arnett, Frank C, Radstake, Timothy RDJ, Mayes, Maureen D, and Martin, Javier

Abstract

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84×10(-21), OR = 0.55) and ATA (P = 1.14×10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

Published
2011

149. A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort.

Author

Bossini-Castillo, L., Broen, Jasper C., Simeón, Carmen P., Beretta, L., Vonk, Madelon C., Ortego-Centeno, N., Espinosa, Gerard, Carreira, P., Camps, M. T., Navarrete, N., González-Escribano, María Francisca, Vicente, Esther, Rodríguez-Rodríguez, Luis, Tolosa, Carlos, Román-Ivorra, J. A., Gómez-Gracía, I., García-Hernández, Francisco José, Castellví, I., Gallego, María, Fernández-Nebro, Antonio, García-Portales, Rosa, Egurbide, M. V., Fonollosa, V., García de la Peña, P., Pros, A., González-Gay, M. A., Hesselstrand, R., Riemekasten, G., Witte, Torsten, Coenen, M. J., Koeleman, B. P., Houssiau, F., Smith, V., Keyser, F. de, Westhovens, R., Langhe, E. de, Voskuyl, Alexandre E., Schuerwegh, A. J., Chee, M. M., Madhok, R., Shiels, Paul G., Fonseca, C., Denton, C., Claes, K., Padyukov, Leonid, Nordin, A., Palm, Øyvind, Lie, B. A., Airó, Paolo, Scorza, R., Laar, Jacob M. van, Hunzelmann, Nicolas, Kreuter, A., Herrick, A., Worthington, J., Radstake, T. R., Martín, J., Rueda, B., Bossini-Castillo, L., Broen, Jasper C., Simeón, Carmen P., Beretta, L., Vonk, Madelon C., Ortego-Centeno, N., Espinosa, Gerard, Carreira, P., Camps, M. T., Navarrete, N., González-Escribano, María Francisca, Vicente, Esther, Rodríguez-Rodríguez, Luis, Tolosa, Carlos, Román-Ivorra, J. A., Gómez-Gracía, I., García-Hernández, Francisco José, Castellví, I., Gallego, María, Fernández-Nebro, Antonio, García-Portales, Rosa, Egurbide, M. V., Fonollosa, V., García de la Peña, P., Pros, A., González-Gay, M. A., Hesselstrand, R., Riemekasten, G., Witte, Torsten, Coenen, M. J., Koeleman, B. P., Houssiau, F., Smith, V., Keyser, F. de, Westhovens, R., Langhe, E. de, Voskuyl, Alexandre E., Schuerwegh, A. J., Chee, M. M., Madhok, R., Shiels, Paul G., Fonseca, C., Denton, C., Claes, K., Padyukov, Leonid, Nordin, A., Palm, Øyvind, Lie, B. A., Airó, Paolo, Scorza, R., Laar, Jacob M. van, Hunzelmann, Nicolas, Kreuter, A., Herrick, A., Worthington, J., Radstake, T. R., Martín, J., and Rueda, B.

Abstract

Objectives: The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. Methods: A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers. Results: A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively). Conclusions: The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.

Published
2011

150. Confirmation of association of the macrophage migration inhibitory factor gene with systemic sclerosis in a large European population.

Author

Bossini-Castillo, L., Simeón, Carmen P., Beretta, L., Vo, M. C., Callejas-Rubio, J. L., Espinosa, Gerard, Carreira, P., Camps, M. T., Rodríguez-Rodríguez, Luis, Rodríguez-Carballeira, Mónica, García-Hernández, Francisco José, López-Longo, Francisco Javier, Hernández-Hernández, V., Sáez-Comet, L., Egurbide, M. V., Hesselstrand, R., Nordin, A., Hoffmann-Vold, A. M., Vanthuyne, M., Smith, V., Langhe, E. de, Kreuter, A., Riemekasten, G., Witte, Torsten, Hunzelmann, Nicolas, Voskuyl, Alexandre E., Schuerwegh, A. J., Lunardi, C., Airó, Paolo, Scorza, R., Shiels, Paul G., Laar, Jacob M. van, Fonseca, C., Denton, C., Herrick, A., Worthington, J., Koeleman, B. P., Rueda, B., Radstake, T. R., Martín, J., Bossini-Castillo, L., Simeón, Carmen P., Beretta, L., Vo, M. C., Callejas-Rubio, J. L., Espinosa, Gerard, Carreira, P., Camps, M. T., Rodríguez-Rodríguez, Luis, Rodríguez-Carballeira, Mónica, García-Hernández, Francisco José, López-Longo, Francisco Javier, Hernández-Hernández, V., Sáez-Comet, L., Egurbide, M. V., Hesselstrand, R., Nordin, A., Hoffmann-Vold, A. M., Vanthuyne, M., Smith, V., Langhe, E. de, Kreuter, A., Riemekasten, G., Witte, Torsten, Hunzelmann, Nicolas, Voskuyl, Alexandre E., Schuerwegh, A. J., Lunardi, C., Airó, Paolo, Scorza, R., Shiels, Paul G., Laar, Jacob M. van, Fonseca, C., Denton, C., Herrick, A., Worthington, J., Koeleman, B. P., Rueda, B., Radstake, T. R., and Martín, J.

Abstract

The aim of this study was to confirm the implication of macrophage migration inhibitory factor (MIF) gene in SSc susceptibility or clinical phenotypes in a large European population.

Published
2011

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