36 results on '"Douroudis K"'
Search Results
2. Frequency of rare recessive mutations in unexplained late onset cerebellar ataxia
- Author
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Keogh, M. J., Steele, H., Douroudis, K., Pyle, A., Duff, J., Hussain, R., Smertenko, T., Griffin, H., Santibanez-Koref, M., Horvath, R., and Chinnery, P. F.
- Published
- 2015
- Full Text
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3. 038 Differences in clinical features and comorbid burden between HLA-C*06:02 carrier groups in more than 9,000 people with psoriasis
- Author
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Douroudis, K., primary, Ramessur, R., additional, Dand, N., additional, Smith, C., additional, and Simpson, M., additional
- Published
- 2021
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4. Cytotoxic T-lymphocyte antigen 4 gene polymorphisms are associated with latent autoimmune diabetes in adults
- Author
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Douroudis, K., Prans, E., Kisand, K., Nemvalts, V., and Uibo, R.
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- 2009
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5. PTPN22 gene regulates natural killer cell proliferation during in vitro expansion
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Douroudis, K., Shcherbakova, A., Everaus, H., and Aints, A.
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- 2010
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6. The CD226 gene in susceptibility of type 1 diabetes
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Douroudis, K., Nemvalts, V., Rajasalu, T., Kisand, K., and Uibo, R.
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- 2009
- Full Text
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7. Protein tyrosine phosphatase non-receptor type 22 gene variants at position 1858 are associated with type 1 and type 2 diabetes in Estonian population
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Douroudis, K., Prans, E., Haller, K., Nemvalts, V., Rajasalu, T., Tillmann, V., Kisand, K., and Uibo, R.
- Published
- 2008
8. HLA alleles as predisposal factors for postmenopausal osteoporosis in a Greek population
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Douroudis, K., Tarassi, K., Athanassiades, T., Giannakopoulos, F., Kominakis, A., Thalassinos, N., and Papasteriades, Ch.
- Published
- 2007
9. Exome sequencing in dementia with Lewy bodies
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Keogh, MJ, Kurzawa-Akanbi, M, Griffin, H, Douroudis, K, Ayers, KL, Hussein, RI, Hudson, G, Pyle, A, Cordell, HJ, Attems, J, McKeith, IG, O'Brien, JT, Burn, DJ, Morris, CM, Thomas, AJ, Chinnery, PF, O'Brien, John [0000-0002-0837-5080], Chinnery, Patrick [0000-0002-7065-6617], and Apollo - University of Cambridge Repository
- Subjects
Lewy Body Disease ,Male ,Humans ,Exome ,Female ,Aged - Abstract
Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.
- Published
- 2016
10. Exome sequencing in dementia with Lewy bodies
- Author
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Keogh, M J, primary, Kurzawa-Akanbi, M, additional, Griffin, H, additional, Douroudis, K, additional, Ayers, K L, additional, Hussein, R I, additional, Hudson, G, additional, Pyle, A, additional, Cordell, H J, additional, Attems, J, additional, McKeith, I G, additional, O'Brien, J T, additional, Burn, D J, additional, Morris, C M, additional, Thomas, A J, additional, and Chinnery, P F, additional
- Published
- 2016
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11. Clinical heterogeneity of primary familial brain calcification due to a novel mutation in PDGFB
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Keogh, M. J., primary, Pyle, A., additional, Daud, D., additional, Griffin, H., additional, Douroudis, K., additional, Eglon, G., additional, Miller, J., additional, Horvath, R., additional, and Chinnery, P. F., additional
- Published
- 2015
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12. Polymorphisms in the ATG16L1 Gene are Associated with Psoriasis Vulgaris
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Douroudis, K, primary, Kingo, K, additional, Traks, T, additional, Reimann, E, additional, Raud, K, additional, Rätsep, R, additional, Mössner, R, additional, Silm, H, additional, Vasar, E, additional, and Kõks, S, additional
- Published
- 2012
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13. The PRO2268 Gene as a Novel Susceptibility Locus for Vitiligo
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Douroudis, K, primary, Kingo, K, additional, Karelson, M, additional, Silm, H, additional, Reimann, E, additional, Traks, T, additional, Vasar, E, additional, and Kõks, S, additional
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- 2011
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14. TheCD226gene in susceptibility of type 1 diabetes
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Douroudis, K., primary, Nemvalts, V., additional, Rajasalu, T., additional, Kisand, K., additional, and Uibo, R., additional
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- 2009
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15. Association of vitamin D receptor gene polymorphisms with bone mineral density in postmenopausal women of Hellenic origin
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Douroudis, K., primary, Tarassi, K., additional, Ioannidis, G., additional, Giannakopoulos, F., additional, Moutsatsou, P., additional, Thalassinos, N., additional, and Papasteriades, Chr., additional
- Published
- 2003
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16. Behr's Syndrome is Typically Associated with Disturbed Mitochondrial Translation and Mutations in the C12orf65 Gene
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Pyle A, Ramesh V, Bartsakoulia M, Boczonadi V, Aurora Gomez-Duran, Herczegfalvi A, El, Blakely, Smertenko T, Duff J, Eglon G, Moore D, Py, Man, Douroudis K, Santibanez-Koref M, Griffin H, Lochmüller H, Karcagi V, Rw, Taylor, Pf, Chinnery, and Horvath R
17. Frequency of rare recessive mutations in unexplained late onset cerebellar ataxia
- Author
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Keogh, MJ, Steele, H, Douroudis, K, Pyle, A, Duff, J, Hussain, R, Smertenko, T, Griffin, H, Santibanez-Koref, M, Horvath, R, and Chinnery, PF
- Subjects
Adult ,Male ,Genes, Recessive ,Sequence Analysis, DNA ,Middle Aged ,3. Good health ,Cohort Studies ,England ,Mutation Rate ,Mutation ,Humans ,Exome ,Female ,Aged ,Spinocerebellar Degenerations - Abstract
Sporadic late onset cerebellar ataxia is a well-described clinical presentation with a broad differential diagnosis that adult neurologists should be familiar with. However, despite extensive clinical investigations, an acquired cause is identified in only a minority of cases. Thereafter, an underlying genetic basis is often considered, even in those without a family history. Here we apply whole exome sequencing to a cohort of 12 patients with late onset cerebellar ataxia. We show that 33% of 'idiopathic' cases harbor compound heterozygous mutations in known ataxia genes, including genes not included on multi-gene panels, or primarily associated with an ataxic presentation.
18. Allelic variants in the PHTF1-PTPN22, C12orf30 and CD226 regions as candidate susceptibility factors for the type 1 diabetes in the Estonian population
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Rajasalu Tarvo, Nemvalts Virge, Kisand Kalle, Douroudis Konstantinos, and Uibo Raivo
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Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Type 1 diabetes is a multifactorial disease with a strong genetic component. The aim of the study was to assess the impact of single nucleotide polymorphisms (SNPs) in several genes as susceptible markers in the risk of type 1 diabetes in the Estonian population. Methods: The rs6679677 (1p13), rs17696736 (12q24) and rs763361 (18q22) were genotyped in a total of 230 controls and 154 type 1 diabetes patients of Estonian origin. Results The rs6679677 A (OR = 2.13, 95%CI = 1.48-3.08, p = 0.00001), rs17696736 G (OR = 1.53, 95%CI = 1.14-2.04, p = 0.0046) and rs763361 T (OR = 1.48, 95%CI = 1.11-1.98, p = 0.0084) alleles were associated with risk of type 1 diabetes. Conclusions The current study supports the rs6679677 (PHTF1-PTPN22), rs17696736 (C12orf30) and rs763361 (CD226) SNPs as susceptibility factors for type 1 diabetes outside the major histocompatibility region (MHC) region. The full study had 80% or above to detect an odds ratio of 1.8 under the assumption of an additive model at type 1 error rate, α = 0.05.
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- 2010
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19. Differences in Clinical Features and Comorbid Burden between HLA-C∗06:02 Carrier Groups in >9,000 People with Psoriasis.
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Douroudis K, Ramessur R, Barbosa IA, Baudry D, Duckworth M, Angit C, Capon F, Chung R, Curtis CJ, Di Meglio P, Goulding JMR, Griffiths CEM, Lee SH, Mahil SK, Parslew R, Reynolds NJ, Shipman AR, Warren RB, Yiu ZZN, Simpson MA, Barker JN, Dand N, and Smith CH
- Subjects
- Alleles, Biomarkers, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Humans, HLA-C Antigens genetics, Psoriasis epidemiology, Psoriasis genetics
- Abstract
The identification of robust endotypes-disease subgroups of clinical relevance-is fundamental to stratified medicine. We hypothesized that HLA-C∗06:02 status, the major genetic determinant of psoriasis, defines a psoriasis endotype of clinical relevance. Using two United Kingdom-based cross-sectional datasets-an observational severe-psoriasis study (Biomarkers of Systemic Treatment Outcomes in Psoriasis; n = 3,767) and a large population-based bioresource (UK Biobank, including n = 5,519 individuals with psoriasis)-we compared demographic, environmental, and clinical variables of interest in HLA-C∗06:02-positive (one or two copies of the HLA-C∗06:02 allele) with those in HLA-C∗06:02‒negative (no copies) individuals of European ancestry. We used multivariable regression analyses to account for mediation effects established a priori. We confirm previous observations that HLA-C∗06:02-positive status is associated with earlier age of psoriasis onset and extend findings to reveal an association with disease expressivity in females (Biomarkers of Systemic Treatment Outcomes in Psoriasis: P = 2.7 × 10
-14 , UK Biobank: P = 1.0 × 10-8 ). We also show HLA-C∗06:02-negative status to be associated with characteristic clinical features (large plaque disease, OR for HLA-C∗06:02 = 0.73, P = 7.4 × 10-4 ; nail involvement, OR = 0.70, P = 2.4 × 10-6 ); higher central adiposity (Biomarkers of Systemic Treatment Outcomes in Psoriasis: waist circumference difference of 2.0 cm, P = 8.4 × 10-4 ; UK Biobank: waist circumference difference of 1.4 cm, P = 1.5 × 10-4 ), especially in women; and a higher prevalence of other cardiometabolic comorbidities. These findings extend the clinical phenotype delineated by HLA-C∗06:02 and highlight its potential as an important biomarker to consider in future multimarker stratified medicine approaches., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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20. Genetic Analysis of Copy Number Variation in Large Chorangiomas.
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Sirotkina M, Douroudis K, Westgren M, and Papadogiannakis N
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- Comparative Genomic Hybridization, Female, Genetic Testing, Gestational Age, Hemangioma pathology, Humans, Placenta pathology, Pregnancy, Segmental Duplications, Genomic genetics, Sequence Deletion, DNA Copy Number Variations genetics, Hemangioma genetics
- Abstract
Introduction: Chorangioma (CA) is the most common nontrophoblastic, vascular tumor-like lesion of the placenta with a reported incidence of 0.5% to 1% in all examined placentas. The underlying molecular mechanisms of CAs are still poorly elucidated, and a systematic investigation of the genetic background of CAs has not previously been done., Materials and Methods: Tissue biopsies from 8 large (>40 mm) histologically confirmed CAs and 8 unaffected matched placenta controls, along with standard control DNA samples were analyzed for large genomic deletions and duplications using array comparative genomic hybridization (array-CGH) method., Results: Array-CGH analysis revealed no rare or novel copy number variants in the CA samples compared with either standard control DNA or unaffected placenta DNA from the same individual., Discussion: In this study, a systematic genetic investigation of 8 large CAs failed to demonstrate any large-scale pathogenic genetic changes. This lack of association might support a nongenetic, nontumorous origin of these lesions; however, additional genetic studies focusing on smaller genomic alterations are required to fully assess any possible genetic contribution.
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- 2019
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21. Exploring the association between chorangioma and infantile haemangioma in singleton and multiple pregnancies: a case-control study in a Swedish tertiary centre.
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Sirotkina M, Douroudis K, Wahlgren CF, Westgren M, and Papadogiannakis N
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- Adult, Case-Control Studies, Female, Humans, Incidence, Infant, Newborn, Logistic Models, Male, Multivariate Analysis, Placenta pathology, Pregnancy, Risk Factors, Sweden epidemiology, Tertiary Care Centers, Hemangioma epidemiology, Pre-Eclampsia epidemiology, Pregnancy Complications, Neoplastic epidemiology, Pregnancy, Multiple statistics & numerical data
- Abstract
Objectives: Placenta or placental chorangioma could be the origin site of infantile haemangioma since they share various histochemical and genetic characteristics with placental vascular tissue. The aim of the current study was to investigate the association between chorangiomas and infantile haemangiomas in singleton and multiple pregnancies., Materials and Methods: An informative questionnaire enquiring about the presence or not of infantile haemangioma and including illustrative photos of haemangioma was sent to 469 (153 cases with chorangioma and 316 controls) mothers of 323 singleton (104 cases and 219 controls) and 146 multiple (49 cases and 97 controls) liveborn neonates registered in Sweden. Overall, 310 mothers (66.1%) from 216 singleton and 94 multiple pregnancies (96 cases and 214 controls) provided feedback and their consent to participate in the current case-control study., Results: The incidence of infantile haemangioma showed no statistically significant differences between cases and controls (18.8% vs 18.2%) or between singleton and multiple pregnancies (18.9% vs 17.0%). The frequency of pre-eclampsia was significantly higher in cases with chorangioma compared with controls (41.7% vs 24.3%, OR=2.22, 95% CI 1.33 to 3.71, p=0.0022) and in singleton compared with multiple pregnancies (33.3% vs 21.3%, OR=1.85, 95% CI 1.04 to 3.26, p=0.034), whereas there were no significant differences in the incidence of infantile haemangioma in neonates of mothers with or without pre-eclampsia or in neonates of mothers with multiple compared with singleton pregnancies., Conclusion: There was no association between placental chorangiomas and infantile haemangiomas. Multiple pregnancies or pre-eclampsia were not significantly related to higher incidence of infantile haemangioma., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
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- 2017
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22. Clinical Outcome in Singleton and Multiple Pregnancies with Placental Chorangioma.
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Sirotkina M, Douroudis K, Papadogiannakis N, and Westgren M
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- Adult, Apgar Score, Female, Gestational Age, Hemangioma complications, Hemangioma diagnosis, Humans, Infant, Newborn, Infant, Small for Gestational Age, Parity, Pre-Eclampsia diagnosis, Pregnancy, Pregnancy Outcome, Risk Factors, Smoking physiopathology, Tumor Burden, Hemangioma pathology, Placenta pathology, Pre-Eclampsia pathology, Pregnancy, Multiple
- Abstract
Introduction: Chorangiomas (CAs) are the most common non-trophoblastic tumor-like-lesions of the placenta. Although the clinical significance of small CAs is unknown, the large lesions are often associated with maternal and fetal complications. The aim of our study was to assess the maternal clinical characteristics and neonatal outcome in singleton and multiple pregnancies with placental CA., Materials and Methods: Among 15742 selected placentas 170 CAs were diagnosed. Pregnancy and neonatal outcomes were analyzed in singleton (n = 121) and multiple (n = 49) pregnancy groups including 121 and 100 neonates, respectively., Results: The frequency of APGAR score <7 at 5 minutes (p = 0,012), abnormal pulsatility index (p = 0,034), and abnormal blood flow class (p = 0,011) were significantly higher in neonates from singleton compared to multiple pregnancies. Significantly smaller CAs in singleton pregnancies were related to small for gestational age neonates (p = 0,00040) and neonates admitted to the neonatal care unit (p = 0,028). In singleton pregnancies, significantly smaller CAs were associated to maternal preeclampsia (p = 0,039) and larger CAs to multiparity (p = 0,005) and smoking (p = 0,001) groups. The frequency of preeclampsia was high in both singleton and multiple pregnancy groups (41,32% vs 26,53%, respectively), however, the difference did not reach the level of statistical significance., Discussion: A high incidence of preeclampsia in cohort of placental CA might lead to a possible recognition of CAs as potential morphologic indicator of placental hypoxia., Conclusion: A more favorable pregnancy outcome in multiple gestations compared to the singleton gestations with CAs might reflect an adaptive mechanism for increased demand of oxygen and associated placental tissue hypoxia in this group., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
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23. Association of chorangiomas to hypoxia-related placental changes in singleton and multiple pregnancy placentas.
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Sirotkina M, Douroudis K, Westgren M, and Papadogiannakis N
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- Adult, Case-Control Studies, Female, Hemangioma pathology, Humans, Hypoxia pathology, Placenta Diseases pathology, Pregnancy, Hemangioma epidemiology, Hypoxia epidemiology, Placenta pathology, Placenta Diseases epidemiology, Pregnancy, Multiple
- Abstract
Introduction: Chorangiomas (CAs) are the most frequent non-trophoblastic tumor-like-lesions of the placenta, and since they occur with an unusual frequency in pregnancies at high altitude, they are considered as a part of a spectrum of hypoxia-related vascular lesions of the placenta. The aim of our study is to describe the morphological features of the CAs and to show associations between CAs and other hypoxia related morphological changes in placentas of singleton and multiple pregnancies., Materials and Methods: Placentas from singleton (121 vs 242) and multiple (49 vs 98) pregnancies, with and without CAs, respectively, were selected from a cohort of 15,742 placentas and enrolled into a case control study., Results: Singleton placentas with CAs showed increased incidence of hypoxia-related placental changes including accelerated maturation of chorionic villi (OR = 2.40, p < 0.001), infarction (OR = 2.89, p < 0.001), decidual arteriopathy (OR = 3.24, p < 0.001), fetal thrombosis (OR = 4.05, p < 0.001) and hypercoiled umbilical cords (OR = 5.55, p < 0.001). The incidence of CAs in multiple placentas was higher in our studied cohort and a significant associated change was shown with fetal thrombosis (OR = 4.58, p = 0.017). There were no significant morphological changes between CAs in singleton compared to multiple pregnancies., Discussion: In singleton placentas, CA is associated with several placental changes related to hypoxia, whereas in multiple pregnancies this relationship is not present. We speculate that CAs in multiple pregnancies might reflect an adaptive mechanism for relative hypoxia per se in these pregnancies., Conclusion: Our study provides evidence that CAs are associated with an increased rate of hypoxia related changes in singleton placentas., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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24. SCP2 mutations and neurodegeneration with brain iron accumulation.
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Horvath R, Lewis-Smith D, Douroudis K, Duff J, Keogh M, Pyle A, Fletcher N, and Chinnery PF
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- Brain pathology, Humans, Male, Middle Aged, Neurodegenerative Diseases diagnosis, Brain metabolism, Carrier Proteins genetics, Iron metabolism, Mutation genetics, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism
- Published
- 2015
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25. Whole exome sequencing and the clinician: we need clinical skills and functional validation in variant filtering.
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Daud D, Griffin H, Douroudis K, Kleinle S, Eglon G, Pyle A, Chinnery PF, and Horvath R
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- Aged, Back Pain complications, Disease Progression, Dynactin Complex, Humans, Kinesins genetics, Male, Microtubule-Associated Proteins genetics, Mutation genetics, Neurofilament Proteins genetics, Sciatica complications, Sciatica genetics, Basal Ganglia Diseases complications, Basal Ganglia Diseases genetics, Movement Disorders complications, Movement Disorders genetics, Sequence Analysis, DNA
- Abstract
Whole exome sequencing (WES) is a recently developed technique in genetics research that attempts to identify causative mutations in complex, undiagnosed genetic conditions. Causative mutations are usually identified after filtering the hundreds of variants on WES from an individual's DNA selected by the phenotype. We investigated a patient with a slowly progressive chronic axonal distal motor neuropathy and extrapyramidal syndrome using WES, in whom common genetic mutations had been excluded. Variant filtering identified potentially deleterious mutations in three known disease genes: DCTN1, KIF5A and NEFH, which have been all associated with similar clinical presentations of amyotrophic lateral sclerosis, Parkinsonism and/or hereditary spastic paraplegia. Predicting the functional effect of the mutations were analysed in parallel with detailed clinical investigations. This case highlights the difficulties and pitfalls of applying WES in patients with complex neurological diseases and serves as an instructive tale.
- Published
- 2015
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26. Phenotypic variability of TRPV4 related neuropathies.
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Evangelista T, Bansagi B, Pyle A, Griffin H, Douroudis K, Polvikoski T, Antoniadi T, Bushby K, Straub V, Chinnery PF, Lochmüller H, and Horvath R
- Subjects
- Charcot-Marie-Tooth Disease pathology, Child, Dwarfism pathology, Female, Humans, Male, Middle Aged, Muscular Atrophy, Spinal pathology, Mutation, Missense, Osteochondrodysplasias pathology, Phenotype, Charcot-Marie-Tooth Disease genetics, Dwarfism genetics, Muscular Atrophy, Spinal genetics, Osteochondrodysplasias genetics, TRPV Cation Channels genetics
- Abstract
Mutations in the transient receptor potential vanilloid 4 (TRPV4) gene have been associated with autosomal dominant skeletal dysplasias and peripheral nervous system syndromes (PNSS). PNSS include Charcot-Marie-Tooth disease (CMT) type 2C, congenital spinal muscular atrophy and arthrogryposis and scapuloperoneal spinal muscular atrophy. We report the clinical, electrophysiological and muscle biopsy findings in two unrelated patients with two novel heterozygous missense mutations in the TRPV4 gene. Whole exome sequencing was carried out on genomic DNA using Illumina Truseq(TM) 62Mb exome capture. Patient 1 harbours a de novo c.805C > T (p.Arg269Cys) mutation. Clinically, this patient shows signs of both scapuloperoneal spinal muscular atrophy and skeletal dysplasia. Patient 2 harbours a novel c.184G > A (p.Asp62Asn) mutation. While the clinical phenotype is compatible with CMT type 2C with the patient's muscle harbours basophilic inclusions. Mutations in the TRPV4 gene have a broad phenotypic variability and disease severity and may share a similar pathogenic mechanism with Heat Shock Protein related neuropathies., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
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27. Respiratory chain deficiency in nonmitochondrial disease.
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Pyle A, Nightingale HJ, Griffin H, Abicht A, Kirschner J, Baric I, Cuk M, Douroudis K, Feder L, Kratz M, Czermin B, Kleinle S, Santibanez-Koref M, Karcagi V, Holinski-Feder E, Chinnery PF, and Horvath R
- Abstract
Objective: In this study, we report 5 patients with heterogeneous phenotypes and biochemical evidence of respiratory chain (RC) deficiency; however, the molecular diagnosis is not mitochondrial disease., Methods: The reported patients were identified from a cohort of 60 patients in whom RC enzyme deficiency suggested mitochondrial disease and underwent whole-exome sequencing., Results: Five patients had disease-causing variants in nonmitochondrial disease genes ORAI1, CAPN3, COLQ, EXOSC8, and ANO10, which would have been missed on targeted next-generation panels or on MitoExome analysis., Conclusions: Our data demonstrate that RC abnormalities may be secondary to various cellular processes, including calcium metabolism, neuromuscular transmission, and abnormal messenger RNA degradation.
- Published
- 2015
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28. Exome sequencing in undiagnosed inherited and sporadic ataxias.
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Pyle A, Smertenko T, Bargiela D, Griffin H, Duff J, Appleton M, Douroudis K, Pfeffer G, Santibanez-Koref M, Eglon G, Yu-Wai-Man P, Ramesh V, Horvath R, and Chinnery PF
- Subjects
- Adolescent, Adult, Age of Onset, Child, Child, Preschool, Computational Biology, Female, Humans, Male, Middle Aged, Mutation genetics, Neurologic Examination, Sequence Analysis, DNA, White People, Young Adult, Exome genetics, Spinocerebellar Degenerations genetics
- Abstract
Inherited ataxias are clinically and genetically heterogeneous, and a molecular diagnosis is not possible in most patients. Having excluded common sporadic, inherited and metabolic causes, we used an unbiased whole exome sequencing approach in 35 affected individuals, from 22 randomly selected families of white European descent. We defined the likely molecular diagnosis in 14 of 22 families (64%). This revealed de novo dominant mutations, validated disease genes previously described in isolated families, and broadened the clinical phenotype of known disease genes. The diagnostic yield was the same in both young and older-onset patients, including sporadic cases. We have demonstrated the impact of exome sequencing in a group of patients notoriously difficult to diagnose genetically. This has important implications for genetic counselling and diagnostic service provision., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2015
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29. Behr's Syndrome is Typically Associated with Disturbed Mitochondrial Translation and Mutations in the C12orf65 Gene.
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Pyle A, Ramesh V, Bartsakoulia M, Boczonadi V, Gomez-Duran A, Herczegfalvi A, Blakely EL, Smertenko T, Duff J, Eglon G, Moore D, Yu-Wai-Man P, Douroudis K, Santibanez-Koref M, Griffin H, Lochmüller H, Karcagi V, Taylor RW, Chinnery PF, and Horvath R
- Abstract
Background: Behr's syndrome is a classical phenotypic description of childhood-onset optic atrophy combined with various neurological symptoms, including ophthalmoparesis, nystagmus, spastic paraparesis, ataxia, peripheral neuropathy and learning difficulties., Objective: Here we describe 4 patients with the classical Behr's syndrome phenotype from 3 unrelated families who carry homozygous nonsense mutations in the C12orf65 gene encoding a protein involved in mitochondrial translation., Methods: Whole exome sequencing was performed in genomic DNA and oxygen consumption was measured in patient cell lines., Results: We detected 2 different homozygous C12orf65 nonsense mutations in 4 patients with a homogeneous clinical presentation matching the historical description of Behr's syndrome. The first symptom in all patients was childhood-onset optic atrophy, followed by spastic paraparesis, distal weakness, motor neuropathy and ophthalmoparesis., Conclusions: We think that C12orf65 mutations are more frequent than previously suggested and screening of this gene should be considered not only in patients with mitochondrial respiratory chain deficiencies, but also in inherited peripheral neuropathies, spastic paraplegias and ataxias, especially with pre-existing optic atrophy.
- Published
- 2014
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30. Identification of seven loci affecting mean telomere length and their association with disease.
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Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J, Buxton JL, Hottenga JJ, Fischer K, Esko T, Surakka I, Broer L, Nyholt DR, Mateo Leach I, Salo P, Hägg S, Matthews MK, Palmen J, Norata GD, O'Reilly PF, Saleheen D, Amin N, Balmforth AJ, Beekman M, de Boer RA, Böhringer S, Braund PS, Burton PR, de Craen AJ, Denniff M, Dong Y, Douroudis K, Dubinina E, Eriksson JG, Garlaschelli K, Guo D, Hartikainen AL, Henders AK, Houwing-Duistermaat JJ, Kananen L, Karssen LC, Kettunen J, Klopp N, Lagou V, van Leeuwen EM, Madden PA, Mägi R, Magnusson PK, Männistö S, McCarthy MI, Medland SE, Mihailov E, Montgomery GW, Oostra BA, Palotie A, Peters A, Pollard H, Pouta A, Prokopenko I, Ripatti S, Salomaa V, Suchiman HE, Valdes AM, Verweij N, Viñuela A, Wang X, Wichmann HE, Widen E, Willemsen G, Wright MJ, Xia K, Xiao X, van Veldhuisen DJ, Catapano AL, Tobin MD, Hall AS, Blakemore AI, van Gilst WH, Zhu H, Erdmann J, Reilly MP, Kathiresan S, Schunkert H, Talmud PJ, Pedersen NL, Perola M, Ouwehand W, Kaprio J, Martin NG, van Duijn CM, Hovatta I, Gieger C, Metspalu A, Boomsma DI, Jarvelin MR, Slagboom PE, Thompson JR, Spector TD, van der Harst P, and Samani NJ
- Subjects
- Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Risk Factors, Biomarkers, Tumor genetics, Disease genetics, Genetic Loci genetics, Leukocytes metabolism, Telomerase genetics, Telomere genetics
- Abstract
Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
- Published
- 2013
- Full Text
- View/download PDF
31. ATG16L1 gene polymorphisms are associated with palmoplantar pustulosis.
- Author
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Douroudis K, Kingo K, Traks T, Rätsep R, Silm H, Vasar E, and Kõks S
- Subjects
- Adult, Aged, Alleles, Autophagy-Related Proteins, Case-Control Studies, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Carrier Proteins genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics, Psoriasis genetics
- Abstract
Genes in autophagy pathway play an important role in innate and adaptive immunity. The aim of the study was to assess the impact of ATG16L1 gene on susceptibility of palmoplantar pustulosis. Four single nucleotide polymorphisms (SNPs) within the ATG16L1 region (rs2241880, rs2241879, rs7587633, and rs13005285) were genotyped in 241 control subjects and 38 palmoplantar pustulosis (PPP) patients of Estonian descent. The data analysis revealed a significantly higher frequency distribution of the rs2241880 G (odds ratio [OR] = 1.88, p = 0.0073) and rs2241879 A (OR = 1.87, p = 0.0079) allele in the PPP group when compared with the control group. The frequency distribution of the GACG haplotype was significantly higher (OR = 1.82, p = 0.016) in the PPP group when compared with the control group. The current study provides evidence of an association of the ATG16L1 gene in susceptibility to palmoplantar pustulosis, and supports the notion that the ATG16L1 gene as a member of the autophagy pathway most likely plays an important role in immune response., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
32. Immunohistochemical expression of the PRO2268 protein in psoriasis vulgaris skin.
- Author
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Douroudis K, Sirotkina M, Kingo K, Mössner R, and Kõks S
- Subjects
- Autoimmunity, Cytokines genetics, Humans, Immunohistochemistry, Inflammation, Proteins genetics, Proteins immunology, Psoriasis genetics, Psoriasis immunology, Skin pathology, Chromosomes, Human, Pair 12 genetics, Multigene Family genetics, Proteins metabolism, Psoriasis metabolism, Skin metabolism
- Abstract
The PRO2268 gene encodes for the PRO2268 molecule and maps to a chromosomal region (12q14), which clusters genes with a key role in immune signaling. Although the PRO2268 protein is as yet of unknown function, we should not exclude the possibility that the PRO2268 gene, because of its location, might have a distinct role in autoimmunity and inflammation. The aim of the present study was to investigate the expression pattern of the PRO2268 protein in psoriasis skin. Formalin-fixed paraffin-embedded sections from normal and psoriasis skin tissue were studied immunohistochemically using custom-ordered antibodies (anti-PRO2268#1 and anti-PRO2268#2) against the PRO2268. The present study revealed an expression of the anti-PRO2268#2 in the inflammatory infiltrate, and suggesting a possible role for the PRO2268 molecule in pathophysiology of psoriasis, which needs further investigation., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
33. The CD226 Gly307Ser gene polymorphism is associated with severity of psoriasis.
- Author
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Douroudis K, Kingo K, Silm H, Reimann E, Traks T, Vasar E, and Kõks S
- Subjects
- Adult, Age of Onset, Alleles, Autoimmunity, Cohort Studies, Female, Gene Frequency, Genotype, Humans, Male, Antigens, Differentiation, T-Lymphocyte biosynthesis, Glycine chemistry, Polymorphism, Genetic, Psoriasis genetics, Serine chemistry
- Published
- 2010
- Full Text
- View/download PDF
34. Allelic variants in the PHTF1-PTPN22, C12orf30 and CD226 regions as candidate susceptibility factors for the type 1 diabetes in the Estonian population.
- Author
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Douroudis K, Kisand K, Nemvalts V, Rajasalu T, and Uibo R
- Subjects
- Adolescent, Adult, Alleles, Case-Control Studies, Estonia, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Major Histocompatibility Complex genetics, Male, Middle Aged, N-Terminal Acetyltransferase B, Odds Ratio, Polymorphism, Single Nucleotide, Risk Factors, Antigens, Differentiation, T-Lymphocyte genetics, Diabetes Mellitus, Type 1 genetics, Homeodomain Proteins genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics, Proteins genetics, Transcription Factors genetics, White People genetics
- Abstract
Background: Type 1 diabetes is a multifactorial disease with a strong genetic component. The aim of the study was to assess the impact of single nucleotide polymorphisms (SNPs) in several genes as susceptible markers in the risk of type 1 diabetes in the Estonian population., Methods: The rs6679677 (1p13), rs17696736 (12q24) and rs763361 (18q22) were genotyped in a total of 230 controls and 154 type 1 diabetes patients of Estonian origin., Results: The rs6679677 A (OR = 2.13, 95%CI = 1.48-3.08, p = 0.00001), rs17696736 G (OR = 1.53, 95%CI = 1.14-2.04, p = 0.0046) and rs763361 T (OR = 1.48, 95%CI = 1.11-1.98, p = 0.0084) alleles were associated with risk of type 1 diabetes., Conclusions: The current study supports the rs6679677 (PHTF1-PTPN22), rs17696736 (C12orf30) and rs763361 (CD226) SNPs as susceptibility factors for type 1 diabetes outside the major histocompatibility region (MHC) region. The full study had 80% or above to detect an odds ratio of 1.8 under the assumption of an additive model at type 1 error rate, alpha = 0.05.
- Published
- 2010
- Full Text
- View/download PDF
35. CTLA-4 promoter polymorphisms are associated with latent autoimmune diabetes in adults.
- Author
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Douroudis K, Prans E, and Uibo R
- Subjects
- Alleles, Antigens, CD immunology, CTLA-4 Antigen, Diabetes Mellitus, Type 1 immunology, Female, Humans, Male, Middle Aged, Antigens, CD genetics, Diabetes Mellitus, Type 1 genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Promoter Regions, Genetic
- Abstract
The cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule is an important regulator of T-cell activation and a susceptibility candidate for autoimmune diseases. To evaluate the impact of CTLA-4 promoter allelic variants of the CTLA-4 gene in latent autoimmune diabetes in adults (LADA), the MH30 (rs231806), -1147 (rs16840252), and -318 (rs5742909) single nucleotide polymorphisms (SNPs) were studied in a population of Estonian origin, including 61 LADA patients and 230 controls. The MH30 GG genotype (p = 0.0051) and the G allele (p = 0.0023) were significantly associated with LADA. The frequency distribution of alleles and genotypes of rs16840252 and rs5742909 SNPs were not significantly different between the patient and control groups. The frequency of the CTLA-4 GCC (p = 0.000073) haplotype was significantly higher in LADA patients, whereas the frequency of the CTLA-4 CCC (p = 0.0019) was significantly lower in LADA patients in comparison with the control group. The current study confirms the involvement of CTLA-4 gene promoter polymorphisms in the susceptibility of LADA and extends our previous findings of associations with other CTLA-4 polymorphisms.
- Published
- 2009
- Full Text
- View/download PDF
36. Association of CTLA4 but not ICOS polymorphisms with type 1 diabetes in two populations with different disease rates.
- Author
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Douroudis K, Laine AP, Heinonen M, Hermann R, Lipponen K, Veijola R, Simell O, Knip M, Uibo R, Ilonen J, and Kisand K
- Subjects
- Adolescent, Adult, Alleles, CTLA-4 Antigen, Child, Diabetes Mellitus, Type 1 epidemiology, Estonia epidemiology, Finland epidemiology, Gene Frequency, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Incidence, Inducible T-Cell Co-Stimulator Protein, Linkage Disequilibrium, Middle Aged, Odds Ratio, Risk Factors, Young Adult, Antigens, CD genetics, Antigens, Differentiation, T-Lymphocyte genetics, Diabetes Mellitus, Type 1 genetics, Polymorphism, Single Nucleotide
- Abstract
Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and inducible T-cell co-stimulator (ICOS) genes are important mediators of T-cell activation in autoimmune diseases. The aim of the current study was to assess the impact of CTLA-4 and ICOS genes on the susceptibility to type 1 diabetes among two populations with different disease incidence rates. Three single nucleotide polymorphisms (SNPs) within the CTLA-4 region (+49A/G, CT60A/G, CTBC217_1C/T) and two SNPs within the ICOS region (CTIC154_1 C/T, CTIC159 C/G) were genotyped in 955 control subjects and 574 diabetic patients of Estonian and Finnish descent. The current study confirms the involvement of the CTLA-4 but not the ICOS gene in susceptibility to type 1 diabetes. However, the risk alleles and the defined main risk haplotype were more common in the Finnish controls compared with the Estonians, indicating that this gene locus might also be one of the contributing factors to the higher disease incidence in Finland.
- Published
- 2009
- Full Text
- View/download PDF
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