دورية أكاديمية
Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy
| العنوان: | Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy |
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| المؤلفون: | Esslinger, U, Garnier, S, Korniat, A, Proust, C, Kararigas, G, Mueller-Nurasyid, M, Empana, J-P, Morley, MP, Perret, C, Stark, K, Bick, AG, Prasad, SK, Kriebel, J, Li, J, Tiret, L, Strauch, K, O'Regan, DP, Marguiles, KB, Seidman, JG, Boutouyrie, P, Lacolley, P, Jouven, X, Hengstenberg, C, Komajda, M, Hakonarson, H, Isnard, R, Arbustini, E, Grallert, H, Cook, SA, Seidman, CE, Regitz-Zagrosek, V, Cappola, TP, Charron, P, Cambien, F, Villard, E |
| المساهمون: | Fondation Leducq, National Institute for Health Research, British Heart Foundation, Wellcome Trust, Department of Health |
| بيانات النشر: | PUBLIC LIBRARY OF SCIENCE |
| سنة النشر: | 2017 |
| المجموعة: | Imperial College London: Spiral |
| مصطلحات موضوعية: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, SKELETAL-MUSCLES, COMMON VARIANTS, HEART-FAILURE, P19CL6 CELLS, PROTEIN, MUTATIONS, HSPB7, FHOD3, DIFFERENTIATION, ARCHITECTURE, General Science & Technology, MD Multidisciplinary |
| الوصف: | Aims: Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Methods and results: 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here. Conclusion: We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1932-6203 |
| العلاقة: | PLOS ONE; http://hdl.handle.net/10044/1/45990Test; https://dx.doi.org/10.1371/journal.pone.0172995Test; 11 CVD-01; RDB02 79560; PG/12/27/29489; HICF-R6-373 |
| DOI: | 10.1371/journal.pone.0172995 |
| الإتاحة: | https://doi.org/10.1371/journal.pone.0172995Test http://hdl.handle.net/10044/1/45990Test |
| حقوق: | © 2017 The Author(s). This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmi tted, modifie d, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0Test/) public domain dedication. |
| رقم الانضمام: | edsbas.5DD9042 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 19326203 |
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| DOI: | 10.1371/journal.pone.0172995 |