#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Family-based genome-wide association study of leprosy in Vietnam


Autoři: Chaima Gzara aff001;  Monica Dallmann-Sauer aff003;  Marianna Orlova aff003;  Nguyen Van Thuc aff006;  Vu Hong Thai aff006;  Vinicius M. Fava aff003;  Marie-Thérèse Bihoreau aff007;  Anne Boland aff007;  Laurent Abel aff001;  Alexandre Alcaïs aff001;  Erwin Schurr aff003;  Aurélie Cobat aff001
Působiště autorů: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France aff001;  Université de Paris, Imagine Institute, Paris, France aff002;  McGill International TB Centre, Montreal, QC, Canada aff003;  Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada aff004;  Department of Medicine and Human Genetics, Faculty of Medicine, McGill University, Montreal, QC, Canada aff005;  Hospital for Dermato-Venereology, District, Ho Chi Minh City, Vietnam aff006;  Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France aff007;  St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States of America aff008
Vyšlo v časopise: Family-based genome-wide association study of leprosy in Vietnam. PLoS Pathog 16(5): e32767. doi:10.1371/journal.ppat.1008565
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008565

Souhrn

Leprosy is a chronic infectious disease of the skin and peripheral nerves with a strong genetic predisposition. Recent genome-wide approaches have identified numerous common variants associated with leprosy, almost all in the Chinese population. We conducted the first family-based genome-wide association study of leprosy in 622 affected offspring from Vietnam, followed by replication in an independent sample of 1181 leprosy cases and 668 controls of the same ethnic origin. The most significant results were observed within the HLA region, in which six SNPs displayed genome-wide significant associations, all of which were replicated in the independent case/control sample. We investigated the signal in the HLA region in more detail, by conducting a multivariate analysis on the case/control sample of 319 GWAS-suggestive HLA hits for which evidence for replication was obtained. We identified three independently associated SNPs, two located in the HLA class I region (rs1265048: OR = 0.69 [0.58–0.80], combined p-value = 5.53x10-11; and rs114598080: OR = 1.47 [1.46–1.48], combined p-value = 8.77x10-13), and one located in the HLA class II region (rs3187964 (OR = 1.67 [1.55–1.80], combined p-value = 8.35x10-16). We also validated two previously identified risk factors for leprosy: the missense variant rs3764147 in the LACC1 gene (OR = 1.52 [1.41–1.63], combined p-value = 5.06x10-14), and the intergenic variant rs6871626 located close to the IL12B gene (OR = 0.73 [0.61–0.84], combined p-value = 6.44x10-8). These results shed new light on the genetic control of leprosy, by dissecting the influence of HLA SNPs, and validating the independent role of two additional variants in a large Vietnamese sample.

Klíčová slova:

Genetic loci – Genome-wide association studies – Genomics statistics – Genotyping – Inflammatory bowel disease – Leprosy – Molecular genetics – Variant genotypes


Zdroje

1. Smith WC, van Brakel W, Gillis T, Saunderson P, Richardus JH. The missing millions: a threat to the elimination of leprosy. PLoS Negl Trop Dis. 2015;9(4):e0003658. Epub 2015/04/24. doi: 10.1371/journal.pntd.0003658 25905706; PubMed Central PMCID: PMC4408099.

2. Gaschignard J, Grant AV, Thuc NV, Orlova M, Cobat A, Huong NT, et al. Pauci- and Multibacillary Leprosy: Two Distinct, Genetically Neglected Diseases. PLoS Negl Trop Dis. 2016;10(5):e0004345. doi: 10.1371/journal.pntd.0004345 27219008; PubMed Central PMCID: PMC4878860.

3. Cole ST, Eiglmeier K, Parkhill J, James KD, Thomson NR, Wheeler PR, et al. Massive gene decay in the leprosy bacillus. Nature. 2001;409(6823):1007–11. Epub 2001/03/10. doi: 10.1038/35059006 11234002.

4. Monot M, Honore N, Garnier T, Araoz R, Coppee JY, Lacroix C, et al. On the origin of leprosy. Science. 2005;308(5724):1040–2. Epub 2005/05/17. doi: 10.1126/science/1109759 15894530.

5. Fava VM, Dallmann-Sauer M, Schurr E. Genetics of leprosy: today and beyond. Hum Genet. 2019. Epub 2019/11/13. doi: 10.1007/s00439-019-02087-5 31713021.

6. Mira MT, Alcais A, Van Thuc N, Thai VH, Huong NT, Ba NN, et al. Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat Genet. 2003;33(3):412–5. Epub 2003/02/11. doi: 10.1038/ng1096 12577057.

7. Mira MT, Alcais A, Nguyen VT, Moraes MO, Di Flumeri C, Vu HT, et al. Susceptibility to leprosy is associated with PARK2 and PACRG. Nature. 2004;427(6975):636–40. Epub 2004/01/23. doi: 10.1038/nature02326 14737177.

8. Alcais A, Alter A, Antoni G, Orlova M, Nguyen VT, Singh M, et al. Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy. Nat Genet. 2007;39(4):517–22. Epub 2007/03/14. doi: 10.1038/ng2000 17353895.

9. Zhang FR, Huang W, Chen SM, Sun LD, Liu H, Li Y, et al. Genomewide association study of leprosy. N Engl J Med. 2009;361(27):2609–18. Epub 2009/12/19. doi: 10.1056/NEJMoa0903753 20018961.

10. Zhang F, Liu H, Chen S, Low H, Sun L, Cui Y, et al. Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy. Nat Genet. 2011;43(12):1247–51. Epub 2011/10/25. doi: 10.1038/ng.973 22019778.

11. Liu H, Irwanto A, Fu X, Yu G, Yu Y, Sun Y, et al. Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy. Nat Genet. 2015;47(3):267–71. Epub 2015/02/03. doi: 10.1038/ng.3212 25642632.

12. Wang Z, Sun Y, Fu X, Yu G, Wang C, Bao F, et al. A large-scale genome-wide association and meta-analysis identified four novel susceptibility loci for leprosy. Nat Commun. 2016;7:13760. Epub 2016/12/16. doi: 10.1038/ncomms13760 27976721; PubMed Central PMCID: PMC5172377.

13. Wong SH, Gochhait S, Malhotra D, Pettersson FH, Teo YY, Khor CC, et al. Leprosy and the adaptation of human toll-like receptor 1. PLoS Pathog. 2010;6:e1000979. Epub 2010/07/10. doi: 10.1371/journal.ppat.1000979 20617178; PubMed Central PMCID: PMC2895660.

14. Liu H, Wang Z, Li Y, Yu G, Fu X, Wang C, et al. Genome-Wide Analysis of Protein-Coding Variants in Leprosy. J Invest Dermatol. 2017;137(12):2544–51. Epub 2017/08/27. doi: 10.1016/j.jid.2017.08.004 28842327.

15. Wang Z, Mi Z, Wang H, Sun L, Yu G, Fu X, et al. Discovery of 4 exonic and 1 intergenic novel susceptibility loci for leprosy. Clin Genet. 2018;94(2):259–63. Epub 2018/05/04. doi: 10.1111/cge.13376 29722023.

16. Wang D, Fan Y, Malhi M, Bi R, Wu Y, Xu M, et al. Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese. Am J Hum Genet. 2018;102(5):794–805. Epub 2018/05/01. doi: 10.1016/j.ajhg.2018.03.006 29706348; PubMed Central PMCID: PMC5986702.

17. Dallmann-Sauer M, Correa-Macedo W, Schurr E. Human genetics of mycobacterial disease. Mamm Genome. 2018;29(7–8):523–38. Epub 2018/08/18. doi: 10.1007/s00335-018-9765-4 30116885; PubMed Central PMCID: PMC6132723.

18. Cambri G, Mira MT. Genetic Susceptibility to Leprosy-From Classic Immune-Related Candidate Genes to Hypothesis-Free, Whole Genome Approaches. Front Immunol. 2018;9:1674. Epub 2018/08/07. doi: 10.3389/fimmu.2018.01674 30079069; PubMed Central PMCID: PMC6062607.

19. Cobat A, Abel L, Alcais A, Schurr E. A general efficient and flexible approach for genome-wide association analyses of imputed genotypes in family-based designs. Genet Epidemiol. 2014;38(6):560–71. Epub 2014/07/22. doi: 10.1002/gepi.21842 25044438.

20. Grant AV, Alter A, Huong NT, Orlova M, Van Thuc N, Ba NN, et al. Crohn's disease susceptibility genes are associated with leprosy in the Vietnamese population. J Infect Dis. 2012;206(11):1763–7. Epub 2012/09/18. doi: 10.1093/infdis/jis588 22984114.

21. Fava VM, Cobat A, Van Thuc N, Latini AC, Stefani MM, Belone AF, et al. Association of TNFSF8 regulatory variants with excessive inflammatory responses but not leprosy per se. J Infect Dis. 2015;211(6):968–77. Epub 2014/10/17. doi: 10.1093/infdis/jiu566 25320285.

22. Fava VM, Manry J, Cobat A, Orlova M, Van Thuc N, Ba NN, et al. A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy. PLoS Negl Trop Dis. 2016;10(2):e0004412. doi: 10.1371/journal.pntd.0004412 26844546; PubMed Central PMCID: PMC4742274.

23. Fava VM, Xu YZ, Lettre G, Van Thuc N, Orlova M, Thai VH, et al. Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson's disease. Proc Natl Acad Sci U S A. 2019;116(31):15616–24. Epub 2019/07/17. doi: 10.1073/pnas.1901805116 31308240; PubMed Central PMCID: PMC6681704.

24. Fava VM, Manry J, Cobat A, Orlova M, Van Thuc N, Moraes MO, et al. A genome wide association study identifies a lncRna as risk factor for pathological inflammatory responses in leprosy. PLoS Genet. 2017;13(2):e1006637. doi: 10.1371/journal.pgen.1006637 28222097; PubMed Central PMCID: PMC5340414.

25. Teo YY, Inouye M, Small KS, Gwilliam R, Deloukas P, Kwiatkowski DP, et al. A genotype calling algorithm for the Illumina BeadArray platform. Bioinformatics. 2007;23(20):2741–6. Epub 2007/09/12. doi: 10.1093/bioinformatics/btm443 17846035; PubMed Central PMCID: PMC2666488.

26. Purcell S, Chang C. PLINK 1.9. Available from: www.cog-genomics.org/plink/1.9/.

27. Delaneau O, Marchini J, Zagury JF. A linear complexity phasing method for thousands of genomes. Nat Methods. 2011;9(2):179–81. Epub 2011/12/06. doi: 10.1038/nmeth.1785 22138821.

28. O'Connell J, Gurdasani D, Delaneau O, Pirastu N, Ulivi S, Cocca M, et al. A general approach for haplotype phasing across the full spectrum of relatedness. PLoS Genet. 2014;10(4):e1004234. Epub 2014/04/20. doi: 10.1371/journal.pgen.1004234 24743097; PubMed Central PMCID: PMC3990520.

29. Marchini J, Howie B, Myers S, McVean G, Donnelly P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet. 2007;39(7):906–13. Epub 2007/06/19. doi: 10.1038/ng2088 17572673.

30. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7. Epub 2015/02/28. doi: 10.1186/s13742-015-0047-8 25722852; PubMed Central PMCID: PMC4342193.

31. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–8. Epub 2011/04/12. doi: 10.1038/ng.806 21478889; PubMed Central PMCID: PMC3083463.

32. Laird NM, Horvath S, Xu X. Implementing a unified approach to family-based tests of association. Genet Epidemiol. 2000;19 Suppl 1:S36–42. doi: 10.1002/1098-2272(2000)19:1+<::AID-GEPI6>3.0.CO;2-M 11055368.

33. Cordell HJ, Barratt BJ, Clayton DG. Case/pseudocontrol analysis in genetic association studies: A unified framework for detection of genotype and haplotype associations, gene-gene and gene-environment interactions, and parent-of-origin effects. Genet Epidemiol. 2004;26(3):167–85. Epub 2004/03/17. doi: 10.1002/gepi.10307 15022205.

34. Grant AV, El Baghdadi J, Sabri A, El Azbaoui S, Alaoui-Tahiri K, Abderrahmani Rhorfi I, et al. Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region. Am J Hum Genet. 2013;92(3):407–14. Epub 2013/02/19. doi: 10.1016/j.ajhg.2013.01.013 23415668; PubMed Central PMCID: PMC3591857.

35. Grant AV, Sabri A, Abid A, Abderrahmani Rhorfi I, Benkirane M, Souhi H, et al. A genome-wide association study of pulmonary tuberculosis in Morocco. Hum Genet. 2016;135(3):299–307. Epub 2016/01/16. doi: 10.1007/s00439-016-1633-2 26767831; PubMed Central PMCID: PMC5042142.

36. Wellcome Trust Case Control C. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661–78. Epub 2007/06/08. doi: 10.1038/nature05911 17554300; PubMed Central PMCID: PMC2719288.

37. Karczewski Konrad J., Francioli Laurent C., Tiao Grace, Cummings Beryl B., Jessica Alföldi Qingbo Wang, et al. Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. bioRXiv. 2019. https://doi.org/10.1101/531210.

38. Machiela MJ, Chanock SJ. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2015;31(21):3555–7. Epub 2015/07/04. doi: 10.1093/bioinformatics/btv402 26139635; PubMed Central PMCID: PMC4626747.

39. Zhang X, Cheng Y, Zhang Q, Wang X, Lin Y, Yang C, et al. Meta-Analysis Identifies Major Histocompatiblity Complex Loci in or Near HLA-DRB1, HLA-DQA1, HLA-C as Associated with Leprosy in Chinese Han Population. J Invest Dermatol. 2019;139(4):957–60. Epub 2018/11/06. doi: 10.1016/j.jid.2018.09.029 30389493.

40. Jarduli LR, Sell AM, Reis PG, Sippert EA, Ayo CM, Mazini PS, et al. Role of HLA, KIR, MICA, and cytokines genes in leprosy. Biomed Res Int. 2013;2013:989837. Epub 2013/08/13. doi: 10.1155/2013/989837 23936864; PubMed Central PMCID: PMC3722889.

41. Krause-Kyora B, Nutsua M, Boehme L, Pierini F, Pedersen DD, Kornell SC, et al. Ancient DNA study reveals HLA susceptibility locus for leprosy in medieval Europeans. Nat Commun. 2018;9(1):1569. Epub 2018/05/03. doi: 10.1038/s41467-018-03857-x 29717136; PubMed Central PMCID: PMC5931558.

42. Matzaraki V, Kumar V, Wijmenga C, Zhernakova A. The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biol. 2017;18(1):76. Epub 2017/04/30. doi: 10.1186/s13059-017-1207-1 28449694; PubMed Central PMCID: PMC5406920.

43. Parks T, Elliott K, Lamagni T, Auckland K, Mentzer AJ, Guy R, et al. Elevated risk of invasive group A streptococcal disease and host genetic variation in the human leucocyte antigen locus. Genes Immun. 2019. Epub 2019/08/30. doi: 10.1038/s41435-019-0082-z 31462703.

44. Barreiro LB, Quintana-Murci L. From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet. 2010;11(1):17–30. doi: 10.1038/nrg2698 19953080.

45. Manry J, Vincent QB, Johnson C, Chrabieh M, Lorenzo L, Theodorou I, et al. Genome-wide association study of Buruli ulcer in rural Benin highlights role of two LncRNAs and the autophagy pathway. Commun Biol. 2020;3(1):177.

46. Alter A, Huong NT, Singh M, Orlova M, Van Thuc N, Katoch K, et al. Human leukocyte antigen class I region single-nucleotide polymorphisms are associated with leprosy susceptibility in Vietnam and India. J Infect Dis. 2011;203(9):1274–81. Epub 2011/04/05. doi: 10.1093/infdis/jir024 21459816; PubMed Central PMCID: PMC3069725.

47. Luo Y, Na Z, Slavoff SA. P-Bodies: Composition, Properties, and Functions. Biochemistry. 2018;57(17):2424–31. Epub 2018/01/31. doi: 10.1021/acs.biochem.7b01162 29381060; PubMed Central PMCID: PMC6296482.

48. Parker R, Sheth U. P bodies and the control of mRNA translation and degradation. Mol Cell. 2007;25(5):635–46. doi: 10.1016/j.molcel.2007.02.011 17349952.

49. Yu X, Li B, Jang GJ, Jiang S, Jiang D, Jang JC, et al. Orchestration of Processing Body Dynamics and mRNA Decay in Arabidopsis Immunity. Cell Rep. 2019;28(8):2194–205 e6. doi: 10.1016/j.celrep.2019.07.054 31433992; PubMed Central PMCID: PMC6716526.

50. Radzisheuskaya A, Chia Gle B, dos Santos RL, Theunissen TW, Castro LF, Nichols J, et al. A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages. Nat Cell Biol. 2013;15(6):579–90. Epub 2013/05/01. doi: 10.1038/ncb2742 23629142; PubMed Central PMCID: PMC3671976.

51. Wong SH, Hill AV, Vannberg FO, India-Africa-United Kingdom Leprosy Genetics C. Genomewide association study of leprosy. N Engl J Med. 2010;362(15):1446–7; author reply 7–8. Epub 2010/04/16. doi: 10.1056/NEJMc1001451 20393182.

52. Xiong JH, Mao C, Sha XW, Jin Z, Wang H, Liu YY, et al. Association between genetic variants in NOD2, C13orf31, and CCDC122 genes and leprosy among the Chinese Yi population. Int J Dermatol. 2016;55(1):65–9. Epub 2015/08/04. doi: 10.1111/ijd.12981 26235265.

53. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40(8):955–62. Epub 2008/07/01. doi: 10.1038/ng.175 18587394; PubMed Central PMCID: PMC2574810.

54. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet. 2010;42(12):1118–25. Epub 2010/11/26. doi: 10.1038/ng.717 21102463; PubMed Central PMCID: PMC3299551.

55. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24. Epub 2012/11/07. doi: 10.1038/nature11582 23128233; PubMed Central PMCID: PMC3491803.

56. Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979–86. Epub 2015/07/21. doi: 10.1038/ng.3359 26192919; PubMed Central PMCID: PMC4881818.

57. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5. Epub 2014/02/04. doi: 10.1038/ng.2892 24487276; PubMed Central PMCID: PMC3992975.

58. Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47(D1):D886–D94. Epub 2018/10/30. doi: 10.1093/nar/gky1016 30371827; PubMed Central PMCID: PMC6323892.

59. Cader MZ, Boroviak K, Zhang Q, Assadi G, Kempster SL, Sewell GW, et al. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nat Immunol. 2016;17(9):1046–56. Epub 2016/08/02. doi: 10.1038/ni.3532 27478939; PubMed Central PMCID: PMC6581540.

60. Lahiri A, Hedl M, Yan J, Abraham C. Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes. Nat Commun. 2017;8:15614. Epub 2017/06/09. doi: 10.1038/ncomms15614 28593945; PubMed Central PMCID: PMC5472760.

61. Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43(3):246–52. Epub 2011/02/08. doi: 10.1038/ng.764 21297633; PubMed Central PMCID: PMC3084597.

62. Raychaudhuri S, Plenge RM, Rossin EJ, Ng AC, International Schizophrenia C, Purcell SM, et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 2009;5(6):e1000534. Epub 2009/06/27. doi: 10.1371/journal.pgen.1000534 19557189; PubMed Central PMCID: PMC2694358.

63. Boisson-Dupuis S, Ramirez-Alejo N, Li Z, Patin E, Rao G, Kerner G, et al. Tuberculosis and impaired IL-23-dependent IFN-gamma immunity in humans homozygous for a common TYK2 missense variant. Sci Immunol. 2018;3(30). Epub 2018/12/24. doi: 10.1126/sciimmunol.aau8714 30578352; PubMed Central PMCID: PMC6341984.

64. Martinez-Barricarte R, Markle JG, Ma CS, Deenick EK, Ramirez-Alejo N, Mele F, et al. Human IFN-gamma immunity to mycobacteria is governed by both IL-12 and IL-23. Sci Immunol. 2018;3(30). Epub 2018/12/24. doi: 10.1126/sciimmunol.aau6759 30578351; PubMed Central PMCID: PMC6380365.

65. Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity. Semin Immunol. 2014;26(6):454–70. Epub 2014/12/03. doi: 10.1016/j.smim.2014.09.008 25453225; PubMed Central PMCID: PMC4357480.

66. International Genetics of Ankylosing Spondylitis C, Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet. 2013;45(7):730–8. Epub 2013/06/12. doi: 10.1038/ng.2667 23749187; PubMed Central PMCID: PMC3757343.

67. Terao C, Yoshifuji H, Kimura A, Matsumura T, Ohmura K, Takahashi M, et al. Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population. Am J Hum Genet. 2013;93(2):289–97. Epub 2013/07/09. doi: 10.1016/j.ajhg.2013.05.024 23830516; PubMed Central PMCID: PMC3738822.

68. Nakajima T, Yoshifuji H, Shimizu M, Kitagori K, Murakami K, Nakashima R, et al. A novel susceptibility locus in the IL12B region is associated with the pathophysiology of Takayasu arteritis through IL-12p40 and IL-12p70 production. Arthritis Res Ther. 2017;19(1):197. Epub 2017/09/07. doi: 10.1186/s13075-017-1408-8 28874185; PubMed Central PMCID: PMC5585951.


Článek vyšel v časopise

PLOS Pathogens


2020 Číslo 5
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Důležitost adherence při depresivním onemocnění
nový kurz
Autoři: MUDr. Eliška Bartečková, Ph.D.

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Všechny kurzy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#