#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects


The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.


Vyšlo v časopise: Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects. PLoS Genet 9(11): e32767. doi:10.1371/journal.pgen.1003926
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003926

Souhrn

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.


Zdroje

1. RamagopalanSV, KnightJC, EbersGC (2009) Multiple sclerosis and the major histocompatibility complex. Curr Opin Neurol 22: 219–225.

2. FernandoMM, StevensCR, WalshEC, De JagerPL, GoyetteP, et al. (2008) Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet 4: e1000024.

3. OksenbergJR, BarcellosLF, CreeBA, BaranziniSE, BugawanTL, et al. (2004) Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 74: 160–167.

4. StewartGJ, TeutschSM, CastleM, HeardRN, BennettsBH (1997) HLA-DR, -DQA1 and -DQB1 associations in Australian multiple sclerosis patients. Eur J Immunogenet 24: 81–92.

5. MarrosuMG, MurruMR, CostaG, MurruR, MuntoniF, et al. (1998) DRB1-DQA1-DQB1 loci and multiple sclerosis predisposition in the Sardinian population. Hum Mol Genet 7: 1235–1237.

6. de BakkerPI, McVeanG, SabetiPC, MirettiMM, GreenT, et al. (2006) A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 38: 1166–1172.

7. SawcerS, HellenthalG, PirinenM, SpencerCC, PatsopoulosNA, et al. (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476: 214–219.

8. PereyraF, JiaX, McLarenPJ, TelentiA, de BakkerPI, et al. (2010) The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330: 1551–1557.

9. FieldJ, BrowningSR, JohnsonLJ, DanoyP, VarneyMD, et al. (2010) A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis. PLoS One 5: e13454.

10. SimpsonEH (1951) The Interpretation of Interaction in Contingency Tables. J R Stat Soc Series B 13: 238–241.

11. RajT, KuchrooM, ReplogleJM, RaychaudhuriS, StrangerBE, et al. (2013) Common risk alleles for inflammatory diseases are targets of recent positive selection. Am J Hum Genet 92: 517–529.

12. BernsteinBE, BirneyE, DunhamI, GreenED, GunterC, et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57–74.

13. Roadmap Epigenomics Project. http://www.roadmapepigenomics.org.

14. ErnstJ, KellisM (2012) ChromHMM: automating chromatin-state discovery and characterization. Nat Methods 9: 215–216.

15. KaushanskyN, AltmannDM, AscoughS, DavidCS, LassmannH, et al. (2009) HLA-DQB1*0602 determines disease susceptibility in a new “humanized” multiple sclerosis model in HLA-DR15 (DRB1*1501;DQB1*0602) transgenic mice. J Immunol 183: 3531–3541.

16. KaushanskyN, AltmannDM, DavidCS, LassmannH, Ben-NunA (2012) DQB1*0602 rather than DRB1*1501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP). J Neuroinflammation 9: 29.

17. BrynedalB, DuvefeltK, JonasdottirG, RoosIM, AkessonE, et al. (2007) HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS One 2: e664.

18. Fogdell-HahnA, LigersA, GronningM, HillertJ, OlerupO (2000) Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease. Tissue Antigens 55: 140–148.

19. BergamaschiL, BanM, BarizzoneN, LeoneM, FerranteD, et al. (2011) Association of HLA class I markers with multiple sclerosis in the Italian and UK population: evidence of two independent protective effects. J Med Genet 48: 485–492.

20. CreeBA, RiouxJD, McCauleyJL, GourraudPA, GoyetteP, et al. (2010) A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01. PLoS One 5: e11296.

21. HealyBC, LiguoriM, TranD, ChitnisT, GlanzB, et al. (2010) HLA B*44: protective effects in MS susceptibility and MRI outcome measures. Neurology 75: 634–640.

22. RiouxJD, GoyetteP, VyseTJ, HammarstromL, FernandoMM, et al. (2009) Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proc Natl Acad Sci U S A 106: 18680–18685.

23. YeoTW, De JagerPL, GregorySG, BarcellosLF, WaltonA, et al. (2007) A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann Neurol 61: 228–236.

24. Fernandez-MoreraJL, Rodriguez-RoderoS, TunonA, Martinez-BorraJ, Vidal-CastineiraJR, et al. (2008) Genetic influence of the nonclassical major histocompatibility complex class I molecule MICB in multiple sclerosis susceptibility. Tissue Antigens 72: 54–59.

25. AllcockRJ, de la ConchaEG, Fernandez-ArqueroM, VigilP, ConejeroL, et al. (1999) Susceptibility to multiple sclerosis mediated by HLA-DRB1 is influenced by a second gene telomeric of the TNF cluster. Hum Immunol 60: 1266–1273.

26. GlasJ, MartinK, BrunnlerG, KoppR, FolwacznyC, et al. (2001) MICA, MICB and C1_4_1 polymorphism in Crohn's disease and ulcerative colitis. Tissue Antigens 58: 243–249.

27. Lopez-ArbesuR, Ballina-GarciaFJ, Alperi-LopezM, Lopez-SotoA, Rodriguez-RoderoS, et al. (2007) MHC class I chain-related gene B (MICB) is associated with rheumatoid arthritis susceptibility. Rheumatology (Oxford) 46: 426–430.

28. BolstadAI, Le HellardS, KristjansdottirG, VasaitisL, KvarnstromM, et al. (2012) Association between genetic variants in the tumour necrosis factor/lymphotoxin alpha/lymphotoxin beta locus and primary Sjogren's syndrome in Scandinavian samples. Ann Rheum Dis 71: 981–988.

29. ShichiD, KikkawaEF, OtaM, KatsuyamaY, KimuraA, et al. (2005) The haplotype block, NFKBIL1-ATP6V1G2-BAT1-MICB-MICA, within the class III-class I boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus-associated dilated cardiomyopathy. Tissue Antigens 66: 200–208.

30. De JagerPL, JiaX, WangJ, de BakkerPI, OttoboniL, et al. (2009) Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 41: 776–782.

31. AllenM, Sandberg-WollheimM, SjogrenK, ErlichHA, PettersonU, et al. (1994) Association of susceptibility to multiple sclerosis in Sweden with HLA class II DRB1 and DQB1 alleles. Hum Immunol 39: 41–48.

32. Saruhan-DireskeneliG, EsinS, Baykan-KurtB, OrnekI, VaughanR, et al. (1997) HLA-DR and -DQ associations with multiple sclerosis in Turkey. Hum Immunol 55: 59–65.

33. TeutschSM, BennettsBH, BuhlerMM, HeardRN, StewartGJ (1999) The DRB1 Val86/Val86 genotype associates with multiple sclerosis in Australian patients. Hum Immunol 60: 715–722.

34. WucherpfennigKW, SetteA, SouthwoodS, OseroffC, MatsuiM, et al. (1994) Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. J Exp Med 179: 279–290.

35. VerreckFA, TermijtelenA, KoningF (1993) HLA-DR beta chain residue 86 controls DR alpha beta dimer stability. Eur J Immunol 23: 1346–1350.

36. BarcellosLF, SawcerS, RamsayPP, BaranziniSE, ThomsonG, et al. (2006) Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Hum Mol Genet 15: 2813–2824.

37. RamagopalanSV, McMahonR, DymentDA, SadovnickAD, EbersGC, et al. (2009) An extension to a statistical approach for family based association studies provides insights into genetic risk factors for multiple sclerosis in the HLA-DRB1 gene. BMC Med Genet 10: 10.

38. RaychaudhuriS, SandorC, StahlEA, FreudenbergJ, LeeHS, et al. (2012) Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 44: 291–296.

39. PatsopoulosNA, EspositoF, ReischlJ, LehrS, BauerD, et al. (2011) Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann Neurol 70: 897–912.

40. HaflerDA, CompstonA, SawcerS, LanderES, DalyMJ, et al. (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357: 851–862.

41. (ANZgene) AaNZMSGC (2009) Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet 41: 824–828.

42. BrowningBL, BrowningSR (2009) A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 84: 210–223.

43. TibshiraniR (1996) Regression shrinkage and selection via the lasso. J Royal Statist Soc B 58: 267–288.

44. ZouHH (2005) T (2005) Regularization and variable selection via the elastic net. J R Stat Soc Series B Stat Methodol 67: 301–320.

45. EfronBHT (2012) JohnstoneI (2012) TibshiraniR (2012) Least angle regression. Ann Stat 32: 407–499.

46. HastieTTJ (2007) TibshiraniR (2007) WaltherG (2007) Forward stagewise regression and the monotone lasso. Electron J Stat 1: 1–29.

47. NagelkerkeN (1991) A note on a general definition of the coefficient of determination. Biometrika 78: 691–692.

48. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.

49. PettersenEF, GoddardTD, HuangCC, CouchGS, GreenblattDM, et al. (2004) UCSF Chimera–a visualization system for exploratory research and analysis. J Comput Chem 25: 1605–1612.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2013 Číslo 11
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#