Mapping of PARK2 and PACRG Overlapping Regulatory Region Reveals LD Structure and Functional Variants in Association with Leprosy in Unrelated Indian Population Groups

English version České info

Leprosy is a chronic infectious disease caused by Mycobacterium Leprae, where the host genetic background plays an important role toward the disease pathogenesis. Various studies have identified a number of human genes in association with leprosy or its clinical forms. However, non-replication of results has hinted at the heterogeneity among associations between different population groups, which could be due to differently evolved LD structures and differential frequencies of SNPs within the studied regions of the genome. A need for systematic and saturated mapping of the associated regions with the disease is warranted to unravel the observed heterogeneity in different populations. Mapping of the PARK2 and PACRG gene regulatory region with 96 SNPs, with a resolution of 1 SNP per 1 Kb for PARK2 gene regulatory region in a North Indian population, showed an involvement of 11 SNPs in determining the susceptibility towards leprosy. The association was replicated in a geographically distinct and unrelated population from Orissa in eastern India. In vitro reporter assays revealed that the two significantly associated SNPs, located 63.8 kb upstream of PARK2 gene and represented in a single BIN of 8 SNPs, influenced the gene expression. A comparison of BINs between Indian and Vietnamese populations revealed differences in the BIN structures, explaining the heterogeneity and also the reason for non-replication of the associated genomic region in different populations.

Vyšlo v časopise: Mapping of PARK2 and PACRG Overlapping Regulatory Region Reveals LD Structure and Functional Variants in Association with Leprosy in Unrelated Indian Population Groups. PLoS Genet 9(7): e32767. doi:10.1371/journal.pgen.1003578
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003578

Souhrn

Zdroje

1. Hasting R, Opromolla D (1994) Pathology of Leprosy. 2nd edition. Edinburgh: Churchill Livingstone. pp 291.

2. WHO (2010) Global leprosy situation. Wkly Epidemiol Rec 85 : 337–348.

3. FinePE (1983) Natural history of leprosy–aspects relevant to a leprosy vaccine. Int J Lepr Other Mycobact Dis 51 : 553–555.

4. Quintana-MurciL, AlcaisA, AbelL, CasanovaJL (2007) Immunology in natura: clinical, epidemiological and evolutionary genetics of infectious diseases. Nat Immunol 8 : 1165–1171.

5. ModlinRL (1994) Th1–Th2 paradigm: insights from leprosy. J Invest Dermatol 102 : 828–832.

6. MonotM, HonoreN, GarnierT, AraozR, CoppeeJY, et al. (2005) On the origin of leprosy. Science 308 : 1040–1042.

7. ShieldsED, RussellDA, Pericak-VanceMA (1987) Genetic epidemiology of the susceptibility to leprosy. J Clin Invest 79 : 1139–1143.

8. ChakravarttiM, VogelF (1973) A twin study on leprosy. Topics in human genetics. Stuttgart, Germany: Georg Thieme Verlag 1 : 1–123.

9. AbelL, DemenaisF (1988) Detection of major genes for susceptibility to leprosy and its subtypes in a Caribbean island: Desirade island. Am J Hum Genet 42 : 256–266.

10. AbelL, VuDL, ObertiJ, NguyenVT, VanVC, et al. (1995) Complex segregation analysis of leprosy in southern Vietnam. Genet Epidemiol 12 : 63–82.

11. ToddJR, WestBC, McDonaldJC (1990) Human leukocyte antigen and leprosy: study in northern Louisiana and review. Rev Infect Dis 12 : 63–74.

12. WongSH, GochhaitS, MalhotraD, PetterssonFH, TeoYY, et al. (2010) Leprosy and the adaptation of human toll-like receptor 1. PLoS Pathog 6: e1000979.

13. ZhangFR, HuangW, ChenSM, SunLD, LiuH, et al. (2009) Genomewide association study of leprosy. N Engl J Med 361 : 2609–2618.

14. MoraesMO, CardosoCC, VanderborghtPR, PachecoAG (2006) Genetics of host response in leprosy. Lepr Rev 77 : 189–202.

15. ZhangF, LiuH, ChenS, WangC, ZhuC, et al. (2009) Evidence for an association of HLA-DRB1*15 and DRB1*09 with leprosy and the impact of DRB1*09 on disease onset in a Chinese Han population. BMC Med Genet 10 : 133.

16. AlcaisA, AlterA, AntoniG, OrlovaM, NguyenVT, et al. (2007) Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy. Nat Genet 39 : 517–522.

17. SchuringRP, HamannL, FaberWR, PahanD, RichardusJH, et al. (2009) Polymorphism N248S in the human Toll-like receptor 1 gene is related to leprosy and leprosy reactions. J Infect Dis 199 : 1816–1819.

18. BochudPY, HawnTR, SiddiquiMR, SaundersonP, BrittonS, et al. (2008) Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. J Infect Dis 197 : 253–261.

19. SiddiquiMR, MeisnerS, ToshK, BalakrishnanK, GheiS, et al. (2001) A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nat Genet 27 : 439–441.

20. MiraMT, AlcaisA, Van ThucN, ThaiVH, HuongNT, et al. (2003) Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat Genet 33 : 412–415.

21. JamiesonSE, MillerEN, BlackGF, PeacockCS, CordellHJ, et al. (2004) Evidence for a cluster of genes on chromosome 17q11–q21 controlling susceptibility to tuberculosis and leprosy in Brazilians. Genes Immun 5 : 46–57.

22. ToshK, MeisnerS, SiddiquiMR, BalakrishnanK, GheiS, et al. (2002) A region of chromosome 20 is linked to leprosy susceptibility in a South Indian population. J Infect Dis 186 : 1190–1193.

23. MiraMT, AlcaisA, NguyenVT, MoraesMO, Di FlumeriC, et al. (2004) Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427 : 636–640.

24. ShimuraH, HattoriN, KuboS, MizunoY, AsakawaS, et al. (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25 : 302–305.

25. SchurrE, AlcaisA, de LeseleucL, AbelL (2006) Genetic predisposition to leprosy: A major gene reveals novel pathways of immunity to Mycobacterium leprae. Semin Immunol 18 : 404–410.

26. MalhotraD, DarvishiK, LohraM, KumarH, GroverC, et al. (2006) Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population. Eur J Hum Genet 14 : 438–442.

27. LiJ, LiuH, LiuJ, FuX, YuY, et al. (2012) Association study of the single nucleotide polymorphisms of PARK2 and PACRG with leprosy susceptibility in Chinese population. Eur J Hum Genet 20 : 488–489.

28. PakstisAJ, SpeedWC, FangR, HylandFC, FurtadoMR, et al. (2010) SNPs for a universal individual identification panel. Hum Genet 127 : 315–324.

29. AlterA, FavaVM, HuongNT, SinghM, OrlovaM, et al. (2012) Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy. Hum Genet

30. TanEK, PuongKY, ChanDK, YewK, Fook-ChongS, et al. (2005) Impaired transcriptional upregulation of Parkin promoter variant under oxidative stress and proteasomal inhibition: clinical association. Hum Genet 118 : 484–488.

31. WestAB, MaraganoreD, CrookJ, LesnickT, LockhartPJ, et al. (2002) Functional association of the parkin gene promoter with idiopathic Parkinson's disease. Hum Mol Genet 11 : 2787–2792.

32. MatysV, FrickeE, GeffersR, GosslingE, HaubrockM, et al. (2003) TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res 31 : 374–378.

33. WardLD, KellisM (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40: D930–934.

34. MarinI, LucasJI, GradillaAC, FerrusA (2004) Parkin and relatives: the RBR family of ubiquitin ligases. Physiol Genomics 17 : 253–263.

35. Abou-SleimanPM, MuqitMM, WoodNW (2006) Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci 7 : 207–219.

36. GreeneJC, WhitworthAJ, AndrewsLA, ParkerTJ, PallanckLJ (2005) Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis. Hum Mol Genet 14 : 799–811.

37. ChenZJ (2005) Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7 : 758–765.

38. ChuangTH, UlevitchRJ (2004) Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors. Nat Immunol 5 : 495–502.

39. LiuYC, PenningerJ, KarinM (2005) Immunity by ubiquitylation: a reversible process of modification. Nat Rev Immunol 5 : 941–952.

40. MuellerDL (2004) E3 ubiquitin ligases as T cell anergy factors. Nat Immunol 5 : 883–890.

41. Garcia-CovarrubiasL, ManningEW3rd, SorellLT, PhamSM, MajetschakM (2008) Ubiquitin enhances the Th2 cytokine response and attenuates ischemia-reperfusion injury in the lung. Crit Care Med 36 : 979–982.

42. MajetschakM (2011) Extracellular ubiquitin: immune modulator and endogenous opponent of damage-associated molecular pattern molecules. J Leukoc Biol 89 : 205–219.

43. MajetschakM, KrehmeierU, BardenheuerM, DenzC, QuintelM, et al. (2003) Extracellular ubiquitin inhibits the TNF-alpha response to endotoxin in peripheral blood mononuclear cells and regulates endotoxin hyporesponsiveness in critical illness. Blood 101 : 1882–1890.

44. PatelMB, MajetschakM (2007) Distribution and interrelationship of ubiquitin proteasome pathway component activities and ubiquitin pools in various porcine tissues. Physiol Res 56 : 341–350.

45. SainiV, RomeroJ, MarcheseA, MajetschakM (2010) Ubiquitin receptor binding and signaling in primary human leukocytes. Commun Integr Biol 3 : 608–610.

46. SinghM, RoginskayaM, DalalS, MenonB, KaverinaE, et al. (2010) Extracellular ubiquitin inhibits beta-AR-stimulated apoptosis in cardiac myocytes: role of GSK-3beta and mitochondrial pathways. Cardiovasc Res 86 : 20–28.

47. RidleyDS, JoplingWH (1966) Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis 34 : 255–273.

48. BarrettJC, FryB, MallerJ, DalyMJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21 : 263–265.

49. AggarwalS, AliS, ChopraR, SrivastavaA, KalaiarasanP, et al. (2011) Genetic variations and interactions in anti-inflammatory cytokine pathway genes in the outcome of leprosy: a study conducted on a MassARRAY platform. J Infect Dis 204 : 1264–1273.

50. AliS, ChopraR, AggarwalS, SrivastavaAK, KalaiarasanP, et al. (2012) Association of variants in BAT1-LTA-TNF-BTNL2 genes within 6p21.3 region show graded risk to leprosy in unrelated cohorts of Indian population. Hum Genet 131 : 703–716.