A non-synonymous polymorphism in IL-23R Gene (rs1884444) is associated with reduced risk to schistosomiasis-associated Immune Reconstitution Inflammatory Syndrome in a Kenyan population

BMC Infectious Diseases

Pauline N Mwinzi³  Robert Colebunders²  Erick O Muok³  Walter GZO Jura¹  Collins Ouma¹  George O Ogola¹ 

[1] Maseno University, Maseno, Kenya;Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium;Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya

关键词: Schistosomiasis;    SNP;    Non-synonymous;    IRIS;    HAART;   

Others  :  1127580
DOI  :  10.1186/1471-2334-14-316

 received in 2014-01-21, accepted in 2014-05-29,  发布年份 2014

【 摘 要 】

Background

Human Immunodeficiency Virus (HIV) and Schistosomiasis co-infection is common among residents at the shores of Lake Victoria in Kenya. About 36% of this population initiating antiretroviral therapy (ART) experience Immune Reconstitution Inflammatory Syndrome (IRIS) that complicates recovery. Several IL-23R alleles have been associated with susceptibility to both autoimmune and inflammatory diseases through T-helper type 17 (TH₁₇) cells. However, whether or not variants within the IL-23R increase susceptibility to IRIS in western Kenya is unknown. The objective of the current study was to determine the association between IL-23R gene polymorphisms, CD4+ cell counts and HIV RNA levels and IRIS in HIV and Schistosoma mansoni co-infected patients undergoing highly active anti-retroviral therapy (HAART).

Methods

A three-month case–control study was conducted on antiretroviral naïve schistosomiasis/HIV co-infected fishermen starting HAART in Uyoma Rarieda, Siaya County, Kenya. Seventy one patients were sampled at baseline and followed up for three months, to establish if they developed Schistosoma-related IRIS. In addition, the CD4+ cell counts and HIV RNA levels were determined in pre- and post-administration of HAART. Variations at five polymorphic sites of IL-23R (rs1884444, rs11465754, rs6682925, rs7530511 and rs7539625) based on >10% minor allele frequency in Yoruban reference population was determined using Allelic Discrimination Assay. The association between the five variants and susceptibility to IRIS was determined using logistic regression while controlling for potential confounders. In addition, the functional differences between the baseline CD4 + Cell counts and viral loads were determined using medians while across IL-23R genotypes were determined using Kruskal-Wallis tests.

Results

Overall, 26 (36.6%) patients developed schistosomiasis-associated IRIS at a median age of 35.5 years. Carriage of the TT genotype at the non-synonymous rs1884444 T > G relative to GG, was associated with a decreased risk of schistosomiasis-associated IRIS (OR, 0.25, 95% CI, 0.07-0.96, P = 0.043) while both baseline CD4+ cell counts and viral loads had no association with IRIS.

Conclusion

These findings indicate that the non-synonymous variant rs1884444 T > G of IL-23R is associated with a decreased risk to schistosomiasis-associated IRIS. However, additional studies in a larger cohort and with an all inclusive polymorphic variants in the synonymous and non-synonymous regions need to be evaluated.

【 授权许可】

   
2014 Ogola et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]World AIDS day East Mediterr Health J 2011, 17(12):901.
• [2]Murdoch DM, Venter WD, Feldman C, Van Rie A: Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 2008, 22(5):601-610.
• [3]Kumarasamy N, Chaguturu S, Mayer KH, Solomon S, Yepthomi HT, Balakrishnan P, Flanigan TP: Incidence of immune reconstitution syndrome in HIV/tuberculosis-coinfected patients after initiation of generic antiretroviral therapy in India. J Acquir Immune Defic Syndr 2004, 37(5):1574-1576.
• [4]Smith K, Kuhn L, Coovadia A, Meyers T, Hu CC, Reitz C, Barry G, Strehlau R, Sherman G, Abrams EJ: Immune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy. AIDS 2009, 23(9):1097-1107.
• [5]Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White AC Jr, Hamill RJ: Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005, 19(4):399-406.
• [6]Jevtovic DJ, Salemovic D, Ranin J, Pesic I, Zerjav S, Djurkovic-Djakovic O: The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretroviral therapy. HIV Med 2005, 6(2):140-143.
• [7]Lawn SD, Bekker LG, Miller RF: Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005, 5(6):361-373.
• [8]Lawn SD, Myer L, Bekker LG, Wood R: Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 2007, 21(3):335-341.
• [9]Shelburne SA, Montes M, Hamill RJ: Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother 2006, 57(2):167-170.
• [10]Puthanakit T, Oberdorfer P, Akarathum N, Wannarit P, Sirisanthana T, Sirisanthana V: Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected thai children. Pediatr Infect Dis J 2006, 25(1):53-58.
• [11]Stoll M, Schmidt RE: Adverse events of desirable gain in immunocompetence: the Immune Restoration Inflammatory Syndromes. Autoimmun Rev 2004, 3(4):243-249.
• [12]Stoll M, Schmidt RE: Immune restoration inflammatory syndromes: apparently paradoxical clinical events after the initiation of HAART. Curr HIV/AIDS Rep 2004, 1(3):122-127.
• [13]Dhasmana DJ, Dheda K, Ravn P, Wilkinson RJ, Meintjes G: Immune reconstitution inflammatory syndrome in HIV-infected patients receiving antiretroviral therapy: pathogenesis, clinical manifestations and management. Drugs 2008, 68(2):191-208.
• [14]Haddow LJ, Colebunders R, Meintjes G, Lawn SD, Elliott JH, Manabe YC, Bohjanen PR, Sungkanuparph S, Easterbrook PJ, French MA, Boulware DR, International Network for the Study of HIV-associated IRIS (INSHI): Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis 2010, 10(11):791-802.
• [15]Lawn SD, Wood R: Immune reconstitution inflammatory syndrome. Lancet Infect Dis 2010, 10(12):833-834.
• [16]Price P, Mathiot N, Krueger R, Stone S, Keane NM, French MA: Immune dysfunction and immune restoration disease in HIV patients given highly active antiretroviral therapy. J Clin Virol 2001, 22(3):279-287.
• [17]Price P, Morahan G, Huang D, Stone E, Cheong KY, Castley A, Rodgers M, McIntyre MQ, Abraham LJ, French MA: Polymorphisms in cytokine genes define subpopulations of HIV-1 patients who experienced immune restoration diseases. AIDS 2002, 16(15):2043-2047.
• [18]Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O'Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW: A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 2002, 168(11):5699-5708.
• [19]Lankford CS, Frucht DM: A unique role for IL-23 in promoting cellular immunity. J Leukoc Biol 2003, 73(1):49-56.
• [20]Iwakura Y, Nakae S, Saijo S, Ishigame H: The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev 2008, 226:57-79.
• [21]Romagnani S: Human Th17 cells. Arthritis Res Ther 2008, 10(2):206. BioMed Central Full Text
• [22]Langrish CL, McKenzie BS, Wilson NJ, de Waal Malefyt R, Kastelein RA, Cua DJ: IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev 2004, 202:96-105.
• [23]Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, Soars D, Drummond H, Lees CW, Khawaja SA, Bagnall R, Burke DA, Todhunter CE, Ahmad T, Onnie CM, McArdle W, Strachan D, Bethel G, Bryan C, Lewis CM, Deloukas P, Forbes A, Sanderson J, Jewell DP, Satsangi J, Mansfield JC, Cardon L, Mathew CG, Wellcome Trust Case Control Consortium, et al.: Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet 2007, 39(7):830-832.
• [24]Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, Matsunami N, Ardlie KG, Civello D, Catanese JJ, Leong DU, Panko JM, McAllister LB, Hansen CB, Papenfuss J, Prescott SM, White TJ, Leppert MF, Krueger GG, Begovich AB: A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 2007, 80(2):273-290.
• [25]Van Limbergen J, Russell RK, Nimmo ER, Drummond HE, Smith L, Davies G, Anderson NH, Gillett PM, McGrogan P, Hassan K, Weaver L, Bisset WM, Mahdi G, Wilson DC, Satsangi J: IL23R Arg381Gln is associated with childhood onset inflammatory bowel disease in Scotland. Gut 2007, 56(8):1173-1174.
• [26]Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH: A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006, 314(5804):1461-1463.
• [27]Huffmeier U, Lascorz J, Bohm B, Lohmann J, Wendler J, Mossner R, Reich K, Traupe H, Kurrat W, Burkhardt H, Reis A: Genetic variants of the IL-23R pathway: association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis. J Invest Dermatol 2009, 129(2):355-358.
• [28]Ouma C, Davenport GC, Awandare GA, Keller CC, Were T, Otieno MF, Vulule JM, Martinson J, Ong'echa JM, Ferrell RE, Perkins DJ: Polymorphic variability in the interleukin (IL)-1beta promoter conditions susceptibility to severe malarial anemia and functional changes in IL-1beta production. J Infect Dis 2008, 198(8):1219-1226.
• [29]Ouma C, Keller CC, Davenport GC, Were T, Konah S, Otieno MF, Hittner JB, Vulule JM, Martinson J, Ong'echa JM, Ferrell RE, Perkins DJ: A novel functional variant in the stem cell growth factor promoter protects against severe malarial anemia. Infect Immun 2010, 78(1):453-460.
• [30]Haase AT: Perils at mucosal front lines for HIV and SIV and their hosts. Nat Rev Immunol 2005, 5(10):783-792.
• [31]Jurriaans S, Van Gemen B, Weverling GJ, Van Strijp D, Nara P, Coutinho R, Koot M, Schuitemaker H, Goudsmit J: The natural history of HIV-1 infection: virus load and virus phenotype independent determinants of clinical course? Virology 1994, 204(1):223-233.
• [32]Yates A, Stark J, Klein N, Antia R, Callard R: Understanding the slow depletion of memory CD4+ T cells in HIV infection. PLoS Med 2007, 4(5):e177.
• [33]Karanja DM, Boyer AE, Strand M, Colley DG, Nahlen BL, Ouma JH, Secor WE: Studies on schistosomiasis in western Kenya: II. Efficacy of praziquantel for treatment of schistosomiasis in persons coinfected with human immunodeficiency virus-1. Am J Trop Med Hyg 1998, 59(2):307-311.
• [34]Karanja DM, Colley DG, Nahlen BL, Ouma JH, Secor WE: Studies on schistosomiasis in western Kenya: I. Evidence for immune-facilitated excretion of schistosome eggs from patients with Schistosoma mansoni and human immunodeficiency virus coinfections. Am J Trop Med Hyg 1997, 56(5):515-521.
• [35]Mwinzi PN, Karanja DM, Colley DG, Orago AS, Secor WE: Cellular immune responses of schistosomiasis patients are altered by human immunodeficiency virus type 1 coinfection. J Infect Dis 2001, 184(4):488-496.
• [36]Watanabe K, Mwinzi PN, Black CL, Muok EM, Karanja DM, Secor WE, Colley DG: T regulatory cell levels decrease in people infected with Schistosoma mansoni on effective treatment. Am J Trop Med Hyg 2007, 77(4):676-682.
• [37]Peters PA, El Alamy M, Warren KS, Mahmoud AA: Quick Kato smear for field quantification of Schistosoma mansoni eggs. Am J Trop Med Hyg 1980, 29(2):217-219.
• [38]de Silva S, Walsh J, Brown M: Symptomatic Schistosoma mansoni infection as an immune restoration phenomenon in a patient receiving antiretroviral therapy. Clin Infect Dis 2006, 42(2):303-304.
• [39]Pietschmann P, Gollob E, Brosch S, Hahn P, Kudlacek S, Willheim M, Woloszczuk W, Peterlik M, Tragl KH: The effect of age and gender on cytokine production by human peripheral blood mononuclear cells and markers of bone metabolism. Exp Gerontol 2003, 38(10):1119-1127.
• [40]Kan SH, Mancini G, Gallagher G: Identification and characterization of multiple splice forms of the human interleukin-23 receptor alpha chain in mitogen-activated leukocytes. Genes Immun 2008, 9(7):631-639.
• [41]Rutitzky LI, Bazzone L, Shainheit MG, Joyce-Shaikh B, Cua DJ, Stadecker MJ: IL-23 is required for the development of severe egg-induced immunopathology in schistosomiasis and for lesional expression of IL-17. J Immunol 2008, 180(4):2486-2495.
• [42]Rutitzky LI, Stadecker MJ: CD4 T cells producing pro-inflammatory interleukin-17 mediate high pathology in schistosomiasis. Mem Inst Oswaldo Cruz 2006, 101(Suppl 1):327-330.
• [43]Smith PM, Shainheit MG, Bazzone LE, Rutitzky LI, Poltorak A, Stadecker MJ: Genetic control of severe egg-induced immunopathology and IL-17 production in murine schistosomiasis. J Immunol 2009, 183(5):3317-3323.
• [44]Haddow LJ, Moosa MY, Mosam A, Moodley P, Parboosing R, Easterbrook PJ: Incidence, clinical spectrum, risk factors and impact of HIV-associated immune reconstitution inflammatory syndrome in South Africa. PLoS One 2012, 7(11):e40623.