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

Abstract

BackgroundHuman 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).MethodsA 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.ResultsOverall, 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.ConclusionThese 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.

Aberrant plasma MMP and TIMP dynamics in Schistosoma - Immune reconstitution inflammatory syndrome (IRIS)

“…fishing villages along the shores of Lake Victoria. Areas such as these could form focal-points of IRIS development, as demonstrated previously in a Kenyan cohort with ~36% of Schistosomiasis-HIV patients on ART developing worsening schistosomiasis symptoms consistent with IRIS [ 11 ]. Thus, while perhaps not as prevalent as IRIS associated with tuberculosis (TB-IRIS) [ 3 , 12 ], the clinical burden of Schisto-IRIS in the field should not be underestimated.…”

“…Patients from a prospective case-control study at the fishing community in Uyoma, Rarieda District, Kenya, were studied as described previously [ 10 , 11 ]. The study focused on a group of permanent residents that are occupationally-exposed to water infested with the infective stage of the Schistosoma mansoni parasite ( S1 Fig ).…”

“…mansoni , followed by successful PZQ treatment in close proximity to ART initiation (and eggs were no longer detectable during the next visit) [ 7 ]. Based on a clinical Schisto-IRIS description used previously [ 11 ], symptoms were re-evaluated according to frequency and relevance, and classified as “major” or “minor” symptoms. Schisto + HIV + patients were diagnosed with paradoxical Schisto-IRIS when presenting with at least 2 major, or 1 major and 3 minor re-emerging symptoms of otherwise successfully treated schistosomiasis during ART.…”

“…Since I-FABP is used as a marker for damage to the intestinal epithelium, we further hypothesized that persisting levels of I-FABP could be associated with intestinal symptoms associated with Schisto-IRIS. Using samples collected from Schistosoma mansoni-HIV co-infected fishermen starting ART in Kenya [ 11 ], we conducted a nested 3-month case-control analysis of plasma MMPs, TIMPs, ANAs, sCD14, and I-FABP among those who developed Schisto-IRIS.…”

Functional Polymorphisms in Interleukin-23 Receptor and Susceptibility to Coronary Artery Disease

“…The IL-23R rs1884444T/G polymorphism is associated with various diseases. It has been reported that rs1884444 is correlated with reduced risk to schistosomiasis-associated immune reconstitution inflammatory syndrome in a Kenyan population (Ogola et al, 2014). This SNP can be found in the Chinese population as well.…”