Successful HCV Therapy Reduces Liver Disease Severity and Inflammation Biomarkers in HIV/HCV-Coinfected Patients With Advanced Cirrhosis: A Cohort Study.

Background: Eradication of hepatitis C virus (HCV) promotes an improvement in liver disease and the deactivation of the immune system. Here, we aimed to evaluate the changes in liver disease scores and plasma biomarkers following HCV clearance with direct-acting antivirals (DAAs) in HIV-infected patients with advanced HCV-related cirrhosis. Methods: We performed an observational study of 50 patients with advanced cirrhosis who received DAAs therapy. Variables were assessed at baseline and 48 weeks after HCV treatment completion. Epidemiological and clinical data were collected through an online form. Liver stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and Child-Pugh-Turcotte (CTP) were evaluated by physicians. Plasma biomarkers were measured by multiplex immunoassay. Results: We found significant decreases in severity scores of liver disease [LSM (q-value < 0.001), HVPG (q-value = 0.011), and CTP (q-value = 0.045)] and plasma biomarkers [LBP (q-value < 0.001), IP-10 (q-value < 0.001), IL-8 (q-value < 0.001), IL-18 (q-value < 0.001), IL-1RA (q-value = 0.013), OPG (q-value < 0.001), sVCAM-1 (q-value < 0.001), sICAM-1 (q-value < 0.001), PAI-1 (q-value = 0.001), and VEGF-A (q-value = 0.006)]. We also found a significant direct association between the change in LSM values and the change in values of LBP (q-value < 0.001), IP-10 (q-value < 0.001), MCP-1 (q-value = 0.008), IL-8 (q-value < 0.001), IL-18 (q-value < 0.001), OPG (q-value = 0.004), sVCAM-1 (q-value < 0.001), sICAM-1 (q-value < 0.001), and PAI-1 (q-value = 0.002). For CTP values, we found significant positive associations with IP-10 (q-value = 0.010), IL-6 (q-value = 0.010), IL-1RA (q-value = 0.033), and sICAM-1 (q-value = 0.010). Conclusion: The HCV eradication with all-oral DAAs in HIV/HCV-coinfected patients with advanced cirrhosis promoted an improvement in the severity of advanced cirrhosis and plasma biomarkers (inflammation, coagulopathy, and angiogenesis). The decrease in plasma biomarkers was mainly related to the reduction in LSM values.

Near normalization of peripheral blood markers in HIV-infected patients on long-term suppressive antiretroviral therapy: a case-control study.

OBJECTIVE: To explore the differences in peripheral blood markers between HIV well controlled patients on long-term suppressive antiretroviral therapy (HIV-group) and age-matched healthy controls, to evaluate the benefits of virological suppression in those patients. METHODS: We performed a case-control study in 22 individuals in the HIV-group and 14 in the healthy control-group. RNA-seq analysis was performed from peripheral blood mononuclear cells. Peripheral blood T-cell subsets were evaluated by flow cytometry and plasma biomarkers by immunoassays. All P values were corrected by the false discovery rate (q values). RESULTS: Only the serine/arginine repetitive matrix 4 gene, which is involved in alternative RNA splicing events, was differentially expressed between HIV and healthy control groups (q value ≤0.05 and fold-change ≥2). However, 147 differentially expressed genes were found with a more relaxed threshold (P value ≤0.05 and fold-change ≥1.5), of which 67 genes with values of variable importance in projection at least one were selected for pathway analysis. We found that six ribosomal genes represented significant ribosome-related pathways, all of them downregulated in the HIV-group, which may be a strategy to facilitate viral production. T cells subset and plasma biomarkers did not show significant differences after false discovery rate correction (q value >0.05), but a noncorrected analysis showed higher values of regulatory CD4 T cells (CD4CD25CD127), MCP-1, and sVEGF-R1 in the HIV-group (P value ≤0.05). CONCLUSION: T-cell subsets, plasma biomarkers, and gene expression were close to normalization in HIV-infected patients on long-term suppressive combination antiretroviral therapy compared with healthy controls. However, residual alterations remain, mainly at the gene expression, which still reveals the impact of HIV infection in these patients.

Plasma IP-10 and IL-6 are linked to Child-Pugh B cirrhosis in patients with advanced HCV-related cirrhosis: a cross-sectional study.

We aimed to evaluate the association of plasma biomarkers linked to inflammation (bacterial translocation, inflammatory response, and endothelial dysfunction), coagulopathy, and angiogenesis with the severity of liver cirrhosis (assessed by the Child-Pugh-Turcotte score, CTP) and Child-Pugh B cirrhosis (CTP 7-9) in patients with advanced hepatitis C virus (HCV)-related cirrhosis. We carried out a cross-sectional study in 97 patients with advanced HCV-related cirrhosis (32 HCV-monoinfected and 65 HIV/HCV-coinfected). Plasma biomarkers were measured by ProcartaPlex multiplex immunoassays. The outcome variable was the CTP score and the Child-Pugh B cirrhosis (CTP 7-9). HIV/HCV-coinfected patients and HCV-monoinfected patients with advanced HCV-related cirrhosis had near-equivalent values of plasma biomarkers. Higher values of plasma biomarkers linked to an inflammatory response (IP-10, IL-8, IL-6, and OPG), endothelial dysfunction (sVCAM-1 and sICAM-1), and coagulopathy (D-dimer) were related to higher CTP values. The most significant biomarkers to detect the presence of Child-Pugh B cirrhosis (CTP 7-9) were IP-10 (p-value= 0.008) and IL-6 (p-value=0.002). The AUC-ROC values of IP-10, IL-6, and both biomarkers combined (IP-10+IL-6) were 0.78, 0.88, and 0.96, respectively. In conclusion, HIV infection does not appear to have a significant impact on the analyzed plasma biomarkers in patients with advanced HCV-related cirrhosis. However, plasma biomarkers linked to inflammation (inflammatory response and endothelial dysfunction) were related to the severity of liver cirrhosis (CTP score), mainly IP-10 and IL-6, which discriminated patients with Child-Pugh B concerning Child-Pugh A.

Mild profile improvement of immune biomarkers in HIV/HCV-coinfected patients who removed hepatitis C after HCV treatment: A prospective study.

OBJECTIVE: There are a lack of consistency among articles in regards to the evolution of peripheral immune biomarkers after HCV therapy. We aimed to detect the most relevant changes in peripheral immune biomarkers among HIV/HCV-coinfected patients who achieved sustained virologic response (SVR) following peg-IFN-α/ribavirin therapy and to evaluate its normalization with respect to an HIV-monoinfected control group. METHODS: We performed a prospective cohort study in 99 HIV/HCV-coinfected patients with samples at baseline (HIV/HCV-b-group) and at week 24 after SVR (HIV/HCV-f-group). We also used a control group of 39 HIV-monoinfected patients (HIV-group) negative for HCV and HBV infections, and who had undetectable HIV viral load and CD4+ >500 cells/mm3. Peripheral T cell subsets were assessed by flow cytometry and plasma biomarkers by immunoassays. RESULTS: HIV/HCV-coinfected patients had higher values of in IL-10, IL-4, IP-10, IL-8, IL-1ß, IL-18, IL-6, IFN-γ, IL-12p70, TNF-α, sVCAM-1, sICAM-1, and sTNFR-1 than HIV control subjects, both at the beginning and at the end of follow-up. Moreover, three biomarkers (CD4+CD38+, telomere length, and IL-1RA) were normalized in relation to the control group at the end of follow-up (the HIV/HCV-b group had higher values and the HIV/HCV-f group had similar values as the HIV-group). Additionally, LPS, IL-2, and IL-17A levels were higher in the HIV/HCV-f group than the HIV-group (24 weeks after SVR). During the follow-up, HIV/HCV-coinfected patients had a significant decrease by the end of follow-up in CD8+CD45RA-CD28+, CD4+CD38+, CD4+CD25+CD127-/low, CD4+CD25+CD127-/low CD45RA-, FABP2, LBP, IP-10, sVCAM1. Only CD4+CD38+ was normalized. CONCLUSION: HIV/HCV-patients showed a slight improvement in the overall profile of immune biomarkers after achieving SVR.

Genetic variants upstream of TNFAIP3 in the 6q23 region are associated with liver disease severity in HIV/HCV-coinfected patients: A cross-sectional study.

BACKGROUND: TNFAIP3 is a crucial hepatoprotective factor due to its anti-inflammatory, anti-apoptotic, anti-oxidant and pro-regenerative functions. The aim of this study was to analyze the associations between genetic variants upstream of TNFAIP3 (rs675520, rs9376293 and rs6920220) and liver fibrosis severity and inflammation in HIV/HCV-coinfected patients. METHODS: A cross-sectional study was carried out in 215 HIV/HCV-coinfected patients, who underwent a liver biopsy. TNFAIP3 polymorphisms were genotyped using GoldenGate® assay. Outcome variables were: a) liver fibrosis (Metavir score) [fibrosis stage (F0, F1, F2, F3 and F4) and advanced fibrosis and cirrhosis (F ≥ 3 and F4, respectively)]; b) non-invasive indexes [FIB-4, APRI, and their cut-offs (FIB-4 ≥ 3.25 and APRI≥1.5)]; c) inflammation-related biomarkers (leptin, HGF, NGF, sFasL, sFas, MIF, HA, Ang-2, TIMP1, MMP1 and MMP2). RESULTS: Patients with rs675520 AG/GG genotypes had decreased odds of having cirrhosis (F4) and advanced fibrosis (FIB-4 ≥ 3.25 and APRI≥1.5) [adjusted Odd Ratio (aOR) = 0.30 (p = 0.025), aOR = 0.20 (p = 0.014), and aOR = 0.34 (p = 0.017), respectively] and lower levels of FIB-4 and APRI [adjusted arithmetic mean ratio (aAMR) = 0.76 (p = 0.003) and aAMR = 0.72 (p = 0.006), respectively]. Patients with rs9376293 CT/CC genotypes had decreased odds of APRI≥1.5 [aOR = 0.39 (p = 0.030)] and lower levels of APRI [aAMR = 0.77 (p = 0.018)]. Patients with rs6920220 AG/AA genotypes had higher odds of having FIB-4 ≥ 3.25 [aOR = 3.72 (p = 0.043)]. Moreover, rs675520 AG/GG genotypes, compared to AA genotype, were associated with lower levels of leptin and NGF (p = 0.002 and p = 0.001, respectively) and higher levels of sFas, MIF, TIMP1 and MMP2 (p = 0.004, p = 0.007, p = 0.020 and p = 0.036, respectively). Also, rs9376293 CT/CC genotypes were related to lower leptin levels (p = 0.026) and higher sFas, MIF, TIMP1 and MMP2 levels (p = 0.029, p = 0.040, p = 0.022 and p = 0.024, respectively). CONCLUSIONS: Genetic variants upstream of TNFAIP3 were associated with the liver fibrosis severity and inflammation in HIV/HCV-coinfected patients.

Expression patterns common and unique to ulcerative colitis and celiac disease.

Autoimmune diseases like celiac disease (CeD) and ulcerative colitis (UC) show a common genetic background defined by the existence of shared susceptibility loci. We aimed to go deeper into this common genetic background through performing a cross-disease study based on gene expression. We measured the expression of 21 genes located in 13 CeD-UC susceptibility regions, and 10 genes in five CeD risk regions. Determinations were carried out in colon/rectum samples from 13 UC patients (inflamed and uninflamed tissue) and four colon samples from controls. Duodenal samples from 19 CeD patients and 12 controls were used for comparisons. Differences were analyzed using the Bayesian method. The shared chromosomal regions containing TNFAIP3, PTPN2, ICOSLG, C1orf106, and IL21 showed similar results in both diseases. FASLG, PLEK, CCR4, and TAGAP, all located in CeD risk loci, were up-regulated in both CeD and UC patients. Finally, ZFP36L1, ZMIZ1, PUS10, UBE2L3, and BACH2 showed opposite results in CeD and UC. A high complexity underlies autoimmune common susceptibility loci, as the expression pattern of the studied genes does not always correlate with the one expected attending to the apparent genetic background. Differentially expressed genes such as ZFP36L1, ZMIZ1, PUS10, and BACH2 deserve further research in autoimmune diseases.

Dysregulation of the Immune System in HIV/HCV-Coinfected Patients According to Liver Stiffness Status.

BACKGROUND: Advanced cirrhosis is related to alterations in immunity. We aimed to evaluate the levels of peripheral CD4⁺ T cells (Tregs) and plasma cytokine in patients coinfected with human immunodeficiency virus and hepatitis C virus (HIV/HCV) according to liver fibrosis stages [evaluated as liver stiffness measure (LSM)] and their linear relationship. METHODS: We performed a cross-sectional study on 238 HIV/HCV-coinfected patients (119 had <12.5 kPa, 73 had 12.5⁻25 kPa, and 46 had >25 kPa). Peripheral T-cell subsets were phenotyped by flow cytometry, plasma biomarkers were assessed by multiplex immunoassays, and LSM was assessed by transient elastography. Results: We found HIV/HCV-coinfected patients had higher values of CD4⁺ Tregs (p < 0.001), memory Tregs (p ≤ 0.001), and plasma cytokine levels [IFN-γ (p ≤ 0.05) and IL-10 (p ≤ 0.01)] compared with healthy donors and HIV-monoinfected patients. In the multivariate analysis, higher LSM values were associated with reduced levels of IL-10 (adjusted arithmetic mean ratio (aAMR) = 0.83; p = 0.019), IL-2 (aAMR = 0.78; p = 0.017), TNF-α (aAMR = 0.67; p < 0.001), and IL-17A (aAMR = 0.75; p = 0.006). When we focus on HIV/HCV-coinfected patients analyzed by LSM strata, patients with ≥25 kPa had lower values of IL-2 (aAMR = 0.66; p = 0.021), TNF-α (aAMR = 0.565; p = 0.003), and IL-17A (aAMR = 0.58; p = 0.003) than patients with <12.5 kPa. CONCLUSION: HIV/HCV-coinfected patients showed an immunosuppressive profile compared to healthy controls and HIV-monoinfected patients. Additionally, HIV/HCV-coinfected patients with advanced cirrhosis (LSM ≥ 25 kPa) had the lowest plasma values of cytokines related to Th1 (IL-2 and TNF-α) and Th17 (IL-17A) response.

The IL7RA rs6897932 polymorphism is associated with progression of liver fibrosis in patients with chronic hepatitis C: Repeated measurements design.

The polymorphisms at the α-chain of the IL-7 receptor (IL7RA) have been related to T-cell homeostasis and development and may contribute to immune system deregulation. In the present study, we analyzed the association between IL7RA polymorphisms and the progression of liver fibrosis in patients infected with HCV. We carried out a retrospective study with a design consisting of repeated measurements in 187 HCV-infected patients, to study the risk prediction of liver fibrosis progression using genetic factors. We genotyped the rs6897932, rs987106 and rs3194051 IL7RA polymorphisms using the Agena Bioscience's MassARRAY. Transient elastography was used to measure liver stiffness. The used cut-offs were: <7.1 kPa (F0-F1), 7.1-9.4 kPa (F2; significant fibrosis), 9.5-12.4 kPa (F3; advanced fibrosis), and ≥12.5 kPa (F4; cirrhosis). All HCV genotypes were analyzed. The median of follow-up time was 47.9 months. Baseline liver stiffness measurement (LSM) values did not show significant statistical differences for IL7RA genotypes (p>0.05). In univariate analysis, the rs6897932 T allele had a positive relationship with an increase in LSM (arithmetic mean ratio (AMR) = 1.21 (95%CI = 1.08; 1.36); p = 0.001), progression to advanced fibrosis (F≥3) (odds ratio (OR) = 2.51 (95%CI = 1.29; 4.88); p = 0.006) and progression to cirrhosis (F4) (OR = 2.71 (95%CI = 0.94; 5.03); p = 0.069). In multivariable analysis, the rs6897932 T allele was related to a higher increase of LSM values during follow-up (adjusted AMR = 1.27 (95%CI = 1.13; 1.42); p<0.001) and higher odds of progression to advanced fibrosis [adjusted OR = 4.46 (95%CI = 1.87; 10.62); p = 0.001], and progression to cirrhosis [adjusted OR = 3.92 (95%CI = 1.30; 11.77); p = 0.015]. Regarding IL7RA rs987106 and rs3194051 polymorphisms, we did not find significant results except for the relationship between IL7RA rs987106 and the increase in LSM values [adjusted OR = 1.12 (95%CI = 1.02; 1.23); p = 0.015]. The IL7RA rs6897932 polymorphism seems to be related to increased risk of liver fibrosis progression in HCV-infected patients. Thus, the rs6897932 polymorphism could be related to the physiopathology of CHC and might be used to successfully stratify the risk of CHC progression.

Vitamin D in Human Immunodeficiency Virus Infection: Influence on Immunity and Disease.

People living with human immunodeficiency virus (HIV) infection typically have hypovitaminosis D, which is linked to a large number of pathologies, including immune disorders and infectious diseases. Vitamin D (VitD) is a key regulator of host defense against infections by activating genes and pathways that enhance innate and adaptive immunity. VitD mediates its biological effects by binding to the Vitamin D receptor (VDR), and activating and regulating multiple cellular pathways. Single nucleotide polymorphisms in genes from those pathways have been associated with protection from HIV-1 infection. High levels of VitD and VDR expression are also associated with natural resistance to HIV-1 infection. Conversely, VitD deficiency is linked to more inflammation and immune activation, low peripheral blood CD4+ T-cells, faster progression of HIV disease, and shorter survival time in HIV-infected patients. VitD supplementation and restoration to normal values in HIV-infected patients may improve immunologic recovery during combination antiretroviral therapy, reduce levels of inflammation and immune activation, and increase immunity against pathogens. Additionally, VitD may protect against the development of immune reconstitution inflammatory syndrome events, pulmonary tuberculosis, and mortality among HIV-infected patients. In summary, this review suggests that VitD deficiency may contribute to the pathogenesis of HIV infection. Also, VitD supplementation seems to reverse some alterations of the immune system, supporting the use of VitD supplementation as prophylaxis, especially in individuals with more severe VitD deficiency.

Association of CD14 rs2569190 polymorphism with mortality in shock septic patients who underwent major cardiac or abdominal surgery: A retrospective study.

The aim of this study was to investigate the relationship between the CD14 rs2569190 polymorphism and death related to septic shock in white European patients who underwent major cardiac or abdominal surgery. We carried out a retrospective study in 205 septic shock patients. The septic shock diagnosis was established by international consensus definitions. The outcome variable was the death within 28, 60 and 90 days after septic shock diagnosis. The CD14 rs2569190 polymorphism was analyzed by Agena Bioscience's MassARRAY platform. For the genetic association analysis with survival was selected a recessive inheritance model (GG vs. AA/AG). One hundred thirteen out of 205 patients (55.1%) died with a survival median of 39 days (95%CI = 30.6; 47.4). Patients with rs2569190 GG genotype had shorter survival probability than rs2569190 AA/AG genotype at 60 days (62.3% vs 50%; p = 0.035), and 90 days (62.3% vs 52.6%; p = 0.046). The rs2569190 GG genotype was associated with increased risk of septic shock-related death in the first 60 days (adjusted hazard ratio (aHR) = 1.67; p = 0.016) and 90 days (aHR = 1.64; p = 0.020) compared to rs2569190 AA/AG genotype. In conclusion, the presence of CD14 rs2569190 GG genotype was associated with death in shock septic patients who underwent major surgery. Further studies with bigger sample size are required to verify this relationship.

IL7RA polymorphisms are not associated with AIDS progression.

BACKGROUND: Our aim was to determine whether α-chain of the IL-7 receptor (IL7RA) polymorphisms (rs10491434, rs6897932 and rs987106) are associated with the clinical pattern of AIDS progression in ART-naïve HIV-infected patients. MATERIALS AND METHODS: We carried out a cross-sectional study in 673 HIV-infected patients who were classified into three groups according to the clinical pattern of AIDS progression (188 long-term nonprogressors (LTNPs), 334 moderate progressors (MPs) and 151 rapid progressors (RPs)). Additionally, 134 healthy blood donors participated as a Control-group. We selected three IL7RA polymorphisms located at three regulatory regions [rs6897932 (exon 6), rs987106 (intronic region) and rs10491434 (3'UTR)]. DNA genotyping was performed using Sequenom's MassARRAY platform. RESULTS: The Control-group and all HIV-infected patients had similar age and percentage of males. LTNP-group was older at HIV diagnosis and at the inclusion in the study and had higher percentage of intravenous drug users (IDU) (P < 0·001). Besides, LTNP-group had lower proportion of male patients and homosexual HIV transmission than MP and RP groups (P < 0·001). Moreover, similar values of allelic, genotypic and haplotype frequencies for IL7RA polymorphisms were found between healthy controls and HIV-infected patients (P > 0·05), and among different subgroups of HIV patients according to AIDS progression (LTNPs, MPs and RPs) (P > 0·05). The adjusted logistic regression did not show any significant association between IL7RA polymorphisms and AIDS progression. CONCLUSIONS: IL7RA polymorphisms (rs6897932, rs987106 and rs10491434) were not associated with AIDS progression in Spanish population. Therefore, IL7RA polymorphisms do not seem to help us to understand HIV pathogenesis in untreated HIV-infected patients with different clinical evolution.

CXCL9-11 polymorphisms are associated with liver fibrosis in patients with chronic hepatitis C: a cross-sectional study.

BACKGROUND AND AIMS: CXCL9-11 polymorphisms are related to various infectious diseases, including hepatitis C virus (HCV) infection. In this study, we analyzed the association between CXCL9-11 polymorphisms and liver fibrosis in HCV-infected patients. METHODS: We performed a cross-sectional study in 389 patients who were genotyped for CXCL9-11 polymorphisms (CXCL9 rs10336, CXCL10 rs3921, and CXCL11 rs4619915) using the Sequenom's MassARRAY platform. The primary outcome variable was the liver stiffness measurement (LSM). We established three cut-offs of LSM: LSM ≥ 7.1 kPa (F ≥ 2-significant fibrosis), LSM ≥ 9.5 kPa (F ≥ 3-advanced fibrosis), and LSM ≥ 12.5 kPa (F4-cirrhosis). RESULTS: Recessive, overdominant and codominant models of inheritance showed significant values, but the overdominant model was the best fitting our data. In this case, CXCL9 rs10336 AG, CXCL10 rs3921 CG and CXCL11 rs4619915 AG were mainly associated with lower values of LSM [(adjusted GMR (aGMR) = 0.85 (p = 0.005), aGMR = 0.84 (p = 0.003), and aGMR = 0.84 (p = 0.003), respectively]. Patients with CXCL9 rs10336 AG genotype had lower odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 0.59 (p = 0.016)], advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 0.54 (p = 0.010)], and cirrhosis (LSM ≥ 12.5 kPa) [aOR = 0.56 (p = 0.043)]. Patients with CXCL10 rs3921 CG or CXCL11 rs4619915 AG genotypes had lower odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 0.56 (p = 0.008)], advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 0.55 (p = 0.013)], and cirrhosis (LSM ≥ 12.5 kPa) [aOR = 0.57 (p = 0.051)]. Additionally, CXCL9-11 polymorphisms were related to lower liver stiffness under a codominant model of inheritance, being the heterozygous genotypes also protective against hepatic fibrosis. In the recessive inheritance model, the CXCL9 rs10336 AA, CXCL10 rs3921 CC and CXCL11 rs4619915 AA were associated with higher LSM values [(adjusted GMR (aGMR) = 1.19 (p = 0.030), aGMR = 1.21 (p = 0.023), and aGMR = 1.21 (p = 0.023), respectively]. Moreover, patients with CXCL9 rs10336 AA genotype had higher odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 1.83 (p = 0.044)] and advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 1.85 (p = 0.045)]. Furthermore, patients with CXCL10 rs3921 CC or CXCL11 rs4619915 AA genotypes had higher odds of advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 1.89 (p = 0.038)]. CONCLUSIONS: CXCL9-11 polymorphisms were related to likelihood of having liver fibrosis in HCV-infected patients. Our data suggest that CXCL9-11 polymorphisms may play a significant role against the progression of CHC and could help prioritize antiviral therapy.

IL-6 rs1800795 polymorphism is associated with septic shock-related death in patients who underwent major surgery: a preliminary retrospective study.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, being the primary cause of death from infection, especially if not recognized and treated promptly. The aim of this study was to analyze whether IL-6 rs1800795 polymorphism is associated with septic shock-related death in European white patients who underwent major surgery. METHODS: We performed a retrospective study on 202 septic shock patients who underwent major cardiac or abdominal surgery. The septic shock was established according to the international septic shock definition. The primary outcome variable was the death within 90 days after diagnosis of septic shock. The IL-6 rs1800795 polymorphism was genotyped by Sequenom's MassARRAY platform. RESULTS: The median age of the patients was 73 years, 63.4% were male, and more than 40% of patients had heart disease and hypertension. Overall, the survival analysis showed that 111 (55%) patients died with a survival median of 39 days (95% CI 30.7; 47.2). The genetic analysis association with survival was performed under a recessive genetic model (CC vs. GG/CG). Patients with IL-6 rs1800795 CC genotype had higher mortality rate than the IL-6 rs1800795 GG/CG genotype at days 7 [31.6% (6/19) vs. 10.4% (19/183); log-rank test (p = 0.005)] and 28 [57.9% (11/19) vs. 33.3% (61/183); log-rank test (p = 0.009)], and 90 [68.4% (13/19) vs. 53.5% (98/183); log-rank test (p = 0.006)]. The IL-6 rs1800795 CC genotype was associated with higher risk of septic shock-related death during the first 7 days [adjusted hazard ratio (aHR 4.65; p = 0.002), 28 days (aHR 2.50; p = 0.006), and 90 days (aHR 2.28; p = 0.006)] with septic shock. When patients were stratified by type of surgery, those with IL-6 rs1800795 CC genotype who underwent cardiac surgery had higher risk of death during the first 7 days (aHR 18.39; p = 0.001) and 28 days (aHR 6.1; p = 0.025) than IL-6 rs1800795 GG/GC carrier, whereas patients with IL-6 rs1800795 CC genotype who underwent abdominal surgery had higher risk of death during all follow-up (aHR 1.98; p = 0.050) than IL-6 rs1800795 GG/GC carrier. CONCLUSIONS: The presence of IL-6 rs1800795 CC genotype was associated with higher risk of septic shock-related death in patients who underwent major cardiac or abdominal surgery. These findings need robust validation in bigger independent cohorts.

Response to Infliximab in Crohn's Disease: Genetic Analysis Supporting Expression Profile.

Substantial proportion of Crohn's disease (CD) patients shows no response or a limited response to treatment with infliximab (IFX) and to identify biomarkers of response would be of great clinical and economic benefit. The expression profile of five genes (S100A8-S100A9, G0S2, TNFAIP6, and IL11) reportedly predicted response to IFX and we aimed at investigating their etiologic role through genetic association analysis. Patients with active CD (350) who received at least three induction doses of IFX were included and classified according to IFX response. A tagging strategy was used to select genetic polymorphisms that cover the variability present in the chromosomal regions encoding the identified genes with altered expression. Following genotyping, differences between responders and nonresponders to IFX were observed in haplotypes of the studied regions: S100A8-S100A9 (rs11205276* G/rs3014866* C/rs724781* C/rs3006488* A; P = 0.05); G0S2 (rs4844486* A/rs1473683* T; P = 0.15); TNFAIP6 (rs11677200* C/rs2342910* A/rs3755480* G/rs10432475* A; P = 0.10); and IL11 (rs1126760* C/rs1042506* G; P = 0.07). These differences were amplified in patients with colonic and ileocolonic location for all but the TNFAIP6 haplotype, which evidenced significant difference in ileal CD patients. Our results support the role of the reported expression signature as predictive of anti-TNF outcome in CD patients and suggest an etiological role of those top-five genes in the IFX response pathway.

Inflammatory bowel disease and celiac disease: overlaps and differences.

Recent findings demonstrate the common genetic basis for many immune-mediated diseases, and consequently, the partially shared pathogenesis. We collected these findings and reviewed the extension of these overlaps to other disease characteristics. Two autoimmune diseases were selected that also share the specific target organ, the bowel. The etiology and immunopathogenesis of both conditions characterized by chronic intestinal inflammation, inflammatory bowel disease (IBD) and celiac disease (CeD), are not completely understood. Both are complex diseases with genetics and environment contributing to dysregulation of innate and adaptive immune responses, leading to chronic inflammation and disease. CeD constitutes a particular disease because the main environmental and genetic triggers are largely known. IBD comprises two main clinical forms, Crohn's disease and ulcerative colitis, which most likely involve a complex interplay between some components of the commensal microbiota and other environmental factors in their origin. These multifactorial diseases encompass a broad spectrum of clinical phenotypes and ages of onset, although the clinical presentation often differs depending on childhood or adult onset, with greater heterogeneity commonly observed in adults.

HLA and celiac disease susceptibility: new genetic factors bring open questions about the HLA influence and gene-dosage effects.

Celiac disease (CD) is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03∶01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences involving DRB1*03∶01-carrying haplotypes in CD susceptibility. A family (274 trios) and a case-control sample (369 CD cases/461 controls) were analyzed. DRB1*03∶01-carrying individuals were classified according to the haplotype present (ancestral haplotype (AH) 8.1, AH 18.2 or non-conserved haplotype) after genotyping of HLA-DRB1, -DQA1, -DQB1, -B8, TNF -308, TNF -376 and the TNFa and TNFb microsatellites. We observe that the AH 8.1 confers higher risk than the remaining DRB1*03∶01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB1*02. CD risk for these individuals is similar to the one conferred by inherit DQA1*05 and DQB1*02 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB1*03∶01-carrying haplotypes. This factor could be shared with individuals possessing DQ2.5 trans, according to the similar risk observed in those two groups of individuals.

Th17-related genes and celiac disease susceptibility.

Th17 cells are known to be involved in several autoimmune or inflammatory diseases. In celiac disease (CD), recent studies suggest an implication of those cells in disease pathogenesis. We aimed at studying the role of genes relevant for the Th17 immune response in CD susceptibility. A total of 101 single nucleotide polymorphisms (SNPs), mainly selected to cover most of the variability present in 16 Th17-related genes (IL23R, RORC, IL6R, IL17A, IL17F, CCR6, IL6, JAK2, TNFSF15, IL23A, IL22, STAT3, TBX21, SOCS3, IL12RB1 and IL17RA), were genotyped in 735 CD patients and 549 ethnically matched healthy controls. Case-control comparisons for each SNP and for the haplotypes resulting from the SNPs studied in each gene were performed using chi-square tests. Gene-gene interactions were also evaluated following different methodological approaches. No significant results emerged after performing the appropriate statistical corrections. Our results seem to discard a relevant role of Th17 cells on CD risk.

Analysis of the influence of two CD24 genetic variants in Crohn's disease and ulcerative colitis.

The aim of this study was to evaluate the possible implication of CD24 gene in the genetic predisposition to inflammatory bowel disease (IBD). Our study population consisted of 1321 female Spanish individuals (369 Crohn's disease [CD] patients, 323 ulcerative colitis [UC] patients, and 629 healthy matched controls). Two putative functional polymorphisms, a C to T coding polymorphism (rs8734) and a TG deletion in the 3' untranslated region (rs3838646), were used as CD24 genetic markers and genotyped using a Taqman 5' allelic discrimination assay. The "del" allele of the dinucleotide deletion was associated with an increased risk of CD (odds ratio = 1.61, 95% confidence interval = 1.17-2.21, p(FDR) = 6.4E-03) but not with UC. Moreover, this allele was significant associated with the age of CD diagnosis between 17 and 40 years, the ileocolonic location, and the inflammatory behavior of CD. We observed no significant differences between the allelic or genotypic frequencies of the A57V polymorphism in our studied IBD cohort. Our results suggest that the rs3838646 CD24 polymorphism is part of the genetic background of CD.

MSH5 is not a genetic predisposing factor for immunoglobulin A deficiency but marks the HLA-DRB1*0102 subgroup carrying susceptibility.

The etiology of selective IgA deficiency (IgAD) is clearly influenced by human leukocyte antigen (HLA) genetic composition, although the susceptibility observed has not been ascribed to any specific gene/s. A possible role of the MSH5 gene, mapping on this chromosomal region, has been proposed based on its function and on the association of some MSH5 polymorphisms (L85F/P786S and rs3131378) with the disease. However, the extensive linkage disequilibrium in the HLA region makes mandatory additional analyses. We aimed at evaluating the role of those MSH5 polymorphisms on IgAD susceptibility considering their linkage with other classically associated HLA markers, specifically DRB1*0102 and B*08-DRB1*03. We studied 146 trios composed by IgAD patient and parents to unambiguously establish the gametic phase. Association of those MSH5 variants with IgAD is observed but stratified analyses considering other HLA alleles rule out the role of MSH5 per se as a predisposing factor. However, the minor allele of one of the studied polymorphisms, 85F, defines the subgroup of DRB1*0102 haplotypes carrying susceptibility. The causal factor present on this haplotype (MSH5 85F-DRB1*0102) seems to be at the telomeric end of HLA class II or in Class I or III, as the allele composition in more centromeric markers is shared by all the haplotypes containing DRB1*0102.