Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium.

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

Polymorphisms in Host Immunity-Modulating Genes and Risk of Invasive Aspergillosis: Results from the AspBIOmics Consortium.

Recent studies suggest that immune-modulating single-nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of invasive aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4Rrs2107356 and IL8rs2227307 SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4Rrs2107356 odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20 to 3.09; IL8rs2227307 OR, 1.73; 95% CI, 1.06 to 2.81), whereas the IL12Brs3212227 and IFNγrs2069705 variants were significantly associated with a decreased risk of developing the infection (IL12Brs3212227 OR, 0.60; 95% CI, 0.38 to 0.96; IFNγrs2069705 OR, 0.63; 95% CI, 0.41 to 0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4Rrs2107356 and IFNγrs2069705 SNPs was stronger in allo-HSCT (IL4Rrs2107356 OR, 5.63; 95% CI, 1.20 to 3.09; IFNγrs2069705 OR, 0.24; 95% CI, 0.10 to 0.59) than in non-HSCT patients, suggesting that the presence of these SNPs renders patients more vulnerable to infection, especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFNγrs2069705C allele showed a significantly increased macrophage-mediated neutralization of fungal conidia (P = 0.0003) and, under stimulation conditions, produced higher levels of gamma interferon (IFNγ) mRNA (P = 0.049) and IFNγ and tumor necrosis factor alpha (TNF-α) cytokines (P value for 96 h of treatment with lipopolysaccharide [PLPS-96 h], 0.057; P value for 96 h of treatment with phytohemagglutinin [PPHA-96 h], 0.036; PLPS+PHA-96 h = 0.030; PPHA-72 h = 0.045; PLPS+PHA-72 h = 0.018; PLPS-96 h = 0.058; PLPS+PHA-96 h = 0.0058). Finally, we also observed that the addition of SNPs significantly associated with IA to a model including clinical variables led to a substantial improvement in the discriminatory ability to predict disease (area under the concentration-time curve [AUC] of 0.659 versus AUC of 0.564; P-2 log likehood ratio test = 5.2 · 10(-4) and P50.000 permutation test = 9.34 · 10(-5)). These findings suggest that the IFNγrs2069705 SNP influences the risk of IA and that predictive models built with IFNγ, IL8, IL12p70, and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.

TNFR1 mRNA expression level and TNFR1 gene polymorphisms are predictive markers for susceptibility to develop invasive pulmonary aspergillosis.

Tumour necrosis factor (TNF) is primarily secreted by monocytes/macrophages and activated T lymphocytes in response to fungal infections. TNF acts through TNF receptor 1 (TNFR1) triggering a pro-inflammatory response, and therefore plays a pivotal role in immune regulation and host immune responses. We hypothesized that single nucleotide polymorphisms (SNPs) in TNFR1 gene may influence the innate immune response against Aspergillus. Three SNPs were genotyped in 275 individuals (144 immunocompromised haematological patients with high-risk of developing IPA and 131 healthy controls): TNFR1(-383(A/C)) (rs2234649) and TNFR1(-609(G/T)) (rs4149570) in the 5 prime UTR region, and TNFR1(+36(A/G)) SNP (rs767455) in the first exon of the gene. Of the 144 haematological patients, 77 patients developed Invasive Pulmonary Aspergillosis (IPA) infection and the remaining 67 patients were not infected. TNFR1(+36(A/G)) and TNFR1(-609(G/T)) were associated with IPA susceptibility (p=0.033 and p=0.018, respectively). A role of TNFR1 genetic variants in the susceptibility of patients to develop IPA was also supported by the significantly lower TNFR1 mRNA expression level in IPA than in IPA-resistant patients and the strong correlation between the TNFR1(-609) genetic variant and the expression levels of TNFR1. There was also a tendency for a higher frequency of galactomannan (GM) positivity in patients with TNFR1(-609G/G) genotype than in patients with TNFR1(-609G/T) (p=0.0909) or TNFR1(-609T/T) (p=0.0913) genotype. Predictive sequence analysis of the effects of TNFR1(-609) promoter polymorphism revealed that this SNP might play a critical role in modifying the affinity of ICSBP/IRF-8, a transcription factor that is involved in the TNFR1-mediated activation of NFkappaB signalling pathway. Taken together, these data suggest that TNFR1 polymorphisms influence the risk of IPA disease and might be useful for risk stratification strategies. These findings need to be confirmed in validation studies with larger samples of haematological patients.

Genetic variants of IL6 gene promoter influence on C-reactive protein levels but are not associated with susceptibility to invasive pulmonary aspergillosis in haematological patients.

Several lines of evidence indicate that IL6 plays a major role in the pathogenesis of a number of infectious diseases. The purpose of this study was to determine whether IL6 promoter polymorphisms were genetic markers of susceptibility to invasive pulmonary aspergillosis (IPA). To clarify the relationship between IL6 variants and IPA susceptibility, the IL6-174(G/C) and IL6-634(G/C) promoter single nucleotide polymorphisms (SNPs) were defined and plasma concentrations of IL6 and C-reactive protein (CRP) were measured. The study included 130 patients with haematological malignancies and 145 unrelated healthy individuals. No significant genotypic and allelic differences were found between patients and healthy controls. IPA was diagnosed in 71 of 130 patients according to the consensus criteria. CRP values were significantly associated with both IL6-174(G/C) and IL6-634(G/C) polymorphisms. However, IL6 and CRP values were similar between IPA and non-IPA groups. Neither IL6-174(G/C) nor IL6-634(G/C) polymorphisms were associated with IPA infection (p=0.414 and p=0.184, respectively). No evidence of association was found between allelic frequencies of IL6 promoter polymorphisms and IPA infection (p=0.864 and p=0.104, respectively). Further, no association was detected between IL6 genotypes and clinical profiles in IPA patients. Haplotype analysis also revealed that IL6 gene was not associated with IPA susceptibility in a Spanish population (Global haplotype association p value: 0.31). These findings suggest that IL6 polymorphisms influence on CRP circulating levels but are not associated with IPA susceptibility. Because the sample size is relatively small in our series, larger investigations of IL6-174(G/C)/IL6-634(G/C) genotypes and haplotypes are needed to clarify the potential role of this gene in the pathophysiology of IPA infection.

[Superoxide dismutase and catalase levels in diseases of the aged]. / Niveles de superóxido dismutasa y catalasa en enfermedades del anciano.

UNLABELLED: Superoxide dismutase (SOD) and catalase (CAT) activities were measured in blood from 420 individuals: control population 126, males and females, age between 50 to 93 years of age without any relevant pathology. Pathological population: 294 patients, males and females, age between 50 to 93 years of age, with some disease in the cardiovascular system and in the osteoarticular system, myoma, prostatic pathologies, Chronic Obstructive Pulmonary Disease (EPOC), and Acute Cerebral Vascular Accident (ACVA). The method of Minami and Yoshikawa (SOD) and the method of Aebi (CAT) were judged the techniques of choice for a population study. STATISTICAL METHODS: ANOVA and Student's "t". 1) The results were that levels of activity for SOD and CAT were increased for women in control population, and 2) the level of activity for CAT decreases with aging. In the pathological population, we detected: 3) increased activity for SOD in cardiovascular diseases, myomas, EPOC and ACVA. 4) for CAT the level of activity decreases in cardiovascular and prostatic diseases, EPOC and ACVA. 5) while in osteoarticular diseases levels of activity for SOD and CAT were standard, but SOD level decreases with aging, for CAT in cardiovascular diseases and EPOC, too. Both enzymes work to balance the antioxidant system.