The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control designs and the statistical significance testing procedures being used in most association studies. Our objective here was to investigate whether an alternative approach—in which common disorders are treated as quantitative phenotypes that are continuously distributed over a population—can reveal predictive insights into the early atherosclerosis, as assessed using ultrasound imaging-based quantitative measurement of carotid artery intima-media thickness (IMT). Using our population-based follow-up study of atherosclerosis precursors as a basis for sampling subjects with gradually increasing IMT levels, we searched for such subsets of genetic variants and their interactions that are the most predictive of the various risk classes, rather than using exclusively those variants meeting a stringent level of statistical significance. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the variants, and cross-validation was used to assess how well the predictive models will generalize to other subsets of subjects. By means of our predictive modeling framework with machine learning-based SNP selection, we could improve the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period (average AUC 0.844 and 0.761), compared to that of using conventional cardiovascular risk factors alone (average AUC 0.741 and 0.629), or when combined with the statistically significant variants (average AUC 0.762 and 0.651). The predictive accuracy remained relatively high in an independent validation set of subjects (average decrease of 0.043). These results demonstrate that the modeling framework can utilize the “gray zone” of genetic variation in the classification of subjects with different degrees of risk of developing atherosclerosis.

The genes in the IL-1 complex code for three proteins, IL-1 § , IL-1 g and the IL-1 receptor antagonist (IL-1Ra). The severity of a given infection is influenced by the balance between the levels of IL-1 g , the major extracellular agonist, and that of IL-1Ra. In healthy individuals, IL-1Ra is readily detectable in plasma but IL-1 g levels are usually undetectable. As there are polymorphisms in both of these genes, we have now analyzed whether there are allelic associations between these loci and whether these would have an influence on plasma IL-1Ra levels. In 200 healthy blood donors, the mean plasma IL-1Ra concentration was 681 pg/ ml. The IL-1Ra allele 2 (IL1RN*2) had a clear influence on IL-1Ra levels: its carriers had higher levels than the non-carriers (745 ng/ml vs. 627 pg/ml, p X 0.05, t-test). As marker alleles for IL-1 g we used two biallelic base-exchange polymorphisms (at positions −511 and +3953 relative to the transcriptional start site). The more rare allele of IL-1 g −511 (allele 2) was significantly associated with the presence of IL-1Ra allele 2, but in the case of the IL-1 g +3953, the more rare allele (allele 2) was less frequent in the carriers of the IL-1Ra allele 2. These IL-1 g allelisms did not have a direct influence on plasma IL-1Ra levels, but the enhancing effect of IL-1Ra allele 2 on IL-1Ra plasma levels required the presence of the IL-1 g −511 allele 2 or absence of the IL-1 g +3953 allele 2. Taken together, these results indicate that the IL-1 g gene participates in the regulation of IL-1Ra production in vivo and that the alleles of IL-1 g and IL-1Ra which demonstrate this cooperative effect are often associated.

Self-rated health (SRH) is one of the most frequently used indicators in health and social research. Its robust association with mortality in very different populations implies that it is a comprehensive measure of health status and may even reflect the condition of the human organism beyond clinical diagnoses. Yet the biological basis of SRH is poorly understood. We used data from three independent European population samples (N approx. 15,000) to investigate the associations of SRH with 150 biomolecules in blood or urine (biomarkers). Altogether 57 biomarkers representing different organ systems were associated with SRH. In almost half of the cases the association was independent of disease and physical functioning. Biomarkers weakened but did not remove the association between SRH and mortality. We propose three potential pathways through which biomarkers may be incorporated into an individual’s subjective health assessment, including (1) their role in clinical diseases; (2) their association with health-related lifestyles; and (3) their potential to stimulate physical sensations through interoceptive mechanisms. Our findings indicate that SRH has a solid biological basis and it is a valid but non-specific indicator of the biological condition of the human organism.

Objective To determine whether the haplotypes formed on the basis of single‐base–exchange polymorphisms at positions −1082, −819, or −592 of the interleukin‐10 (IL‐10) gene predispose subjects to primary Sjögren's syndrome (SS). Methods The frequency of IL‐10 polymorphisms was analyzed in 62 patients with primary SS and in 400 healthy subjects. These data were assessed for correlations with the concentration of IL‐10 in the plasma. Results The frequency of the IL‐10 GCC haplotype (G at position −1082, C at position −819, and C at position −592 of the IL‐10 gene) was increased (P < 0.05, odds ratio [OR] 1.90, 95% confidence interval [95% CI] 0.955–3.62) and the frequency of the ACC haplotype decreased (P < 0.05, OR 0.443, 95% CI 0.257–0.764) in primary SS patients compared with healthy controls. Moreover, the frequency of the ATA haplotype was similar in primary SS patients and healthy controls, but the incidence of the GCC/ATA genotype was elevated in the primary SS patients (P < 0.05, OR 2.19, 95% CI 1.19–4.03). The concentration of plasma IL‐10 was significantly higher in patients carrying the GCC haplotype than in non‐carriers of GCC. Conclusion These results suggest that the presence of the GCC haplotype or the GCC/ATA genotype and the absence of the ACC haplotype of the IL‐10 gene are associated with an increased susceptibility to primary SS. This effect is probably mediated by the increased capability to produce IL‐10 among carriers of the GCC haplotype.

No abstract

All-trans-retinoic acid (ATRA) is the drug of choice in the treatment of acute promyelocytic leukemia (APL). ATRA induces both in vitro and in vivo differentiation of APL cells into mature granulocytes. However, the molecular mechanisms involved in ATRA-dependent growth inhibition and cellular differentiation are not presently understood. The NB4 cell line, which is derived from the bone marrow of a patient with APL during relapse, can be used as a model system to study the growth and differentiation of APL cells. Because interferon (IFN) regulatory factors (IRF-1 and IRF-2) and other IFN-inducible gene products regulate cell growth, we analyzed the effects of ATRA on the expression of these genes. We show that ATRA directly activates IRF-1 gene expression, followed by activation of IRF-2 and 2′–5′ oligoadenylate synthetase (OAS) gene expression with slower kinetics. In addition to NB4 cells, ATRA also activated IRF-1 gene expression in HL-60, U937, and THP-1 cells, which all respond to ATRA by growth inhibition. A more than additive increase in IRF-1 gene expression was seen with ATRA and IFN-gamma in NB4 cells. ATRA did not activate nuclear factor kappa B or signal transducer and activator of transcription (STAT) activation pathways, suggesting that an alternate mechanism is involved in IRF-1 gene activation. The ATRA-induced expression of IRF-1, an activator of transcription and repressor of transformation, may be one of the molecular mechanisms of ATRA-induced growth inhibition, and the basis for the synergistic actions of ATRA and IFNs in myeloid leukemia cells.

The presence of circulating microbiome in blood has been reported in both physiological and pathological conditions, although its origins, identities and function remain to be elucidated. This study aimed to investigate the presence of blood microbiome by quantitative real-time PCRs targeting the 16S rRNA gene. To our knowledge, this is the first study in which the circulating microbiome has been analyzed in such a large sample of individuals since the study was carried out on 1285 Randomly recruited Age-Stratified Individuals from the General population (RASIG). The samples came from several different European countries recruited within the EU Project MARK-AGE in which a series of clinical biochemical parameters were determined. The results obtained reveal an association between microbial DNA copy number and geographic origin. By contrast, no gender and age-related difference emerged, thus demonstrating the role of the environment in influencing the above levels independent of age and gender at least until the age of 75. In addition, a significant positive association was found with Free Fatty Acids (FFA) levels, leukocyte count, insulin, and glucose levels. Since these factors play an essential role in both health and disease conditions, their association with the extent of the blood microbiome leads us to consider the blood microbiome as a potential biomarker of human health.

Herein, we demonstrate that HCMV miR-UL112-5p targets ERAP1, thereby inhibiting the processing and presentation of the HCMV pp65 peptide to specific CTLs. In addition, we show that the rs17481334 G variant, naturally occurring in the ERAP1 3' UTR, preserves ERAP1 from miR-UL112-5p-mediated degradation. Specifically, HCMV miR-UL112-5p binds the 3' UTR of ERAP1 A variant, but not the 3' UTR of ERAP1 G variant, and, accordingly, ERAP1 expression is reduced both at RNA and protein levels only in human fibroblasts homozygous for the A variant. Consistently, HCMV-infected GG fibroblasts were more efficient in trimming viral antigens and being lysed by HCMV-peptide-specific CTLs. Notably, a significantly decreased HCMV seropositivity was detected among GG individuals suffering from multiple sclerosis, a disease model in which HCMV is negatively associated with adult-onset disorder. Overall, our results identify a resistance mechanism to HCMV miR-UL112-5p-based immune evasion strategy with potential implications for individual susceptibility to infection and other diseases.