[Real-life efficacy and safety of PCSK9 inhibitors treatment: Experience in three hospitals in Asturias]. / Efectividad y seguridad del tratamiento con iPCSK9 en vida real: experiencia de tres hospitales asturianos.

BACKGROUND: Inhibitors of proprotein convertase subtilisin/kexin type9 (PCSK9 inhibitors) are a treatment option for those patients with familial hypercholesterolemia or in secondary prevention who do not reach the LDL-C target with other therapeutic measures. The aim of this study is to assess the effectiveness and safety of these drugs. METHODS: Retrospective, multicentric, descriptive study. We collected data from all patients that have started PCSK9 inhibitors treatment in three hospitals in Asturias since the beginning of its use in 2016. We analysed changes in lipid profile with PCSK9 inhibitors and its side effects. RESULTS: We registered 98 patients, 75 of them affected by familial hypercholesterolemia (FH) and 23 unaffected. Two months after the beginning of PCSK9 inhibitors treatment, a 61% reduction rate in LDL-C in patients with FH and 52% in those without this condition was observed. This statistically significant reduction remained stable during follow-up. A significant decrease in total cholesterol was observed, without significant changes in HDL-C and triglycerides. 96% of patients had no complications. CONCLUSIONS: PCSK9 inhibitors are safe drugs that rapidly achieve significant reductions in LDL-C after the beginning of treatment, which are maintained over time. Hence, the use of PCSK9 inhibitors is an alternative for the control of LDL-C in those patients in which the LDL-C target is not reached with other therapeutic measures.

Epigenetic regulation of the immune system in health and disease.

Epigenetics comprises various mechanisms that mold chromatin structures and regulate gene expression with stability, thus defining cell identity and function and adapting cells to environmental changes. Alteration of these mechanisms contributes to the inception of various pathological conditions. Given the complexity of the immune system, one would predict that a higher-order, supragenetic regulation is indispensable for generation of its constituents and control of its functions. Here, we summarize various aspects of immune system physiology and pathology in which epigenetic pathways have been implicated. Increasing knowledge in this field, together with the development of specific tools with which to manipulate epigenetic pathways, might form a basis for new strategies of immune function modulation, both to optimize immune therapies for infections or cancer and to control immune alterations in aging or autoimmunity.

The possible role of epigenetics in gestational diabetes: cause, consequence, or both.

Gestational diabetes mellitus (GDM) is defined as the glucose intolerance that is not present or recognized prior to pregnancy. Several risk factors of GDM depend on environmental factors that are thought to regulate the genome through epigenetic mechanisms. Thus, epigenetic regulation could be involved in the development of GDM. In addition, the adverse intrauterine environment in patients with GDM could also have a negative impact on the establishment of the epigenomes of the offspring.

Genetic influence of the nonclassical major histocompatibility complex class I molecule MICB in multiple sclerosis susceptibility.

It has been widely reported that the major histocompatibility complex (MHC) class II region provides the main genetic contribution to multiple sclerosis (MS) susceptibility. However, recent studies have suggested that the MHC class I region may also contribute to the development of MS. In this study, we investigated the possible association of the human leukocyte antigen (HLA)-B, MHC class I chain-related gene B (MICB) and MHC class I chain-related gene A (MICA) genes, located in the MHC class I region, with MS susceptibility. For this purpose, we analyzed the distribution of HLA-DR, HLA-B, MICB and MICA alleles in 121 MS patients and 156 healthy controls. Neither HLA-B nor MICA alleles were found to be associated with MS susceptibility, and only the frequency of HLA-DRB1*01 allele was found to be increased in controls (31% vs 14%, P(c) = 0.011). However, MICB*004 allele frequency was significantly increased in MS patients (46.3% vs 23.3%, P(c) < 0.001, odds ratio = 2.82, 95% confidence interval = 1.68-4.73). Although, MICB*004 and HLA-DRB1*15 belong to the AH 7.1 ancestral haplotype, the association of MICB*004 to MS susceptibility was found to be independent of HLA-DRB1*15 in our population. This and previous studies clearly suggest that the MHC class I, in addition to class II, could be involved in MS susceptibility.

MHC class I chain-related gene B (MICB) is associated with rheumatoid arthritis susceptibility.

OBJECTIVES: Several recent studies have shown that the MHC class III region, located telomeric to HLA-DRB1, contains an additional genetic factor that predisposes to rheumatoid arthritis (RA). In this study, we investigate whether inhibitor of kappaB-like (IkappaBL), MICB or MICA located in the MHC class III region are the second susceptibility gene associated with RA. METHODS: A total of 154 healthy controls and 140 RA patients were genotyped for HLA-DRB1, MICA, MICB and the polymorphism -62 of the IkappaBL gene. RESULTS: A significant increase of HLA-DRB1 shared epitope (SE) alleles was detected in RA patients (61.4 vs 43.5%, P(c) = 0.01, OR = 2.1, 95% CI = 1.3-3.3). Among SE alleles, the HLA-DRB1*0401 (13.5 vs 5.1%, P(c) = 0.04, OR = 3.2, 95% CI = 1.3-8.1) and HLA-DRB1*0404 (6.4 vs 1.2%, P = 0.02, P(c) = NS) showed the most significantly association with RA. No increase of risk was associated with HLA-DRB1*01. Remarkably, the allele MICB*004 was also significantly associated with RA susceptibility (40.7 vs 23.3%, P(c) = 0.01, OR = 2.2, 95% CI = 1.3-3.7). MICB*004 was in linkage disequilibrium with HLA-DRB1*0404 (lambda(s) = 0.33) and HLA-DRB1*0405 (lambda(s) = 0.34). However, MICB*004 was also increased in HLA-DRB1 SE negative patients (37 vs 21.5%, P = 0.04). No significant association between IkappaBL and MICA with RA was found. CONCLUSIONS: MICB*004 allele was associated with RA susceptibility. This allele was in linkage disequilibrium with HLA-DRB1*0404 and DRB1*0405. The association of MICB with RA susceptibility and the functional role of MIC genes in the pathogenesis of RA converts MICB into a candidate to be an additional MHC gene associated with RA susceptibility.