Association of complement receptor 2 polymorphisms withinnate resistance to HIV-1 infection

HIV-1 induces activation of complement through the classical and lectin pathways. However, the virus incorporates several membrane-bound or soluble regulators of complement activation (RCA) that inactivate complement. HIV-1 can also use the complement receptors (CRs) for complement-mediated antibody-dependent enhancement of infection (Ć-ADE). We hypothesize that hypofunctional polymorphisms in RCA or CRs may protect from HIV-1 infection. For this purpose, 139 SNPs located in 19 RCA and CRs genes were genotyped in a population of 201 Spanish HIV-1-exposed seronegative individuals (HESN) and 250 HIV-1-infected patients. Two SNPs were associated with infection susceptibility, rs1567190 in CR2 (odds ratio (OR)=2.27, P=1 × 10-4) and rs2842704 in C4BPA (OR=2.11, P=2 × 10-4). To replicate this finding, we analyzed a cohort of Italian, sexually HESN individuals. Although not significant (P=0.25, OR=1.57), similar genotypic proportions were obtained for the CR2 marker rs1567190. The results of the two association analyses were combined through a random effect meta-analysis, with a significant P-value of 2.6x10-5 (OR=2.07). Furthermore, we found that the protective CR2 genotype is correlated with lower levels CR2 mRNA as well as differences in the ratio of the long and short CR2 isoforms.Genes and Immunity advance online publication, 8 January 2015; doi:10.1038/gene.2014.71.This work was supported by Spanish Health Ministry [PI021476, PI051778 and PI10/01232 to JF, JAP and ACar]; Instituto de Salud Carlos III-RETIC [RD06/006 to JAP]; Fundació Marató TV3 [020730 and 020732 to JF and ACar]; Junta de Andalucía [PI-0335/2009 to ACar]; Fundación Progreso y Salud of the Consejería de Salud de la Junta de Andalucía [AI-0021 to JAP]; and Universidad de Jaen [UJA2013/10/03 to ACar]

Analysis of meiotic recombination in 22q11.2, a region that frequently undergoes deletions and duplications

BACKGROUND: The 22q11.2 deletion syndrome is the most frequent genomic disorder with an estimated frequency of 1/4000 live births. The majority of patients (90%) have the same deletion of 3 Mb (Typically Deleted Region, TDR) that results from aberrant recombination at meiosis between region specific low-copy repeats (LCRs). METHODS: As a first step towards the characterization of recombination rates and breakpoints within the 22q11.2 region we have constructed a high resolution recombination breakpoint map based on pedigree analysis and a population-based historical recombination map based on LD analysis. RESULTS: Our pedigree map allows the location of recombination breakpoints with a high resolution (potential recombination hotspots), and this approach has led to the identification of 5 breakpoint segments of 50 kb or less (8.6 kb the smallest), that coincide with historical hotspots. It has been suggested that aberrant recombination leading to deletion (and duplication) is caused by low rates of Allelic Homologous Recombination (AHR) within the affected region. However, recombination rate estimates for 22q11.2 region show that neither average recombination rates in the 22q11.2 region or within LCR22-2 (the LCR implicated in most deletions and duplications), are significantly below chromosome 22 averages. Furthermore, LCR22-2, the repeat most frequently implicated in rearrangements, is also the LCR22 with the highest levels of AHR. In addition, we find recombination events in the 22q11.2 region to cluster within families. Within this context, the same chromosome recombines twice in one family; first by AHR and in the next generation by NAHR resulting in an individual affected with the del22q11.2 syndrome. CONCLUSION: We show in the context of a first high resolution pedigree map of the 22q11.2 region that NAHR within LCR22 leading to duplications and deletions cannot be explained exclusively under a hypothesis of low AHR rates. In addition, we find that AHR recombination events cluster within families. If normal and aberrant recombination are mechanistically related, the fact that LCR22s undergo frequent AHR and that we find familial differences in recombination rates within the 22q11.2 region would have obvious health-related implications

Straightforward protocol for allele-specific chromatin conformation capture

A key advance in our understanding of gene regulation came with the finding that the genome undergoes three-dimensional nuclear folding in a genetically determined process. This 3D conformation directly influences the association between enhancers and their target promoters. This complex interplay has been proven to be essential for gene regulation, and genetic variants affecting this process have been associated to human diseases. The development of new technologies that quantify these DNA interactions represented a revolution in the field. High throughput techniques like HiC provide a general picture of chromatin topology. However, they often lack resolution to evidence subtle effects that single nucleotide polymorphisms exert over the contacts between cis-regulatory regions and target promoters. Here we propose a cost-efficient approach to perform allele-specific chromatin conformation analysis. As a proof of concept, we analyzed the impact of a common deletion mapping between SIRPB1 promoter and one of its downstream enhancers.JLG-S acknowledges the Spanish Ministerio de Economía y Competitividad (Grant BFU2016-74961-P), the European Research Council (ERC, grant agreement No 740041) and the institutional grant Unidad de Excelencia María de Maeztu (MDM-2016-0687 to the Department of Gene regulation and morphogenesis of Centro Andaluz de Biología del Desarrollo. Project supported by a 2019 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation, granted to JJT (The BBVA Foundation accepts no responsibility for the opinions, statements and contents included in the project and/or the results thereof, which are entirely the responsibility of the authors). We wish to dedicate this work to the memory of Jose Luis Gomez-Skarmeta (1966-2020); mentor, collegue and friend

29. jornadas de genetica luso-espaNolas

AbstractsDT / CINDOC - Centro de Informaciòn y Documentaciòn CientìficaSIGLEESSpai

Perioperative outcome of lung cancer surgery in women: results from a Spanish nationwide prospective cohort study.

To assess possible differences in the perioperative profile between men and women in lung cancer surgery. A prospective cohort multicenter study was design, in which consecutive patients undergoing curative intent surgery for lung cancer in 24 Thoracic Services throughout Spain were included. Clinical features, tumor- and surgery-related data, postoperative complications, and mortality were recorded. There were 2,566 men and 741 women. Women were younger than men [mean (SD) age, 61.8 (10.8) vs. 66.5 (9.1) years, P This multicenter nationwide study of lung cancer surgery with curative intent shows that the perioperative profile is better in women than in men

A multidisciplinary proposal for a diagnostic algorithm in idiopathic pulmonary fibrosis: the role of transbronchial cryobiopsy

The diagnosis of idiopathic pulmonary fibrosis (IPF) is a complex process that requires the multidisciplinary integration of clinical, radiological, and histological variables. Due to its diagnostic yield, surgical lung biopsy has been the recommended procedure for obtaining samples of lung parenchyma, when required. However, given the morbidity and mortality of this technique, alternative techniques which carry a lower risk have been explored. The most important of these is transbronchial cryobiopsy -transbronchial biopsy with a cryoprobe- which is useful for obtaining lung tissue with less comorbidity. Yield may be lower than surgical biopsy, but it is higher than with transbronchial biopsy with standard forceps. This option has been discussed in the recent clinical guidelines for the diagnosis of IPF, but the authors do not go so far as recommend it. The aim of this article, the result of a multidisciplinary discussion forum, is to review current evidence and make proposals for the use of transbronchial cryobiopsy in the diagnosis of IPF