Publications by authors named "Jose Luís Royo"

44 Publications

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

MAOB rs3027452 Modifies Mood Improvement After Tryptophan Supplementation.

Int J Gen Med 2021 6;14:1751-1756. Epub 2021 May 6.

Department of Surgery, Biochemistry and Immunology School of Medicine, University of Malaga, Malaga, Spain.

Purpose: Tryptophan is the only precursor of serotonin, the hormone which helps regulate key human functions such as appetite, memory, mood, and sexual behavior. Connections have been identified between serotonin system dysfunction and the molecular etiology and treatment of mood disorders in a wide range of studies. Proposals have been put forward to co-administer tryptophan supplementation together with serotonin reuptake inhibitors in major depression patients, and also to exploit the sub-therapeutic depressive status in healthy populations. The reported responses, however, have been very dissimilar and this uneven effect may largely be explained by interindividual genetic differences.

Materials And Methods: We studied mood change in 138 healthy subjects using both Goldberg's General Health Questionnaire and the Profile of Mood States Questionnaire to determine the effects of a daily supplementation of 1g of tryptophan or placebo. Buccal DNA samples were provided and (rs1800532), (rs3788862 and rs979605), (rs3027452), and (rs6269 and rs4680) variants were genotyped.

Results: rs3027452 was equally associated with tryptophan supplementation efficacy in the depression subscales of both questionnaires (ΔT-Score.D; ΔT-Score.TMD and ΔPOMS.D p-values <0.01).

Conclusion: Here we provide evidence that tryptophan supplementation has an uneven effect on mood improvement in the general population.
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http://dx.doi.org/10.2147/IJGM.S305443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110250PMC
May 2021

Long runs of homozygosity are associated with Alzheimer's disease.

Transl Psychiatry 2021 02 24;11(1):142. Epub 2021 Feb 24.

Dep. of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain.

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [β (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10; β (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.
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http://dx.doi.org/10.1038/s41398-020-01145-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904832PMC
February 2021

White matter lesions and temporal atrophy are associated with cognitive and neuropsychiatric symptoms in patients with hypertension and Alzheimer's disease.

Int J Geriatr Psychiatry 2020 11 22;35(11):1292-1300. Epub 2020 Jul 22.

Department of Medicine, School of Medicine, University of Málaga, Research Medical Center of Málaga University, Biomedical Research Institute of Málaga, Málaga, Spain.

Objectives: An increasing evidence suggests hypertension (HTN) could be linked to cognitive impairment and incident Alzheimer's disease (AD). The precise mechanisms linking HTN and AD are not well-known. The aim of this study was to assess the putative association between HTN and AD.

Methods: We assessed in patients with AD associations between HTN and demographic and clinical data, vascular risk factors, treatments, APOE genotypes, brain white matter hyperintensities (WMH), and medial temporal atrophy (MTA) in multivariate analysis of covariance.

Results: We studied 92 patients with AD (mean ± SD age: 72.12 ± 6.91; women: 66.30%). Patients with HTN had significantly worse cognitive and functional status and higher frequency and severity of neuropsychiatric symptoms (P = .010). Magnetic resonance imaging analyzes showed significant increases in WMH (P = .018) and in MTA (P = .012) in patients with AD with HTN compared with those without HTN.

Conclusions: Neuroimaging burden (MTA and higher degree of severity of WMH) among patients with AD and HTN are associated with the impaired cognitive function and neuropsychiatric symptoms.
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http://dx.doi.org/10.1002/gps.5366DOI Listing
November 2020

Toll-Like Receptor 2 Promoter -196 to -174 Deletion Affects CD4 Levels Along Human Immunodeficiency Virus Infection Progression.

J Infect Dis 2020 11;222(12):2007-2011

Departamento de Cirugía, Bioquimica e Inmunología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain.

Toll-like receptor 2 (TLR2) plays a key role in innate immune response recognizing molecular patterns expressed by pathogens. rs111200466 is a TLR2 promoter insertion/deletion polymorphism with contradictory data about its role in human immunodeficiency virus type 1 (HIV-1) infection. We analyzed rs111200466 in HIV-1 disease progression and showed a correlation with a faster progression to the CD4+ < 200 cells/μL outcome for deletion allele carriers (Cox regression analysis: hazard ratio, 2.4 [95% confidence interval, 1.4-4]; P = .001). When naive patients with CD4+ < 200 cells/μL started antiretroviral treatment, rs111200466-deletion carriers showed a trend toward a slower, recovery rate (time required to reach CD4+ > 350 cells/μL; Cox P = .36). Our data suggest rs111200466 as a prognosis factor for HIV-1 disease progression.
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http://dx.doi.org/10.1093/infdis/jiaa327DOI Listing
November 2020

Hardy Weinberg Equilibrium Disturbances in Case-Control Studies Lead to Non-Conclusive Results.

Authors:
Jose Luis Royo

Cell J 2021 Jan 22;22(4):572-574. Epub 2020 Apr 22.

Department of Surgery, Biochemisty and Immunology, School of Medicine, University of Malaga, Boulevar Louis Pasteur s/n, Málaga, Spain. Electronic

Recently, it has been proposed the association of a common deletion affecting toll-like receptor 2 promoter (-196 to -177) to type 2 diabetes mellitus risk. However, genotyping results show a significant deviation from the Hardy- Weinberg Equilibrium (HWE). The law of Hardy-Weinberg shows that for an autosomal biallelic marker with allele frequencies f=p and f=q, the proportion of subjects with genotypes AA, Aa, and aa should follow the following: f=p, f=2pq, and f=q. Departure from HWE or Hardy-Weinberg Disequilibrium (HWD) in a human control population can be caused by natural factors such as selective pressure against a certain genotype. However their prevalence is scarce and magnitude of effect over the HWE are small. Other factors such as inbreeding caused by consanguinity, population stratification, or technical problems in genotyping are more usual. Nevertheless, if the control population follows a perfect HWE, the presence HWD among patients might be explained by the genetic association and evidencing a real link between the locus and the trait under study. However, HWD affecting both cases and controls, such as the one reported might be explained by one of the aforementioned issues.
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http://dx.doi.org/10.22074/cellj.2021.7195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211273PMC
January 2021

Monoamino oxidase alleles correlate with the presence of essential hypertension among hypogonadic patients.

Mol Genet Genomic Med 2020 01 19;8(1):e1040. Epub 2019 Nov 19.

Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Málaga, Spain.

Background: Monoamine oxidase (MAO) activity has been traditionally implicated in blood pressure through its effects on biogenic amine levels such as catecholamines, serotonin, and dopamine. Nowadays, this role is considered relegated to side-effects such as orthostatic hypotension and/or hypertensive crisis derived from MAO-inhibitory treatments in patients with psychiatric disease.

Methods: In the present work we have found an association between a polymorphic variant of MAOB gene and arterial hypertension in obese hypogonadic patients. The study cases comprised a series of 219 nondiabetic males with a body mass index ≥30 kg/m and aged <45 years. Hypogonadism was defined as subnormal testosterone concentrations, when free testosterone values ranged <65 pg/ml.

Results: MAOB rs3027452-A allele carriers were significantly over-represented among hypertensive (HT) patients (25.49%) in comparison to either the non-HT patients (10%, OR = 3.079 CI [1.364-6.952], p = .005, Chi-square test) and the control population series of nonobese nor hypogonadic males (also 10%, p = .003 Chi-square test). Upon adjusted, an independent association was shown with the hypogonadic group with hypertension when compared with nonhypertensive hypogonadics (Beta = 3.653, p = .005). When quantitative analysis was performed, hypertensive patients harboring rs3027452-A allele showed higher systolic blood pressure values (p = .038, Mann-Whitney U-test) as well as an increased Systolic-Diastolic range despite following HT treatment (∆mmHg 54 vs. 48 for rs3027452-A and rs3027452-G respectively, p-value .019, Mann-Whitney U-test). Previous studies on MAOB revealed that rs3027452-A allele has been correlated to a lower activity of the enzyme, what gives a functional evidence over our observation.

Conclusion: If this result could be extrapolated to other hypertensive patient groups, it would implicate a review of the markers and therapeutic targets on human hypertension.
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http://dx.doi.org/10.1002/mgg3.1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978270PMC
January 2020

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The [email protected] project.

Alzheimers Dement 2019 10 28;15(10):1333-1347. Epub 2019 Aug 28.

Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain.

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.

Methods: Genome Research at Fundacio ACE ([email protected]) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, [email protected] series were meta-analyzed with additional genome-wide association study data sets.

Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444.

Discussion: The regulation of vasculature is a prominent causal component of probable AD. [email protected] meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
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http://dx.doi.org/10.1016/j.jalz.2019.06.4950DOI Listing
October 2019

Effects of SHBG rs1799941 Polymorphism on Free Testosterone Levels and Hypogonadism Risk in Young Non-Diabetic Obese Males.

J Clin Med 2019 Jul 31;8(8). Epub 2019 Jul 31.

Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29010 Málaga, Spain.

Introduction: Obesity has been associated with increased risk of presenting hypogonadism. Free testosterone (FT) is the fraction of testosterone that carries out the biological function of testosterone, and is determined from total testosterone (TT) and sex-hormone binding globulin (SHBG) levels. We aimed to study the SHBG polymorphism rs1799941 in a cohort of young non-diabetic obese males to unravel the possible implication of this polymorphism in obesity-related hypogonadism.

Methodology: 212 young (<45 years) non-diabetic obese (BMI ≥ 30 kg/m) males participated in this study. Subjects were classified according to TT and FT levels in: Eugonadal ( 55, TT > 3.5 ng/mL and FT ≥ 70 pg/mL; EuG), normal FT hypogonadism ( 40, TT < 3.5 and FT ≥ 70 pg/mL; normal FT HG) and hypogonadism ( 117, TT < 3.5 ng/mL and TL < 70 pg/mL; HG). The SHBG rs1799941 polymorphism (GG/GA/AA) was analyzed using the Taqman Open Array (Applied biosystem).

Results: The rs1799941 frequencies were different among the groups. Higher proportion of the allele (A) was found in HG, compared to EuG and normal FT HG. Among the genotypes, the rare homozygous (AA) were found in the normal FT HG group and higher levels of serum SHBG and lower of FT were observed. The presence of the allele A was related (according to lineal regression models) to an increased of SHBG levels ((GA) β = 3.28; (AA) β = 12.45) and a decreased of FT levels ((GA) β = -9.19; (AA) β = -18.52). The presence of the allele (A) increased the risk of presenting HG compared to normal FT HG (OR = 2.54).

Conclusions: The rs1799941 of the SHBG gene can partially determine the presence of obesity-related hypogonadism in young non-diabetic males and whether these subjects have normal FT HG.
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http://dx.doi.org/10.3390/jcm8081136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722847PMC
July 2019

Synthesis and Characterization of Elongated-Shaped Silver Nanoparticles as a Biocompatible Anisotropic SERS Probe for Intracellular Imaging: Theoretical Modeling and Experimental Verification.

Nanomaterials (Basel) 2019 Feb 13;9(2). Epub 2019 Feb 13.

Departamento de Química, UCIBIO, REQUIMTE, Faculdade de Ciências, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal.

Progress in the field of biocompatible SERS nanoparticles has promising prospects for biomedical applications. In this work, we have developed a biocompatible Raman probe by combining anisotropic silver nanoparticles with the dye rhodamine 6G followed by subsequent coating with bovine serum albumin. This nanosystem presents strong SERS capabilities in the near infrared (NIR) with a very high (2.7 × 10⁷) analytical enhancement factor. Theoretical calculations reveal the effects of the electromagnetic and chemical mechanisms in the observed SERS effect for this nanosystem. Finite element method (FEM) calculations showed a considerable near field enhancement in NIR. Using density functional quantum chemical calculations, the chemical enhancement mechanism of rhodamine 6G by interaction with the nanoparticles was probed, allowing us to calculate spectra that closely reproduce the experimental results. The nanosystem was tested in cell culture experiments, showing cell internalization and also proving to be completely biocompatible, as no cell death was observed. Using a NIR laser, SERS signals could be detected even from inside cells, proving the applicability of this nanosystem as a biocompatible SERS probe.
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http://dx.doi.org/10.3390/nano9020256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409692PMC
February 2019

Comprehensive Toxicity Assessment of PEGylated Magnetic Nanoparticles for in vivo applications.

Colloids Surf B Biointerfaces 2019 May 3;177:253-259. Epub 2019 Feb 3.

BIONAND, Andalusian Centre for Nanomedicine and Biotechnology (Junta de Andalucía-Universidad de Málaga), Málaga, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, 29590 Málaga, Spain. Electronic address:

Magnetic nanoparticles (MNPs) represent one of the greatest promises for the development of a new generation of diagnostic agents for magnetic resonance imaging, with improved specificity and safety. Indeed, during the last decade the number of studies published in this field has grown exponentially. However, the clinical translation achieved so far has been very limited. This situation is likely related to the fact that most studies are focused on the in vitro characterization of these new nanomaterials, and very few provide an exhaustive in vivo characterization, where key aspects, such as pharmacokinetics, bioavailability, and, most importantly, toxicity, are properly evaluated. In this work, we propose a protocol for the comprehensive assessment of the toxicity of MNPs, based on the use of zebrafish embryos as an intermediate screening step between cell culture assays and studies in rodents. MNPs with different cores, ferrite and manganese ferrite oxide, and sizes between 3 and 20 nm, were evaluated. Cell viability at a concentration of 50 μg/mL of PEGylated MNPs was above 90 % in all cases. However, the exposure of zebrafish embryos to manganese based MNPs at concentrations above 100 μg/mL showed a low survival rate (<50 %). In contrast, no mortality (survival rate ∼100 %) and normal hatching rate were obtained for the iron oxide MNPs. Based on these results, together with the physicochemical and magnetic properties (r = 153.6 mM·s), the PEGylated 20 nm cubic shape iron oxide MNPs were selected and tested in mice, showing very good MRI contrast and, as expected, absence of toxicity.
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http://dx.doi.org/10.1016/j.colsurfb.2019.01.051DOI Listing
May 2019

Dysmorphic contribution of neurotransmitter and neuroendocrine system polymorphisms to subtherapeutic mood states.

Brain Behav 2019 02 17;9(2):e01140. Epub 2019 Jan 17.

Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Malaga, Spain.

Objective: From an evolutionary perspective, emotions emerged as rapid adaptive reactions that increase survival rates. Current psychobiology includes the consideration that genetic changes affecting neuroendocrine and neurotransmission pathways may also be affecting mood states. Following this hypothesis, abnormal levels of any of the aminergic neurotransmitters would be of considerable importance in the development of a pathophysiological state.

Materials And Methods: A total of 668 students from the School of Medicine of the University of Malaga (Average = 22.41 ± 3; 41% men) provided self-report measures of mood states using POMS and GHQ-28 questionnaires and buccal cells for genotyping 19 polymorphisms from 14 selected neurotransmitter pathways genes (HTR1A; HTR2A; HTR2C; HTR3B; TPH1; SLC18A1; SLC18A2; COMT; MAOA; MAOB) and neuroendocrine system (AVPR1B; OPRM1; BDNF; OXTR).

Results: MAOA rs3788862 genotype correlates with decreasing levels of Tension among females (beta = -0.168, p-value = 0.003) but it is neutral among males in this subscale. On the contrary, it correlates with lower GHQ-28 depression scores among males (beta = -0.196, p-value = 0.008). Equivalently, SLC18A1 and HTR2A variants correlated with anger and vigor scores, only among males. From the neuroendocrine system, OPRM1 rs1799971 correlated increasing levels of female's Anxiety, depression and Social Dysfunction scores.

Conclusion: Our findings suggest that these polymorphisms contribute to define general population mood levels, although exhibiting a clear sexual dimorphism.
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http://dx.doi.org/10.1002/brb3.1140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379594PMC
February 2019

Discordance in TLR2 (-196 to -174) polymorphism effect on HIV infection risk.

J Gene Med 2018 10 12;20(10-11):e3051. Epub 2018 Oct 12.

Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, Málaga, Spain.

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http://dx.doi.org/10.1002/jgm.3051DOI Listing
October 2018

A Knockout IFNL4 Variant Is Associated With Protection From Sexually Transmitted HIV-1 Infection.

J Infect Dis 2019 02;219(5):772-776

Immunogenetics Unit, Department of Experimental Biology, Universidad de Jaén, Jaen.

An interferon λ4 gene (IFNL4) knockout allele (rs368234815; TT) is associated with spontaneous and IFN-α-dependent cure of hepatitis C virus infection. The role of this polymorphism in the susceptibility to human immunodeficiency virus type 1 (HIV-1) infection is controversial. This study aimed to assess the association of this knockout IFNL4 variant and sexually transmitted HIV-1 infection. A total of 228 HIV-1-positive individuals and 136 HIV-exposed seronegative individuals were investigated for their association with IFNL4 rs368234815 genotypes. The IFNL4 ΔG functional allele is associated with increased susceptibility to HIV-1 infection through the sexual route (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.6; P = .004). A meta-analysis including a population of injection drug users suggests a codominant mode of inheritance of this risk factor (OR, 2.0; 95% CI, 1.3-3.2; P = .001).
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http://dx.doi.org/10.1093/infdis/jiy584DOI Listing
February 2019

Vitamin D Receptor polymorphisms and risk of enveloped virus infection: A meta-analysis.

Gene 2018 Dec 6;678:384-394. Epub 2018 Aug 6.

Department of Basic Medical Sciences, University of Lleida and Institute of Biomedical Research of Lleida (IRBLleida), Lleida, Spain. Electronic address:

Introduction: Vitamin-D plays a role regulating the immune response against to viral infection. In this sense, vitamin-D deficiency may confer increased susceptibility to enveloped virus infection such as HIV, Hepatitis, Dengue and Respiratory Syncytial virus infection, among others. Vitamin D activity is mediated by its receptor (VDR), which acts as a transcription factor modulating the expression of genes triggering the response against viruses. To date, six major VDR polymorphisms (Cdx, A1012G, FokI, BsmI, ApaI and TaqI) have been studied in the context of viral infection susceptibility. Reported studies show controversial results probably due to statistical lack of power and population genetic differences.

Aims: To do a systematic review of the published data and to perform a meta-analysis examining the role of six VDR polymorphisms on infection susceptibility to enveloped virus.

Results: From all markers and virus considered an association of FokI polymorphism with RSV infection emerges as significant. The worldwide distribution of risk T-allele reveals a lower prevalence in African populations that runs parallel with the relative lower incidence of RSV-associated severe ALRI in children <1 year described in African samples.

Conclusion: The results disclose FokI polymorphism as a relevant variant capturing the association of VDR polymorphisms with viral infection.
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http://dx.doi.org/10.1016/j.gene.2018.08.017DOI Listing
December 2018

Sperm count and motility are quantitatively affected by functional polymorphisms of HTR2A, MAOA and SLC18A.

Reprod Biomed Online 2018 May 2;36(5):560-567. Epub 2018 Feb 2.

Department of Biochemistry, Molecular Biology and Immunology, Faculty of Medicine, University of Malaga, 29071, Malaga, Spain. Electronic address:

Spermatozoa and neurones share similar membrane characteristics and features. Associations of multiple polymorphisms traditionally related to neurotransmission were investigated. Infertile men were grouped into controls with normospermia (n = 182) and idiopathic infertile men with asthenozoospermia (n = 103), and analysed as a case-control study and as a quantitative association of each genotype. Ten neurotransmission-associated genetic variants were mapped by SNP analysis using quantitative polymerase chain reaction with TaqMan probes. Men with HTR2A rs6313 had a higher risk of asthenozoospermia (OR = 2.14; P = 0.04). MAOA rs3788862 G carriers displayed an increased risk of asthenozoospermia (OR = 2.29; P = 0.02). The SLC18A1 rs1390938 G allele was more frequent among such cases (0.75 versus 0.87; P < 0.01 and P < 0.01 for Armitage trend test); for SLC18A1 rs2270641 P = 0.02 (case-control frequency) and P = 0.01 (Armitage trend test). MAOA rs3788862 was correlated with sperm motility (Spearman ρ = 0.14; P = 0.02); SLC18A1 rs1390938 was correlated with sperm count and motility (Spearman ρ = 0.20; P < 0.01). Gene polymorphisms of HTR2A, MAOA and SLC18A1, related to neurotransmission, are individually associated with asthenozoospermia through variation in sperm count and motility, without detectable allelic or genotype interaction.
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http://dx.doi.org/10.1016/j.rbmo.2018.01.007DOI Listing
May 2018

A common copy-number variant within SIRPB1 correlates with human Out-of-Africa migration after genetic drift correction.

PLoS One 2018 8;13(3):e0193614. Epub 2018 Mar 8.

Department of Basic Medical Sciences, IRBlleida, University of Lleida, Lleida, Spain.

Previous reports have proposed that personality may have played a role on human Out-Of-Africa migration, pinpointing some genetic variants that were positively selected in the migrating populations. In this work, we discuss the role of a common copy-number variant within the SIRPB1 gene, recently associated with impulsive behavior, in the human Out-Of-Africa migration. With the analysis of the variant distribution across forty-two different populations, we found that the SIRPB1 haplotype containing duplicated allele significantly correlated with human migratory distance, being one of the few examples of positively selected loci found across the human world colonization. Circular Chromosome Conformation Capture (4C-seq) experiments from the SIRPB1 promoter revealed important 3D modifications in the locus depending on the presence or absence of the duplication variant. In addition, a 3' enhancer showed neural activity in transgenic models, suggesting that the presence of the CNV may compromise the expression of SIRPB1 in the central nervous system, paving the way to construct a molecular explanation of the SIRPB1 variants role in human migration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193614PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843225PMC
June 2018

Genetic Association Studies in Host-Pathogen Interaction Analysis.

Methods Mol Biol 2018 ;1734:1-11

Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Seville, Spain.

Studying host-pathogen interactions at a molecular level has been always technically challenging. Identifying the different biochemical and genetic pathways involved in the different stages of infection traditionally require complex molecular biology tools and often the use of costly animal models. In this chapter we illustrate a complementary approach to address host-pathogen interactions, taking advantage of the natural interindividual genetic diversity. The application of genetic association studies allows us to identify alleles involved in infection progression or resistance. Thus, this strategy may be useful to unravel new molecular pathways underlying host-pathogen interactions. Here we present the general steps that might be followed to plan, execute, and analyze a population-based study in order to identify genetic variants affecting human exposition to pathogens.
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http://dx.doi.org/10.1007/978-1-4939-7604-1_1DOI Listing
August 2018

Differential metabolic profiles associated to movement behaviour of stream-resident brown trout (Salmo trutta).

PLoS One 2017 27;12(7):e0181697. Epub 2017 Jul 27.

Institute of Biomedical Research of Lleida (IRBLleida), University of Lleida, Lleida, Spain.

The mechanisms that can contribute in the fish movement strategies and the associated behaviour can be complex and related to the physiology, genetic and ecology of each species. In the case of the brown trout (Salmo trutta), in recent research works, individual differences in mobility have been observed in a population living in a high mountain river reach (Pyrenees, NE Spain). The population is mostly sedentary but a small percentage of individuals exhibit a mobile behavior, mainly upstream movements. Metabolomics can reflect changes in the physiological process and can determine different profiles depending on behaviour. Here, a non-targeted metabolomics approach was used to find possible changes in the blood metabolomic profile of S. trutta related to its movement behaviour, using a minimally invasive sampling. Results showed a differentiation in the metabolomic profiles of the trouts and different level concentrations of some metabolites (e.g. cortisol) according to the home range classification (pattern of movements: sedentary or mobile). The change in metabolomic profiles can generally occur during the upstream movement and probably reflects the changes in metabolite profile from the non-mobile season to mobile season. This study reveals the contribution of the metabolomic analyses to better understand the behaviour of organisms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181697PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531495PMC
September 2017

Fetal alpha 5-reductase Val89Leu mutation is associated with late miscarriage.

Reprod Biomed Online 2017 Jun 21;34(6):653-658. Epub 2017 Mar 21.

Department of Biochemistry, Molecular Biology and Immunology, Faculty of Medicine, University of Malaga, 29071 Malaga, Spain. Electronic address:

The present study was undertaken to determine the role of different polymorphisms affecting the testosterone/oestrogen pathway in miscarriage. Alpha 5-reductase (SRD5A2) rs523349 and rs9282858, cytochrome P450 aromatase (CYP19A1) rs4646, rs10046 and rs2236722 and oestrogen receptor (ESR1) rs9340799, rs2234693 and rs6932902 polymorphisms were selected. The case group consisted of 94 samples of formalin-fixed and paraffin-embedded fetal tissue from a miscarriage at ≤24 weeks. The control group comprised a population of 331 young healthy subjects. Only those single nucleotide polymorphisms (SNPs) fitting the Hardy-Weinberg equilibrium (n = 4) and euploid miscarriage samples (n = 67) were included for downstream analysis. Interestingly, SRD5A2 rs523349 (Val89Leu) was significantly associated with the risk of undergoing miscarriage after Bonferroni correction (odds ratio = 11.245, P < 2.2 × 10). Moreover, when Mantel-Cox regression analysis was performed, we observed that the effect was significantly constrained to the second trimester (P = 0.024, log rank). These results are compatible with an imbalance of testosterone/dihydrotestosterone, associated with a higher risk of miscarriage, especially in late pregnancy.
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http://dx.doi.org/10.1016/j.rbmo.2017.03.011DOI Listing
June 2017

Genotyping of common SIRPB1 copy number variant using Paralogue Ratio Test coupled to MALDI-MS quantification.

Mol Cell Probes 2015 Dec 31;29(6):517-521. Epub 2015 Jul 31.

Department of Basic Medical Sciences, University of Lleida, Spain; Institute of Biomedical Research of Lleida, Spain. Electronic address:

Copy number variant (CNV) regions have been proven to have a significant impact on gene expression. Some of them have been also found to be associated to different human diseases. CNV genotyping is often prone to error and cross-validation with independent methods is frequently required. The platform of choice depends on whether it is a genome-wide discovery screening or a candidate CNV study, the cohort size and the number of CNVs included in the assay and, finally, the budget available. Here we illustrate a affordable approach to determine the CNV genotype using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and based on the quantitative determination of single nucleotide duplicated mismatches (SNDM) mapping the CNV region and a paralogue genomic region that is used as a two-copy reference. We have genotyped nsv436327, a common CNV mapping SIRPB1 intron 1 that has been associated to human personality behavior. SIRP cluster region was subjected to several ancestral duplication events what makes SIRPB1 CNV genotyping technically challenging. We designed three sets of primer pairs that amplified paralogue regions inside and outside the CNV, containing three SNDMs. Post-PCR extension analyses of sequencing oligonucleotides mapping immediately upstream each SNDM allowed us to quantify using MALDI-MS the proportion of PCR products derived from the CNV region versus the external reference. In contrast to other approaches, setting up this genotyping method requires an affordable investment.
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http://dx.doi.org/10.1016/j.mcp.2015.07.009DOI Listing
December 2015

Absence of substantial copy number differences in a pair of monozygotic twins discordant for features of autism spectrum disorder.

Case Rep Genet 2014 19;2014:516529. Epub 2014 Jan 19.

Human Genetic Unit, Department of Basic Medical Sciences, University of Lleida, 25198 Lleida, Catalonia, Spain ; Genetics of Complex Diseases Research Group, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Catalonia, Spain.

Autism spectrum disorder (ASD) is a highly heritable disease (~0.9) with a complex genetic etiology. It is initially characterized by altered cognitive ability which commonly includes impaired language and communication skills as well as fundamental deficits in social interaction. Despite the large amount of studies described so far, the high clinical diversity affecting the autism phenotype remains poorly explained. Recent studies suggest that rare genomic variations, in particular copy number variation (CNV), may account for a significant proportion of the genetic basis of ASD. The use of disease-discordant monozygotic twins represents a powerful strategy to identify de novo and inherited CNV in the disorder. Here we present the results of a comparative genome hybridization (CGH) analysis with a pair of monozygotic twins affected of ASD with significant differences in their clinical manifestations that specially affect speech language impairment and communication skills. Array CGH was performed in three different tissues: blood, saliva, and hair follicle, in an attempt to identify germinal and somatic CNV regions that may explain these differences. Our results argue against a role of large CNV rearrangements as a molecular etiology of the observed differences. This forwards future research to explore de novo point mutation and epigenomic alterations as potential explanations of the observed clinical differences.
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http://dx.doi.org/10.1155/2014/516529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915920PMC
February 2014

Zebrafish as a model organism to study host-pathogen interactions.

Methods 2013 Aug 22;62(3):241-5. Epub 2013 Apr 22.

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, Consejo Superior de Investigaciones Científicas, Junta de Andalucia, Sevilla, Spain.

Zebrafish have been extensively used in biomedical research as a model to study vertebrate development but it is only recently that it has also been adopted into varied fields such as immunology and host-pathogen interactions. Zebrafish have a rapid life cycle, small size and the adults exhibit no territorial behavior in relatively dense cages. Under standard conditions each female lays an average of a hundred eggs per clutch, providing a large number of larvae per week. Their transparency during early life stages allows real time visualization of the different organs, which makes them especially suitable for the study of bacterial host-pathogen interactions. Traditionally, these studies have been technically challenging in higher organisms, given the loss of control over the bacteria once the pathogen infects its host. Here we describe an emerging approach to monitor Salmonella typhimurium infection progression using in vivo fluorescence upon parenteral infection. We have engineered Salmonella with the Cascade expression system; an efficient method to voluntarily activate bacterial heterologous gene expression at any point during infection once inside the Zebrafish macrophages, using a non-toxic inducer.
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http://dx.doi.org/10.1016/j.ymeth.2013.04.012DOI Listing
August 2013

Identification of the first recurrent PAR1 deletion in Léri-Weill dyschondrosteosis and idiopathic short stature reveals the presence of a novel SHOX enhancer.

J Med Genet 2012 Jul;49(7):442-50

Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Spain.

Background: SHOX, located in the pseudoautosomal region 1 (PAR1) of the sexual chromosomes, encodes a transcription factor implicated in human growth. Defects in SHOX or its enhancers have been observed in ∼60% of Leri-Weill dyschondrosteosis (LWD) patients, a skeletal dysplasia characterised by short stature and/or the characteristic Madelung deformity, and in 2-5% of idiopathic short stature (ISS). To identify the molecular defect in the remaining genetically undiagnosed LWD and ISS patients, this study screened previously unanalysed PAR1 regions in 124 LWD and 576 ISS probands.

Methods: PAR1 screening was undertaken by multiplex ligation dependent probe amplification (MLPA). Copy number alterations were subsequently confirmed and delimited by locus-specific custom-designed MLPA, array comparative genomic hybridisation (CGH) and breakpoint junction PCR/sequencing.

Results: A recurrent PAR1 deletion downstream of SHOX spanning 47543 bp with identical breakpoints was identified in 19 LWD (15.3%) and 11 ISS (1.9%) probands, from 30 unrelated families. Eight evolutionarily conserved regions (ECRs 1-8) identified within the deleted sequence were evaluated for SHOX regulatory activity by means of chromosome conformation capture (3C) in chicken embryo limbs and luciferase reporter assays in human U2OS osteosarcoma cells. The 3C assay indicated potential SHOX regulatory activity by ECR1, which was subsequently confirmed to act as a SHOX enhancer, operating in an orientation and position independent manner, in human U2OS cells.

Conclusions: This study has identified the first recurrent PAR1 deletion in LWD and ISS, which results in the loss of a previously uncharacterised SHOX enhancer. The loss of this enhancer may decrease SHOX transcription, resulting in LWD or ISS due to SHOX haploinsufficiency.
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http://dx.doi.org/10.1136/jmedgenet-2011-100678DOI Listing
July 2012

Identification and analysis of conserved cis-regulatory regions of the MEIS1 gene.

PLoS One 2012 20;7(3):e33617. Epub 2012 Mar 20.

Centro Andaluz de Biología del Desarrollo (CABD) CSIC-UPO-Junta de Anadalucía, Sevilla, Spain.

Meis1, a conserved transcription factor of the TALE-homeodomain class, is expressed in a wide variety of tissues during development. Its complex expression pattern is likely to be controlled by an equally complex regulatory landscape. Here we have scanned the Meis1 locus for regulatory elements and found 13 non-coding regions, highly conserved between humans and teleost fishes, that have enhancer activity in stable transgenic zebrafish lines. All these regions are syntenic in most vertebrates. The composite expression of all these enhancer elements recapitulate most of Meis1 expression during early embryogenesis, indicating they comprise a basic set of regulatory elements of the Meis1 gene. Using bioinformatic tools, we identify a number of potential binding sites for transcription factors that are compatible with the regulation of these enhancers. Specifically, HHc2:066650, which is expressed in the developing retina and optic tectum, harbors several predicted Pax6 sites. Biochemical, functional and transgenic assays indicate that pax6 genes directly regulate HHc2:066650 activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033617PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308983PMC
August 2012

Engineered Salmonella allows real-time heterologous gene expression monitoring within infected zebrafish embryos.

J Biotechnol 2012 Feb 8;157(3):413-6. Epub 2011 Dec 8.

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide/Consejo Superior de Investigaciones Científicas/Junta de Andalucía, Ctra. Utrera, Km 1. 41013-Sevilla, Spain.

Microbial host-pathogen interactions have been traditionally well studied at genetic and physiological levels, but cell-resolution analyses have been particularly scarce. This has been especially remarkable for intracellular parasites for two major reasons: first, the inherent loss of bacteria traceability once infects its hosts; second and more important, the limited availability of genetic tools that allow a tight regulated expression of bacterial virulence genes once inside the host tissues. Here we present novel data supporting the use of zebrafish embryos to monitor Salmonella enterica serovar Thyphimurium infection. Intravenous infection of Salmonella can be easily monitored using in vivo fluorescence that allows the visualization of free-swimming bacteria through the circulatory system. Moreover, we have engineered Salmonella to voluntarily activate heterologous gene expression at any point during infection once inside the zebrafish macrophages using a salicylate-based expression system. This approach allows real-time cell-resolution in vivo monitoring of the infection. All together, this approach paves the road to cell-based resolution experiments that would be harder to mimic in other vertebrate infection models.
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http://dx.doi.org/10.1016/j.jbiotec.2011.11.022DOI Listing
February 2012

Dissecting the transcriptional regulatory properties of human chromosome 16 highly conserved non-coding regions.

PLoS One 2011 13;6(9):e24824. Epub 2011 Sep 13.

Centro Andaluz de Biologia del Desarrollo, CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Sevilla, Spain.

Non-coding DNA conservation across species has been often used as a predictor for transcriptional enhancer activity. However, only a few systematic analyses of the function of these highly conserved non-coding regions (HCNRs) have been performed. Here we use zebrafish transgenic assays to perform a systematic study of 113 HCNRs from human chromosome 16. By comparing transient and stable transgenesis, we show that the first method is highly inefficient, leading to 40% of false positives and 20% of false negatives. When analyzed in stable transgenic lines, a great majority of HCNRs were active in the central nervous system, although some of them drove expression in other organs such as the eye and the excretory system. Finally, by testing a fraction of the HCNRs lacking enhancer activity for in vivo insulator activity, we find that 20% of them may contain enhancer-blocking function. Altogether our data indicate that HCNRs may contain different types of cis-regulatory activity, including enhancer, insulators as well as other not yet discovered functions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024824PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172297PMC
February 2012

Transphyletic conservation of developmental regulatory state in animal evolution.

Proc Natl Acad Sci U S A 2011 Aug 15;108(34):14186-91. Epub 2011 Aug 15.

Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Cientificas - Universidad Pablo de Olavide, E-41013 Sevilla, Spain.

Specific regulatory states, i.e., sets of expressed transcription factors, define the gene expression capabilities of cells in animal development. Here we explore the functional significance of an unprecedented example of regulatory state conservation from the cnidarian Nematostella to Drosophila, sea urchin, fish, and mammals. Our probe is a deeply conserved cis-regulatory DNA module of the SRY-box B2 (soxB2), recognizable at the sequence level across many phyla. Transphyletic cis-regulatory DNA transfer experiments reveal that the plesiomorphic control function of this module may have been to respond to a regulatory state associated with neuronal differentiation. By introducing expression constructs driven by this module from any phyletic source into the genomes of diverse developing animals, we discover that the regulatory state to which it responds is used at different levels of the neurogenic developmental process, including patterning and development of the vertebrate forebrain and neurogenesis in the Drosophila optic lobe and brain. The regulatory state recognized by the conserved DNA sequence may have been redeployed to different levels of the developmental regulatory program during evolution of complex central nervous systems.
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http://dx.doi.org/10.1073/pnas.1109037108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161536PMC
August 2011

Estrogen receptor alpha gene variants are associated with Alzheimer's disease.

Neurobiol Aging 2012 Jan 31;33(1):198.e15-24. Epub 2010 Jul 31.

ACE Foundation, Catalan Institute of Applied Neurosciences, Barcelona, Spain.

The present research is aimed at assessing the role of 3 estrogen receptor alpha (ESR1) gene variants in late onset Alzheimer's disease (AD) susceptibility. One thousand one hundred thirteen unrelated late onset sporadic AD patients, 1109 healthy controls and 121 neurologically healthy elderly controls were used to carry out case-control genetic association studies with ESR1 rs3844508, rs2234693, and ESR1 noncoding deletion 1 (ESR1-NCD1) polymorphisms. Thirty-five healthy male samples were used for molecular analyses. The rs2234693 polymorphism is associated with AD in our population (odds ratio [OR], 1.29; p = 0.008). The rs3844508 marker confers protection against AD in males (OR, 0.57; p = 0.001) and the deletion ESR1-NCD1 is a risk factor for AD in women (OR, 1.67; p < 0.001). Molecular analyses on ESR1-NCD1 indicate that this deletion confers a higher response to estradiol activity on ESR1 receptor and it is also associated with differential expression of ESR1 isoforms. Our results support the involvement of ESR1 gene in AD and point to the existence of sexual dimorphism for ESR1 markers. In addition, carriers of ESR1-NCD1 deletion could overrespond to estradiol action.
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http://dx.doi.org/10.1016/j.neurobiolaging.2010.06.016DOI Listing
January 2012

Genetic structure of the Spanish population.

BMC Genomics 2010 May 25;11:326. Epub 2010 May 25.

Department of Structural Genomics, Neocodex, Sevilla, Spain.

Background: Genetic admixture is a common caveat for genetic association analysis. Therefore, it is important to characterize the genetic structure of the population under study to control for this kind of potential bias.

Results: In this study we have sampled over 800 unrelated individuals from the population of Spain, and have genotyped them with a genome-wide coverage. We have carried out linkage disequilibrium, haplotype, population structure and copy-number variation (CNV) analyses, and have compared these estimates of the Spanish population with existing data from similar efforts.

Conclusions: In general, the Spanish population is similar to the Western and Northern Europeans, but has a more diverse haplotypic structure. Moreover, the Spanish population is also largely homogeneous within itself, although patterns of micro-structure may be able to predict locations of origin from distant regions. Finally, we also present the first characterization of a CNV map of the Spanish population. These results and original data are made available to the scientific community.
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http://dx.doi.org/10.1186/1471-2164-11-326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887418PMC
May 2010
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