Biology subjects

Elosua, R.

Publications and source records attributed to Elosua, R..

7 recordsLinked to original sources

bioRxiv2023

Interpretable Inflammation Landscape of Circulating Immune cells

Inflammation is a biological phenomenon involved in a wide variety of physiological and pathological processes. Although a controlled inflammatory response is beneficial for restoring homeostasis, it can become unfavorable if dysregulated. In recent years, major progress has been made in characterizing acute and chronic inflammation in specific diseases. However, a global, holistic understanding of inflammation is still elusive. This is particularly intriguing, considering the crucial function of inflammation for human health and its potential for modern medicine if fully deciphered. Here, we leverage advances in the field of single-cell genomics to delineate the full spectrum of circulating immune cell activation underlying inflammatory processes during infection, immune-mediated inflammatory diseases and cancer. Our single-cell atlas of >6.5 million peripheral blood mononuclear cells from 1047 patients and 19 diseases allowed us to learn a comprehensive model of inflammation in circulating immune cells. The atlas expanded our current knowledge of the biology of inflammation of immune-mediated diseases, acute and chronic inflammatory diseases, infection and solid tumors, and laid the foundation to develop a precision medicine framework using unsupervised as well as explainable machine learning. Beyond a disease-centered analysis, we charted altered activity of inflammatory molecules in peripheral blood cells, depicting discriminative inflammation-related genes to further understand mechanisms of inflammation. Finally, we have laid the groundwork for developing precision medicine diagnostic tools for patients experiencing pathologic inflammation by learning a classifier for inflammatory diseases, presenting cells in circulation as a powerful resource for patient diagnosis.

immunology↗

bioRxiv2019

Identification of 20 novel loci associated to ischemic stroke. Epigenome-Wide Association Study

RationaleDNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1-2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism. ObjectiveTo detect epigenetic variants associated to stroke occurrence and stroke subtypes. Methods and ResultsA two-stage case-control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N=226 and N=166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locus ZFHX3, which includes known genetic variants associated with stroke. The pathways associated to these loci are inflammation and angiogenesis. The meta-analysis identified 384 differentially methylated CpGs, including loci of known stroke and vascular risk genetic variants, enriched by loci involved in lipid metabolism, adipogenesis, circadian clock, and glycolysis pathways. Stratification analysis by stroke subtypes revealed distinct methylation patterns. ConclusionsWe identified a set of 22 CpGs in 21 loci associated with IS. Our analysis suggests that DNA methylation changes may contribute to orchestrating gene expression that contributes to IS.

genetics↗

bioRxiv2019

Heterozygous ATP-binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease

BackgroundFamilial sitosterolemia is a rare, recessive Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency - homozygous loss-of-function (LoF) variants -- in the ATP-binding cassette transporter G5 (ABCG5) or G8 (ABCG8) genes, and have substantially elevated plasma sitosterol and low-density lipoprotein cholesterol (LDL-C) levels. The impact of partial genetic deficiency of ABCG5 or ABCG8, as occurs in heterozygous carriers of LoF variants, on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.\n\nMethodsWe first recruited nine sitosterolemia families, identified causative LoF variants in ABCG5 or ABCG8, and evaluated the associations of these ABCG5 or ABCG8 LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in ABCG5 or ABCG8 in CAD cases (n=29,361) versus controls (n=357,326). We tested the association of rare LoF variants in ABCG5 or ABCG8 with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency less than 0.1% in ABCG5 or ABCG8.\n\nResultsIn sitosterolemia families, seven pedigrees harbored causative LoF variants in ABCG5 and two pedigrees in ABCG8. Homozygous LoF variants in either ABCG5 or ABCG8 led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of ABCG5 LoF variants exhibited increased sitosterol and LDL-C levels compared to non-carriers. Within the large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 were approximately 0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (24.7 mg/dL; 95% confidence interval [CI] 14 to 35; P=1.1x10-6), and were at two-fold increased risk of CAD (odds ratio 2.06, 95% CI 1.27 to 3.35; P=0.004). By contrast, ABCG8 heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.\n\nConclusionsAlthough familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of a LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a two-fold increase in risk of CAD.

genetics↗

bioRxiv2019

DNA Methylation Biomarkers Of Myocardial Infarction And Cardiovascular Disease

ObjectiveTo assess the association between DNA methylation and acute myocardial infarction, the predictive added value of the identified methylation marks, and the causality of those associations. Approach and ResultsWe conducted a case-control, two-stage, epigenome-wide association study on acute myocardial infarction (ndiscovery=391, nvalidation=204). DNA methylation was assessed using the Infinium MethylationEPIC BeadChip (over 850,000 CpGs). DNA methylation was the exposure variable and myocardial infarction the outcome of interest. After a fixed-effects meta-analysis, 34 CpGs fulfilled Bonferroni significance. These findings were also analysed in two independent cohort studies (n[~]1,800 and n[~]2,500) with incident coronary (CHD) and cardiovascular disease (CVD). The Infinium HumanMethylation450 BeadChip was used in these two studies (over 480,000 CpGs) and only 12 of the 34 CpGs were available in those samples. Finally, we validated four of them in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. The four CpGs were also associated with classical cardiovascular risk factors. A methylation risk score based on those CpGs did not improve the predictive capacity of the Framingham risk function. To assess the causal effects of those CpGs we performed Mendelian randomization analysis but only one metQTL could be identified and the results were not conclusive. ConclusionsWe have identified 34 CpGs related to acute myocardial infarction. These loci highlight the relevance of smoking, lipid metabolism, and inflammation in the biological mechanisms related to myocardial infarction. Four were additionally associated with incident CHD and CVD but did not provide additional predictive information.

genomics↗

bioRxiv2019

High-density lipoprotein characteristics and coronary heart disease: a Mendelian randomization study

BackgroundThe causal role of high-density lipoproteins (HDL) in coronary artery disease (CAD) has been questioned. Our aim was to analyze whether genetically determined quantitative and qualitative HDL characteristics were independently associated with CAD. MethodsWe designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I quantity, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al study, N=24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D, N=184,305). We validated these results by defining our genetic variables in another database (METSIM, N=8,372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits (potential pleiotropy) we used the Multi-trait-based Conditional & Joint analysis. ResultsGenetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter ({beta}=0.27 [95%CI=0.19; 0.35]), cholesterol levels in very large HDLs ({beta}=0.29 [95%CI=0.17; 0.40]), and triglyceride content in very large HDLs ({beta}=0.14 [95%CI=0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs ({beta}=-0.076 [95%CI=-0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data. Genetic variants linked to both HDL qualitative traits and CAD risk were located within LIPC, the APOE/C1/C4/C2 cluster, APOB, PCIF1-PLTP, and TTC39B. ConclusionsSome HDL characteristics related to size, particle distribution, and triglyceride content are related to CAD risk whilst HDL cholesterol levels are not. This relationship could be mediated by the hepatic lipase; the apolipoproteins E, C-I, and B; the phospholipid transfer protein; and the tetratricopeptide repeat domain protein 39B, which arise as potential therapeutic targets in cardiovascular disease.

epidemiology↗

bioRxiv2019

A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease

Analyzing 5770 all-cause cirrhosis cases and 572,850 controls from seven cohorts, we identify a missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.88, p=2.1*10-8). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.012 SD, 1.4*10-8), alkaline phosphatase (-0.019 SD, 6.6*10-9), total cholesterol (-0.037 SD, p=1*10-18) and LDL cholesterol (-0.035 SD, p=7.3*10-16). Carriers of rare protein-truncating variants in MARC1 had lower liver enzyme levels, cholesterol levels, and reduced odds of liver disease (OR 0.19, p= 0.04) suggesting that deficiency of the MARC1 enzyme protects against cirrhosis.

genomics↗

bioRxiv2018

Association between long-term air pollution exposure and DNA methylation: the REGICOR study.

BackgroundLimited evidence suggests that epigenetic mechanisms may partially mediate the adverse effects of air pollution on health. Our aims were to identify new genomic loci showing differential DNA methylation associated with long-term exposure to air pollution and to replicate loci previously identified in other studies.\n\nMethodsA two-stage epigenome-wide association study was designed: 630 individuals from the REGICOR study were included in the discovery and 454 participants of the EPIC-Italy study in the validation stage. DNA methylation was assessed using the Infinium HumanMethylation450 BeadChip. NOX, NO2, PM10, PM2.5, PMcoarse, traffic intensity and traffic load exposure were measured according to the ESCAPE protocol. A systematic review was undertaken to identify those cytosine-phosphate-guanine (CpGs) associated with air pollution in previous studies and we screened for them in the discovery study.\n\nResultsIn the discovery stage of the epigenome-wide association study, 81 unique CpGs were associated with air pollution (p-value <10-5) but none of them were validated in the replication sample. Furthemore, we identified 12 CpGs in the systematic review showing differential methylation with a p-value fulfilling the Bonferroni criteria and 1642 CpGs fulfilling the false discovery rate criteria, all of which were related to PM2.5 or NO2. None of them was replicated in the discovery study, in which the top hits were located in an intergenic region on chromosome 1 (cg10893043, p-value=6.79{middle dot}10-5) and in the PXK and ARSA genes (cg16560256, p-value=2.23{middle dot}10-04; cg11953250, p-value=3.64{middle dot}10-04).\n\nConclusionsNeither new genomic loci associated with long-term air pollution were identified, nor previously identified loci were replicated. Continued efforts to test this potential association are warranted.

epidemiology↗