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1.
PLoS Genet ; 18(5): e1010147, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35511767

RESUMEN

Phenotypic differences across sexes are pervasive, but the genetic architecture of sex differences within and across phenotypes is mostly unknown. In this study, we aimed to improve detection power for sex-differentially contributing SNPs previously demonstrated to be enriched in disease association, and we investigate their functions in health, pathophysiology, and genetic function. We leveraged GIANT and UK Biobank summary statistics and defined a set of 2,320 independent SNPs having sexually dimorphic effects within and across biometric traits (MAF > 0.001, P < 5x10-8). Biometric trait sex-heterogeneous SNPs (sex-het SNPs) showed enrichment in association signals for 20 out of 33 diseases/traits at 5% alpha compared to sex-homogeneous matched SNPs (empP < 0.001), and were significantly overrepresented in muscle, skeletal and stem cell development processes, and in calcium channel and microtubule complexes (FDR < 0.05, empP < 0.05). Interestingly, we found that sex-het SNPs significantly map to predicted expression quantitative trait loci (Pr-eQTLs) across brain and other tissues, methylation quantitative trait loci (meQTLs) during development, and transcription start sites, compared to sex-homogeneous SNPs. Finally, we verified that the sex-het disease/trait enrichment was not explained by Pr-eQTL enrichment alone, as sex-het Pr-eQTLs were more enriched than matched sex-homogeneous Pr-eQTLs. We conclude that genetic polymorphisms with sexually dimorphic effects on biometric traits not only contribute to fundamental embryogenic processes, but later in life play an outsized role in disease risk. These sex-het SNPs disproportionately influence gene expression and have a greater influence on disorders of body and brain than other expression-regulatory variation. Together, our data emphasize the genetic underpinnings of sexual dimorphism and its role in human health.


Asunto(s)
Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Animales , Femenino , Expresión Génica , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética
2.
Nature ; 523(7561): 459-462, 2015 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-26131930

RESUMEN

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.


Asunto(s)
Estatura/genética , Cognición , Homocigoto , Evolución Biológica , Presión Sanguínea/genética , LDL-Colesterol/genética , Estudios de Cohortes , Escolaridad , Femenino , Volumen Espiratorio Forzado/genética , Genoma Humano/genética , Humanos , Mediciones del Volumen Pulmonar , Masculino , Fenotipo
3.
Am J Hum Genet ; 100(6): 865-884, 2017 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-28552196

RESUMEN

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.


Asunto(s)
Antropometría , Genoma Humano , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo/genética , Análisis de Secuencia de ADN/métodos , Estatura/genética , Estudios de Cohortes , Metilación de ADN/genética , Bases de Datos Genéticas , Femenino , Variación Genética , Humanos , Lipodistrofia/genética , Masculino , Metaanálisis como Asunto , Obesidad/genética , Mapeo Físico de Cromosoma , Caracteres Sexuales , Síndrome , Reino Unido
4.
PLoS Genet ; 13(1): e1006516, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-28076348

RESUMEN

Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10-16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway.


Asunto(s)
Trastorno del Espectro Autista/genética , Epistasis Genética , Sistema de Señalización de MAP Quinasas/genética , Proteínas ras/genética , Línea Celular , Femenino , Genes Modificadores , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Células-Madre Neurales/metabolismo , Polimorfismo de Nucleótido Simple , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
6.
PLoS Genet ; 12(11): e1006425, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27846226

RESUMEN

Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.


Asunto(s)
Trastorno del Espectro Autista/genética , Trastornos Generalizados del Desarrollo Infantil/genética , Cromosomas Humanos X/genética , Trastorno del Espectro Autista/patología , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Trastornos Generalizados del Desarrollo Infantil/patología , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Caracteres Sexuales
7.
PLoS Genet ; 12(2): e1005874, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26910538

RESUMEN

Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases.


Asunto(s)
Sitios Genéticos , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/genética , Cromosomas Humanos , Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple , Factor A de Crecimiento Endotelial Vascular/metabolismo , Población Blanca/genética
8.
J Am Soc Nephrol ; 29(1): 335-348, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29093028

RESUMEN

Magnesium (Mg2+) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg2+, which is crucial for Mg2+ homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg2+ homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4×10-13) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1×10-11), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg2+ regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg2+ wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg2+ deficiency to insulin resistance and obesity.


Asunto(s)
Factores de Ribosilacion-ADP/genética , Homeostasis/genética , Riñón/metabolismo , Magnesio/sangre , Magnesio/orina , Canales Catiónicos TRPM/genética , Adiposidad/genética , Animales , Proteínas de Unión al GTP/genética , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Humanos , Insulina/sangre , Resistencia a la Insulina/genética , Magnesio/administración & dosificación , Ratones , Obesidad/genética , Fenotipo , Polimorfismo de Nucleótido Simple , ARN Mensajero/metabolismo , Pez Cebra , Proteínas de Pez Cebra/genética
9.
Nature ; 492(7429): 369-75, 2012 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-23222517

RESUMEN

Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.


Asunto(s)
Eritrocitos/metabolismo , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Fenotipo , Animales , Ciclo Celular/genética , Citocinas/metabolismo , Drosophila melanogaster/genética , Eritrocitos/citología , Femenino , Regulación de la Expresión Génica/genética , Hematopoyesis/genética , Hemoglobinas/genética , Humanos , Masculino , Ratones , Especificidad de Órganos , Polimorfismo de Nucleótido Simple/genética , Interferencia de ARN , Transducción de Señal/genética
10.
Pflugers Arch ; 469(1): 91-103, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27915449

RESUMEN

The nature and importance of genetic factors regulating the differential handling of Ca2+ and Mg2+ by the renal tubule in the general population are poorly defined. We conducted a genome-wide meta-analysis of urinary magnesium-to-calcium ratio to identify associated common genetic variants. We included 9320 adults of European descent from four genetic isolates and three urban cohorts. Urinary magnesium and calcium concentrations were measured centrally in spot urine, and each study conducted linear regression analysis of urinary magnesium-to-calcium ratio on ~2.5 million single-nucleotide polymorphisms (SNPs) using an additive model. We investigated, in mouse, the renal expression profile of the top candidate gene and its variation upon changes in dietary magnesium. The genome-wide analysis evidenced a top locus (rs172639, p = 1.7 × 10-12), encompassing CLDN14, the gene coding for claudin-14, that was genome-wide significant when using urinary magnesium-to-calcium ratio, but not either one taken separately. In mouse, claudin-14 is expressed in the distal nephron segments specifically handling magnesium, and its expression is regulated by chronic changes in dietary magnesium content. A genome-wide approach identified common variants in the CLDN14 gene exerting a robust influence on the differential excretion of Mg2+ over Ca2+ in urine. These data highlight the power of urinary electrolyte ratios to unravel genetic determinants of renal tubular function. Coupled with mouse experiments, these results support a major role for claudin-14, a gene associated with kidney stones, in the differential paracellular handling of divalent cations by the renal tubule.


Asunto(s)
Calcio/orina , Claudinas/genética , Magnesio/orina , Polimorfismo de Nucleótido Simple/genética , Orina/química , Animales , Calcio/metabolismo , Humanos , Túbulos Renales/metabolismo , Magnesio/metabolismo
11.
PLoS Genet ; 10(4): e1004234, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24743097

RESUMEN

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.


Asunto(s)
Haplotipos/genética , Mapeo Cromosómico/métodos , Efecto de Cohortes , Familia , Genotipo , Humanos , Modelos Genéticos , Linaje , Fenotipo , Recombinación Genética/genética
12.
Rev Endocr Metab Disord ; 17(2): 209-19, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27129595

RESUMEN

Food preferences are the first factor driving food choice and thus nutrition. They involve numerous different senses such as taste and olfaction as well as various other factors such as personal experiences and hedonistic aspects. Although it is clear that several of these have a genetic basis, up to now studies have focused mostly on the effects of polymorphisms of taste receptor genes. Therefore, we have carried out one of the first large scale (4611 individuals) GWAS on food likings assessed for 20 specific food likings belonging to 4 different categories (vegetables, fatty, dairy and bitter). A two-step meta-analysis using three different isolated populations from Italy for the discovery step and two populations from The Netherlands and Central Asia for replication, revealed 15 independent genome-wide significant loci (p < 5 × 10(-8)) for 12 different foods. None of the identified genes coded for either taste or olfactory receptors suggesting that genetics impacts in determining food likings in a much broader way than simple differences in taste perception. These results represent a further step in uncovering the genes that underlie liking of common foods that in the end will greatly help understanding the genetics of human nutrition in general.


Asunto(s)
Preferencias Alimentarias/fisiología , Sitios Genéticos/genética , Estudio de Asociación del Genoma Completo , Humanos
13.
Hum Mol Genet ; 22(7): 1465-72, 2013 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-23307926

RESUMEN

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.


Asunto(s)
Estudio de Asociación del Genoma Completo , Menopausia Prematura/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Humanos , Insuficiencia Ovárica Primaria/genética , Sitios de Carácter Cuantitativo , Riesgo
14.
J Am Soc Nephrol ; 25(8): 1869-82, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24578125

RESUMEN

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 µg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.


Asunto(s)
Variación Genética/genética , Uromodulina/orina , Población Blanca/genética , Creatinina/metabolismo , Humanos , Polimorfismo de Nucleótido Simple/genética , Uromodulina/genética
15.
Blood ; 118(16): 4459-62, 2011 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-21873547

RESUMEN

The iron hormone hepcidin is inhibited by matriptase-2 (MT2), a liver serine protease encoded by the TMPRSS6 gene. Cleaving the bone morphogenetic protein (BMP) coreceptor hemojuvelin (HJV), MT2 impairs the BMP/son of mothers against decapentaplegic homologs (SMAD) signaling pathway, down-regulates hepcidin, and facilitates iron absorption. TMPRSS6 inactivation causes iron-deficiency anemia refractory to iron administration both in humans and mice. Genome-wide association studies have shown that the SNP rs855791, which causes the MT2 V736A amino acid substitution, is associated with variations of serum iron, transferrin saturation, hemoglobin, and erythrocyte traits. In the present study, we show that, in vitro, MT2 736(A) inhibits hepcidin more efficiently than 736(V). Moreover, in a genotyped population, after exclusion of samples with iron deficiency and inflammation, hepcidin, hepcidin/transferrin saturation, and hepcidin/ferritin ratios were significantly lower and iron parameters were consistently higher in homozygotes 736(A) than in 736(V). Our results indicate that rs855791 is a TMPRSS6 functional variant and strengthen the idea that even a partial inability to modulate hepcidin influences iron parameters and, indirectly, erythropoiesis.


Asunto(s)
Sustitución de Aminoácidos , Péptidos Catiónicos Antimicrobianos/sangre , Péptidos Catiónicos Antimicrobianos/genética , Regulación de la Expresión Génica , Proteínas de la Membrana/genética , Serina Endopeptidasas/genética , Secuencia de Aminoácidos , Dominio Catalítico , Femenino , Hepcidinas , Humanos , Hierro/metabolismo , Masculino , Datos de Secuencia Molecular , Alineación de Secuencia
16.
BMC Nephrol ; 14: 48, 2013 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-23433094

RESUMEN

BACKGROUND: Aim of this study was to evaluate whether the A736V TMPRSS6 polymorphism, a major genetic determinant of iron metabolism in healthy subjects, influences serum levels of hepcidin, the hormone regulating iron metabolism, and erythropoiesis in chronic hemodialysis (CHD). METHODS: To this end, we considered 199 CHD patients from Northern Italy (157 with hepcidin evaluation), and 188 healthy controls without iron deficiency, matched for age and gender. Genetic polymorphisms were evaluated by allele specific polymerase chain reaction assays, and hepcidin quantified by mass spectrometry. RESULTS: Serum hepcidin levels were not different between the whole CHD population and controls (median 7.1, interquartile range (IQR) 0.55-17.1 vs. 7.4, 4.5-17.9 nM, respectively), but were higher in the CHD subgroup after exclusion of subjects with relative iron deficiency (p = 0.04). In CHD patients, the A736V TMPRSS6 polymorphism influenced serum hepcidin levels in individuals positive for mutations in the HFE gene of hereditary hemochromatosis (p < 0.0001). In particular, the TMPRSS6 736 V variant was associated with higher hepcidin levels (p = 0.017). At multivariate analysis, HFE and A736V TMPRSS6 genotypes predicted serum hepcidin independently of ferritin and C reactive protein (p = 0.048). In patients without acute inflammation and overt iron deficiency (C reactive protein <1 mg/dl and ferritin >30 ng/ml; n = 86), hepcidin was associated with lower mean corpuscular volume (p = 0.002), suggesting that it contributed to iron-restricted erythropoiesis. In line with previous results, in patients without acute inflammation and severe iron deficiency the "high hepcidin" 736 V TMPRSS6 variant was associated with higher erythropoietin maintenance dose (p = 0.016), independently of subclinical inflammation (p = 0.02). CONCLUSIONS: The A736V TMPRSS6 genotype influences hepcidin levels, erythropoiesis, and anemia management in CHD patients. Evaluation of the effect of TMPRSS6 genotype on clinical outcomes in prospective studies in CHD may be useful to predict the outcomes of hepcidin manipulation, and to guide treatment personalization by optimizing anemia management.


Asunto(s)
Péptidos Catiónicos Antimicrobianos/sangre , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Hierro/sangre , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple/genética , Diálisis Renal/estadística & datos numéricos , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/rehabilitación , Serina Endopeptidasas/genética , Biomarcadores/sangre , Hepcidinas , Humanos , Persona de Mediana Edad , Prevalencia , Insuficiencia Renal Crónica/epidemiología , Factores de Riesgo , Resultado del Tratamiento
17.
Cell Rep ; 42(10): 113252, 2023 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-37863057

RESUMEN

Apolipoprotein E4 (APOE4) is an important driver of Tau pathology, gliosis, and degeneration in Alzheimer's disease (AD). Still, the mechanisms underlying these APOE4-driven pathological effects remain elusive. Here, we report in a tauopathy mouse model that APOE4 promoted the nucleocytoplasmic translocation and release of high-mobility group box 1 (HMGB1) from hippocampal neurons, which correlated with the severity of hippocampal microgliosis and degeneration. Injection of HMGB1 into the hippocampus of young APOE4-tauopathy mice induced considerable and persistent gliosis. Selective removal of neuronal APOE4 reduced HMGB1 translocation and release. Treatment of APOE4-tauopathy mice with HMGB1 inhibitors effectively blocked the intraneuronal translocation and release of HMGB1 and ameliorated the development of APOE4-driven gliosis, Tau pathology, neurodegeneration, and myelin deficits. Single-nucleus RNA sequencing revealed that treatment with HMGB1 inhibitors diminished disease-associated and enriched disease-protective subpopulations of neurons, microglia, and astrocytes in APOE4-tauopathy mice. Thus, HMGB1 inhibitors represent a promising approach for treating APOE4-related AD.


Asunto(s)
Enfermedad de Alzheimer , Proteína HMGB1 , Tauopatías , Animales , Ratones , Enfermedad de Alzheimer/patología , Apolipoproteína E4/genética , Gliosis , Ratones Transgénicos , Tauopatías/tratamiento farmacológico
18.
Nat Aging ; 3(3): 275-296, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-37118426

RESUMEN

Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy.


Asunto(s)
Enfermedades Neurodegenerativas , Tauopatías , Ratones , Animales , Apolipoproteína E4/genética , Enfermedades Neurodegenerativas/genética , Vaina de Mielina/metabolismo , Gliosis/genética , Tauopatías/genética , Neuronas/metabolismo
19.
Sci Adv ; 9(49): eadj4884, 2023 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-38064566

RESUMEN

Oxygen deprivation and excess are both toxic. Thus, the body's ability to adapt to varying oxygen tensions is critical for survival. While the hypoxia transcriptional response has been well studied, the post-translational effects of oxygen have been underexplored. In this study, we systematically investigate protein turnover rates in mouse heart, lung, and brain under different inhaled oxygen tensions. We find that the lung proteome is the most responsive to varying oxygen tensions. In particular, several extracellular matrix (ECM) proteins are stabilized in the lung under both hypoxia and hyperoxia. Furthermore, we show that complex 1 of the electron transport chain is destabilized in hyperoxia, in accordance with the exacerbation of associated disease models by hyperoxia and rescue by hypoxia. Moreover, we nominate MYBBP1A as a hyperoxia transcriptional regulator, particularly in the context of rRNA homeostasis. Overall, our study highlights the importance of varying oxygen tensions on protein turnover rates and identifies tissue-specific mediators of oxygen-dependent responses.


Asunto(s)
Hiperoxia , Oxígeno , Animales , Ratones , Encéfalo/metabolismo , Hiperoxia/genética , Hiperoxia/metabolismo , Hipoxia/metabolismo , Pulmón/metabolismo , Oxígeno/metabolismo
20.
Nat Neurosci ; 26(12): 2104-2121, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37957317

RESUMEN

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.


Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Animales , Humanos , Ratones , Enfermedad de Alzheimer/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Mutación/genética , Enfermedades Neuroinflamatorias , Tauopatías/genética
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