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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable at https://rgc-covid19.regeneron.com.
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SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5×10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.
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We analyzed two West African samples (Guinea-Bissau: n=289 cases and 322 controls; The Gambia: n=240 cases and 248 controls) to evaluate single-nucleotide polymorphisms (SNPs) in Epiregulin (EREG) and V-ATPase (T-cell immune regulator 1 (TCIRG1)) using single and multilocus analyses to determine whether previously described associations with pulmonary tuberculosis (PTB) in Vietnamese and Italians would replicate in African populations. We did not detect any significant single locus or haplotype associations in either sample. We also performed exploratory pairwise interaction analyses using Visualization of Statistical Epistasis Networks (ViSEN), a novel method to detect only interactions among multiple variables, to elucidate possible interaction effects between SNPs and demographic factors. Although we found no strong evidence of marginal effects, there were several significant pairwise interactions that were identified in either the Guinea-Bissau or the Gambian samples, two of which replicated across populations. Our results indicate that the effects of EREG and TCIRG1 variants on PTB susceptibility, to the extent that they exist, are dependent on gene-gene interactions in West African populations as detected with ViSEN. In addition, epistatic effects are likely to be influenced by inter- and intra-population differences in genetic or environmental context and/or the mycobacterial lineages causing disease.
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Epirregulina/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Tuberculosis Pulmonar/genética , ATPasas de Translocación de Protón Vacuolares/genética , Adulto , Alelos , Población Negra/genética , Epistasis Genética , Gambia , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Genotipo , Guinea Bissau , Humanos , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Oportunidad Relativa , Tuberculosis Pulmonar/etnologíaRESUMEN
Pharmacogenomics (PGx) and pharmacogenetics (PGt) are emerging interdisciplinary areas recently defined by the regulatory authorities at an international level as 'the investigation of variations of DNA and RNA characteristics as related to drug response' (PGx), and the study of 'the influence of variations in DNA sequence on drug efficacy and toxicity' (PGt). In recent years a number of studies have in fact produced growing evidence that, besides the effects of age, sex, diseases, and different drugs interactions, genetic factors play a role in the inter-individual variability of drugs response. The increasing genomic knowledge has also raised the profile and role of the so called 'genomic biomarkers' (GBs) in drug development, approval, and clinical use. The aims of this review are to (a) revisit the general understanding of the role of genomics and genetics in drug response, (b) provide an update on the definition and classification criteria of GBs as recently defined at a global level by regulatory agencies such as the European Medicines Agency and the Food and Drug Administration, and (c) illustrate with some examples current and potential applications of biomarkers in clinical practice and in drug development.
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Aprobación de Drogas , Farmacogenética , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
We investigated the role of DC-SIGN (CD209), long pentraxin 3 (PTX3) and vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) in susceptibility to pulmonary tuberculosis (TB) in 321 TB cases and 347 healthy controls from Guinea-Bissau. Five additional, functionally relevant SNPs within toll-like receptors (TLRs) 2, 4 and 9 were typed but found, when polymorphic, not to affect host vulnerability to pulmonary TB. We did not replicate an association between SNPs in the DC-SIGN promoter and TB. However, we found that two polymorphisms, one in DC-SIGN and one in VDR, were associated in a nonadditive model with disease risk when analyzed in combination with ethnicity (P=0.03 for DC-SIGN and P=0.003 for VDR). In addition, PTX3 haplotype frequencies significantly differed in cases compared to controls and a protective effect was found in association with a specific haplotype (OR 0.78, 95% CI 0.63-0.98). Our findings support previous data showing that VDR SNPs modulate the risk for TB in West Africans and suggest that variation within DC-SIGN and PTX3 also affect the disease outcome.
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Proteína C-Reactiva/genética , Moléculas de Adhesión Celular/genética , Lectinas Tipo C/genética , Polimorfismo de Nucleótido Simple , Receptores de Calcitriol/genética , Receptores de Superficie Celular/genética , Componente Amiloide P Sérico/genética , Adolescente , Adulto , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Moléculas de Adhesión Celular/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Guinea Bissau , Haplotipos , Humanos , Lectinas Tipo C/metabolismo , Masculino , Mycobacterium tuberculosis , Receptores de Calcitriol/metabolismo , Receptores de Superficie Celular/metabolismo , Componente Amiloide P Sérico/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/metabolismoRESUMEN
We identified a novel trinucleotide (ATA)n repeat polymorphism in intron 8 of SLC11AI, a candidate gene for susceptibility to tuberculosis (TB) infection. We characterized the frequency of this polymorphism in 485 individuals originating from eight globally diverse human populations and compared the distribution of (ATA)n alleles in 146 adults and in 80 cord blood samples from newborns in the Gambian population. Lastly, we tested for association of this microsatellite with pulmonary TB in 318 TB cases and 146 controls in the Gambian population. We found no significant difference in frequency or distribution of alleles in adult and cord blood samples, and we found no significant association between this marker and pulmonary TB.
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Proteínas de Transporte de Catión/genética , Predisposición Genética a la Enfermedad , Repeticiones de Trinucleótidos , Tuberculosis Pulmonar/genética , Estudios de Casos y Controles , Frecuencia de los Genes , Humanos , Polimorfismo GenéticoRESUMEN
SETTING: Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide. Studies in a murine model of pulmonary TB have identified a role for Toll-like receptor 4 (TLR4) in the development of chronic lung infection with Mycobacterium tuberculosis. The Asp299Gly polymorphism in the human TLR4 gene is associated with in vivo hyporesponsiveness to lipopolysaccharide (LPS) in Caucasians. OBJECTIVE: To determine whether TLR4 Asp299Gly influences LPS responses or susceptibility to pulmonary TB in humans in a Gambian population sample. DESIGN: We compared whole blood monokine responses to LPS in 245 healthy blood donors stratified by TLR4 Asp299Gly genotype to assess whether this polymorphism was functional in this population. A case-control study of 640 subjects was conducted to investigate whether TLR4 Asp299Gly was associated with TB. RESULTS: LPS-induced tumour necrosis factor, interleukin-1 beta and interleukin-10 production was not influenced by TLR4 Asp299Gly genotype. There was no association between TLR4 Asp299Gly and TB. CONCLUSION: Our data suggest that TLR4 Asp299Gly has no influence on monocyte LPS responses or susceptibility to TB in Gambians and could be an ancient neutral polymorphism.
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Lipopolisacáridos/inmunología , Glicoproteínas de Membrana/genética , Receptores de Superficie Celular/genética , Tuberculosis Pulmonar/genética , Adolescente , Adulto , Estudios de Casos y Controles , Gambia , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Interleucina-1/análisis , Interleucina-10/análisis , Masculino , Glicoproteínas de Membrana/inmunología , Persona de Mediana Edad , Polimorfismo Genético/genética , Receptores de Superficie Celular/inmunología , Receptor Toll-Like 4 , Receptores Toll-Like , Tuberculosis Pulmonar/etnología , Tuberculosis Pulmonar/inmunología , Factor de Necrosis Tumoral alfa/análisis , Regulación hacia ArribaRESUMEN
Caucasians carry TNFA-308*2 in the 8.1 ancestral haplotype (AH) (HLA-A1,B8,DR3). In Gambians, TNFA-308*2 occurs without HLA-B8 or -DR3, suggesting an independent effect of TNFA-308 on disease. Hence we sought a segment of the 8.1 AH in Gambians. BAT1 (intron 10)*2 was selected as a specific marker of the haplotype and was found with TNFA-308*2 in Gambians. Samples homozygous at TNFA-308 and BAT1 (intron 10) demonstrated identity between the African TNFA-308*2 haplotype, the 8.1AH and the Asian diabetogenic 58.1AH (HLA-A33,B58,DR3) across a region spanning BAT1, ATP6G, IKBL, LTA, TNFA, LTB, LST-1 and AIF-1. Conservation of this block in geographically distinct populations suggests a common evolutionary origin and challenges current views of the role of TNFA-308*2 in disease.
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Antígeno HLA-A1/genética , Antígeno HLA-B8/genética , Antígeno HLA-DR3/genética , Haplotipos , Factor de Necrosis Tumoral alfa/genética , Pueblo Asiatico/genética , Biomarcadores , China , Gambia , Antígeno HLA-A1/inmunología , Antígeno HLA-B8/inmunología , Antígeno HLA-DR3/inmunología , Homocigoto , Humanos , Intrones , Repeticiones de Microsatélite , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
Two dinucleotide short tandem-repeat polymorphisms (STRPs) and a polymorphic Alu element spanning a 22-kb region of the PLAT locus on chromosome 8p12-q11.2 were typed in 1,287-1,420 individuals originating from 30 geographically diverse human populations, as well as in 29 great apes. These data were analyzed as haplotypes consisting of each of the dinucleotide repeats and the flanking Alu insertion/deletion polymorphism. The global pattern of STRP/Alu haplotype variation and linkage disequilibrium (LD) is informative for the reconstruction of human evolutionary history. Sub-Saharan African populations have high levels of haplotype diversity within and between populations, relative to non-Africans, and have highly divergent patterns of LD. Non-African populations have both a subset of the haplotype diversity present in Africa and a distinct pattern of LD. The pattern of haplotype variation and LD observed at the PLAT locus suggests a recent common ancestry of non-African populations, from a small population originating in eastern Africa. These data indicate that, throughout much of modern human history, sub-Saharan Africa has maintained both a large effective population size and a high level of population substructure. Additionally, Papua New Guinean and Micronesian populations have rare haplotypes observed otherwise only in African populations, suggesting ancient gene flow from Africa into Papua New Guinea, as well as gene flow between Melanesian and Micronesian populations.
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Elementos Alu/genética , Cromosomas Humanos Par 8/genética , Variación Genética/genética , Haplotipos/genética , Filogenia , Polimorfismo Genético/genética , Secuencias Repetidas en Tándem/genética , África del Sur del Sahara/etnología , Alelos , Animales , Repeticiones de Dinucleótido/genética , Evolución Molecular , Frecuencia de los Genes , Hominidae/genética , Humanos , Desequilibrio de Ligamiento , Micronesia , Papúa Nueva Guinea , Eliminación de Secuencia/genéticaRESUMEN
We showed recently that the yeast mitochondrial intermediate peptidase (YMIP polypeptide; gene symbol, OCT1) promotes mitochondrial iron uptake by catalyzing the maturation of iron-utilizing proteins and exacerbates the mitochondrial iron accumulation that results from loss of yeast frataxin, a mitochondrial protein required for mitochondrial iron efflux. This suggests that the human MIP (HMIP polypeptide; gene symbol MIPEP) may be one of the loci predicted to influence the clinical manifestations of Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease caused by lack of human frataxin. To begin to test this hypothesis, we have characterized HMIP at the functional and genomic levels. We show that HMIP can complement a yeast knock-out mutant lacking YMIP, demonstrating that HMIP and YMIP are functional homologues. The MIPEP gene spans 57 kb and consists of 19 exons that correlate with the functional domains of HMIP. Primer extension analysis has identified a major transcript of the MIPEP gene expressed differentially and predominantly in tissues with high oxygen consumption, while sequence analysis of approximately 2 kb of 5'-flanking DNA has revealed putative Mt1/3/4, NF-kappaB, and AP-1 elements that may regulate MIPEP expression in these tissues. Using a new polymorphic (CA)(n) repeat in intron 4, MIPEP has been genetically mapped within a 7-cM interval between markers D13S283 and D13S217 on 13q12. This work provides the basis for molecular analysis of MIPEP in FRDA and possibly other neurodegenerative diseases.
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Proteínas de Unión a Hierro , Metaloendopeptidasas/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Secuencia de Bases , División Celular , Cromosomas Humanos Par 13 , Mapeo Contig , ADN de Hongos , Salud de la Familia , Proteínas Fúngicas/biosíntesis , Proteínas Fúngicas/genética , Prueba de Complementación Genética , Ligamiento Genético , Humanos , Metaloendopeptidasas/biosíntesis , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Secuencias Repetitivas de Ácidos Nucleicos , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido Nucleico , Transcripción Genética , Levaduras/genética , FrataxinaRESUMEN
Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant type of amyloidosis resulting from the deposition of transthyretin (ATTR) variants in the peripheral and autonomic nervous systems. ATTR V30M-associated FAP exhibits marked genetic anticipation in some families, with clinical symptoms developing at an earlier age in successive generations. The genetic basis of this phenomenon in FAP is unknown. Anticipation has been associated with the dynamic expansion of trinucleotide repeats in several neurodegenerative disorders, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. We have used the repeat expansion detection (RED) assay to screen affected members of Portuguese FAP kindreds for expansion of any of the ten possible trinucleotide repeats. Nine generational pairs with differences in their age of onset greater than 12 years and a control pair with identical ages of onset were tested. No major differences were found in the lengths of the ten trinucleotide repeats analyzed. The distribution of the maximal repeat sizes was consistent with reported studies in unrelated individuals with no known genetic disease. The present data do not support a role for trinucleotide repeat expansions as the molecular mechanism underlying anticipation in Portuguese FAP.
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Neuropatías Amiloides/genética , Anticipación Genética , Expansión de Repetición de Trinucleótido , Adolescente , Adulto , Edad de Inicio , Alelos , Niño , Femenino , Genotipo , Humanos , Masculino , Linaje , Reacción en Cadena de la Polimerasa/métodos , PortugalAsunto(s)
Hominidae/clasificación , Animales , ADN/análisis , Técnicas Genéticas , Hominidae/genética , Humanos , Repeticiones de Minisatélite , FilogeniaRESUMEN
Survivin is a new IAP apoptosis inhibitor expressed during development and in human cancer in vivo. The coding strand of the survivin gene was extensively complementary to that of effector cell protease receptor-1 (EPR-1), prompting the present investigation on the origin and functional relationship of these two transcripts. Southern blots of genomic DNA were consistent with the presence of multiple, evolutionarily conserved, EPR-1/Survivin-related genes. By pulsed field gel electrophoresis and single- and two-color fluorescence in situ hybridization, these were contained within a contiguous physical interval of 75-130 kilobases (kb) on chromosome 17q25. In Northern blots, a single strand-specific probe identified a 1.3-kb EPR-1 mRNA broadly distributed in normal adult and fetal tissues, structurally distinct from the 1.9-kb Survivin transcript expressed in transformed cell lines. Transient co-transfection of an EPR-1 cDNA potentially acting as a Survivin antisense with a lacZ reporter plasmid resulted in loss of viability of HeLa cells. In contrast, co-transfection of an antisense cDNA of intercellular adhesion molecule-1 or a sense-oriented Survivin cDNA was without effect. In stably transfected HeLa cells, ZnSO4 induction of an EPR-1 mRNA under the control of a metallothionein promoter suppressed the expression of endogenous survivin. This resulted in (i) increased apoptosis as detected by analysis of DNA content and in situ internucleosomal DNA fragmentation and (ii) inhibition of cell proliferation as compared with induced vector control transfectants. These findings suggest the existence of a potential EPR-1/survivin gene cluster and identify survivin as a new target for disrupting cell viability pathways in cancer.
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Apoptosis/genética , División Celular/genética , Marcación de Gen , Proteínas Asociadas a Microtúbulos , Proteínas/genética , Mapeo Cromosómico , Cromosomas Humanos Par 17 , Fragmentación del ADN , Regulación hacia Abajo , Células HeLa , Humanos , Proteínas Inhibidoras de la Apoptosis , Proteínas de Neoplasias , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Superficie Celular/genética , SurvivinRESUMEN
In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral. However, the frequency of an allele in a population is generally not a perfect indicator of its ancestral status. A more accurate method to assess ancestral/derived status of polymorphic alleles involves identification of shared alleles between species. We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non-human primates. Cross species polymerase chain reaction (CS-PCR), with primers designed from human sequence, was used to investigate regions of interest. Nineteen polymorphisms at six loci (DRD2, HOXB@, PAH, D4S10, RBP3, and RET) were examined either by restriction fragment length analysis of PCR products (PCR-RFLP) or by direct sequencing. At seventeen of the eighteen PCR-RFLPs, non-human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site. Thus, at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans. In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele. However, not all human alleles can be simply resolved into ancestral and derived; sequence data from one PCR-RFLP (in an intron of the PAH locus) and a single strand conformational polymorphism (SSCP) in the 3' untranslated region (UTR) of the DRD2 gene illustrate this point.
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Alelos , Evolución Molecular , Polimorfismo Genético , Animales , Frecuencia de los Genes , Gorilla gorilla/genética , Humanos , Pan paniscus/genética , Pan troglodytes/genética , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo Conformacional Retorcido-Simple , Pongo pygmaeus/genética , Análisis de Secuencia de ADN/métodos , Especificidad de la EspecieRESUMEN
There are currently 13 diseases known to be caused by unstable triplet repeat mutations; however, there are some instances (as with FRAXF and FRA16) when these mutations appear to be asymptomatic. In a search for polymorphic CTG repeats as candidate genes for bipolar disorder, we screened a genomic human chromosome 18-specific library and identified a 1.6 kb clone (7,6A) with a CTG24 repeat that maps to 18q21.1. The CTG repeat locus, termed CTG18.1, is located within an intron of human SEF2-1, a gene encoding a basic hellx-loop-hellx DNA binding protein involved in transcriptional regulation. The CTGn repeat is highly polymorphic and very enlarged alleles, consistent with expansions of up to CTG2100, were identified. PCR and Southern blot analysis in pedigrees ascertained for a Johns Hopkins University bipolar disorder linkage study and in CEPH reference pedigrees revealed a tripartite distribution of CTG18.1 alleles with stable alleles (CTG10-CTG37), moderately enlarged and unstable alleles (CTG53-CTG250), and very enlarged, unstable alleles (CTG800-CTG2100). Moderately enlarged alleles were not associated with an abnormal phenotype and have a combined enlarged allele frequency of 3% in the CEPH and bipolar populations. Very enlarged alleles, detectable only by Southern blot analysis of genomic digests, have thus far been found in only three individuals from our bipolar pedigrees, and to date, have not been found in any of the CEPH reference pedigrees. These enlarged alleles may arise, at least in part, via somatic mutation.
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Cromosomas Humanos Par 18 , Proteínas de Unión al ADN/genética , Intrones , Transactivadores/genética , Factores de Transcripción/genética , Repeticiones de Trinucleótidos , Alelos , Secuencia de Bases , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Trastorno Bipolar/genética , Southern Blotting , Línea Celular , Clonación Molecular , Femenino , Frecuencia de los Genes , Secuencias Hélice-Asa-Hélice/genética , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Análisis de Secuencia , Factores de Transcripción TCF , Factor de Transcripción 4 , Proteína 2 Similar al Factor de Transcripción 7RESUMEN
The mitochondrial intermediate peptidase of Saccharomyces cerevisiae (YMIP) is a component of the yeast mitochondrial protein import machinery critically involved in the biogenesis of the oxidative phosphorylation (OXPHOS) system. This leader peptidase removes specific octapeptides from the amino terminus of nuclear-encoded OXPHOS subunits and components of the mitochondrial genetic apparatus. To address the biologic role of the human peptidase [MIPEP gene, HMIP polypeptide], we have initiated its molecular and functional characterization. A full-length cDNA was isolated by screening a human liver library using a rat MIP (RMIP) cDNA as a probe. The encoded protein contained a typical mitochondrial leader peptide and showed 92 and 54% homology to RMIP and YMIP, respectively. A survey of human mitochondrial protein precursors revealed that, similar to YMIP, HMIP is primarily involved in the maturation of OXPHOS-related proteins. Northern analysis showed that the MIPEP gene is differentially expressed in human tissues, with the highest levels of expression in the heart, skeletal muscle, and pancreas, three organ systems that are frequently affected in OXPHOS disorders. Using fluorescence in situ hybridization, the MIPEP locus was assigned to 13q12. This information offers the possibility of testing the potential involvement of HMIP in the pathophysiology of nuclear-driven OXPHOS disorders.