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4.
Nat Genet ; 53(1): 65-75, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398198

RESUMO

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.


Assuntos
Grupos de Populações Continentais/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias da Próstata/genética , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Invasividade Neoplásica , Razão de Chances , Neoplasias da Próstata/diagnóstico , Fatores de Risco
5.
Medicine (Baltimore) ; 99(45): e22908, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157933

RESUMO

Previous studies have evaluated the association between the phospholipase A2 m-type receptor (PLA2R1) rs4664308 polymorphism and the risk of idiopathic membranous nephropathy (IMN), but the results need to be integrated. We hypothesized that the PLA2R1 rs4664308 polymorphism is associated with IMN risk in different ethnicities and assessed this hypothesis by using meta-analysis and case-control studies.A literature searches on PLA2R1 rs4664308 and IMN risk was conducted using the EMBASE, PubMed, Cochrane Library, and Chinese Medical Databases. The relationship between PLA2R1 rs4664308 and IMN risk was evaluated in 5 genetic models, namely, allelic (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) models. Subgroup analysis was conducted by ethnicity on Asian and non-Asian populations.Eight sets of data from 6 articles met study objectives were selected and 6797 subjects (IMN: 2324 Controls: 4,473) were included. Heterogeneity was found in the DG, HMG, and HTG models but not in the AG or RG models. The minor allele(G) of PLA2R1 rs4664308 showed a significant negative correlation with IMN risk in all genetic random models: odds ratio of AG: 0.44(0.37-0.51), RG: 0.35(0.29-0.42), DG: 0.38(0.31-0.48), HMG: 0.26(0.19-0.37), and HTG: 0.61(0.48-0.77; P < .00001), and Asians and non-Asians showed the same effect of PLA2R1 rs4664308 on IMN risk. Analysis of Asians and non-Asians revealed no publication bias in any of the 5 genetic models.The minor allele of PLA2R1 rs4664308 has a protective activity against IMN in Asians and non-Asians. It provided new insights into potential curative and preventative treatments for IMN.


Assuntos
Predisposição Genética para Doença , Glomerulonefrite Membranosa/genética , Receptores da Fosfolipase A2/genética , Estudos de Casos e Controles , Grupos de Populações Continentais/genética , Humanos , Metanálise como Assunto , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Projetos de Pesquisa , Revisões Sistemáticas como Assunto
7.
Genes Immun ; 21(4): 269-272, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32759995

RESUMO

The entry of SARS-CoV-2 into host cells is dependent upon angiotensin-converting enzyme 2 (ACE2), which serves as a functional attachment receptor for the viral spike glycoprotein, and the serine protease TMPRSS2 which allows fusion of the viral and host cell membranes. We devised a quantitative measure to estimate genetic determinants of ACE2 and TMPRSS2 expression and applied this measure to >2500 individuals. Our data show significant variability in genetic determinants of ACE2 and TMPRSS2 expression among individuals and between populations, and indicate a genetic predisposition for lower expression levels of both key viral entry genes in African populations. These data suggest that host genetics related to viral entry mechanisms might influence interindividual variability in disease susceptibility and severity of COVID-19.


Assuntos
Infecções por Coronavirus/genética , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Serina Endopeptidases/genética , Grupos de Populações Continentais/genética , Infecções por Coronavirus/etnologia , Feminino , Humanos , Masculino , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/etnologia , Serina Endopeptidases/metabolismo
8.
S Afr Med J ; 110(2): 159-166, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32657689

RESUMO

BACKGROUND: Tacrolimus forms the cornerstone for immunosuppression in solid-organ transplantation. It has a narrow therapeutic window with wide inter- and intra-patient variability (IPV). Cytochrome P-450 3A5 (CYP3A5) is the main enzyme involved in tacrolimus metabolism, and rs776746A>G is the most frequently studied polymorphism in the CYP3A5 gene. The rs776746A>G (i.e. CYP3A5*3) single-nucleotide polymorphism in CYP3A5 alters tacrolimus predose trough concentration (C0) and may also affect IPV, which may lead to immune- and/or drug-mediated allograft injury. CYP3A5*3 may result in absent (*3/*3), partial (*1/*3) or normal (*1/*1) CYP3A5 expression. The effect of CYP3A5*3 on tacrolimus exposure and variability has not been examined in South African (SA) transplant recipients. OBJECTIVES: To determine the frequencies and effect of CYP3A5 and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) polymorphisms on tacrolimus C0/dose ratios in different ethnic groups attending a tertiary renal transplant clinic in SA, and other factors that may explain inter- and IPV in tacrolimus C0. METHODS: All consenting stable renal transplant recipients on tacrolimus at the Livingstone Hospital Renal Unit in Port Elizabeth, SA, were included. Tacrolimus concentrations were obtained using a microparticle enzyme immunoassay method (ARCHITECT analyser, Abbott Laboratories). Polymerase chain reaction/restriction fragment length polymorphism was used to genotype for CYP3A5*3 and *6 allelic variants. RESULTS: There were 43 participants (35% black African, 44% mixed ancestry and 21% white), with a mean age of 44.5 years, median duration post-transplant of 47 months and median (interquartile range) creatinine and estimated glomerular filtration rate levels of 118 (92 - 140) µmol/L and 62 (49 - 76) mL/min at study inclusion. The mean tacrolimus C0 in the study was 6.7 ng/mL, with no difference across the different ethnic groups. However, the mean total daily dose of tacrolimus required was 9.1 mg (0.12 mg/kg), 7.2 mg (0.09 mg/kg) and 4.3 mg (0.06 mg/kg) in black, mixed-ancestry and white patients, respectively (p=0.017). The frequencies for CYP3A5 expressors (i.e. CYP3A5*1/*1 + CYP3A5*1/*3 genotypes) were 72%, 100%, 76% and 12% for all patients combined and black, mixed-ancestry and white patients, respectively. The frequencies for CYP3A5 non-expressors (i.e. CYP3A5*3/*3 genotypes) were 0%, 24% and 88% among the black, mixed-ancestry and white patients, respectively. None of the patients carried the CYP3A5*6 allele. CYP3A5*1/*1 and CYP3A5*1/*3 genotype carriers required a two-fold increase in dose compared with the non-expressor genotype carriers, CYP3A5*3/*3 (p<0.05). CYP3A5*3/*3 carriers also demonstrated higher IPV than CYP3A5*1/*1 and *1/*3 carriers (18.1% v. 14.2%; p=0.125). CONCLUSIONS: Compared with global transplant populations, SA renal transplant recipients demonstrated a very high rate of CYP3A5 expression, with a significant impact on tacrolimus pharmacokinetics. Genetic variation in CYP3A5 expression affects tacrolimus dosing requirements, and knowing the CYP3A5 genotype of transplant patients may allow better dose prediction compared with current standard dosing recommendations in a multi-ethnic population. Overall, black African patients required higher doses of tacrolimus than their white counterparts. While further prospective studies are needed to better evaluate dosing algorithms, it would appear that the starting dose of tacrolimus should be higher in black and mixed-race patients.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Tacrolimo/administração & dosagem , Adulto , Estudos de Coortes , Grupos de Populações Continentais/genética , Relação Dose-Resposta a Droga , Feminino , Variação Genética , Genótipo , Humanos , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , África do Sul , Tacrolimo/farmacocinética
9.
Curr Atheroscler Rep ; 22(9): 48, 2020 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-32710255

RESUMO

PURPOSE OF REVIEW: The COVID-19 pandemic has infected over > 11 million as of today people worldwide and is associated with significant cardiovascular manifestations, particularly in subjects with preexisting comorbidities and cardiovascular risk factors. Recently, a predisposition for arterial and venous thromboses has been reported in COVID-19 infection. We hypothesize that besides conventional risk factors, subjects with elevated lipoprotein(a) (Lp(a)) may have a particularly high risk of developing cardiovascular complications. RECENT FINDINGS: The Lp(a) molecule has the propensity for inhibiting endogenous fibrinolysis through its apolipoprotein(a) component and for enhancing proinflammatory effects such as through its content of oxidized phospholipids. The LPA gene contains an interleukin-6 (IL-6) response element that may induce an acute phase-type increase in Lp(a) levels following a cytokine storm from COVID-19. Thus, subjects with either baseline elevated Lp(a) or those who have an increase following COVID-19 infection, or both, may be at very high risk of developing thromboses. Elevated Lp(a) may also lead to acute destabilization of preexisting but quiescent atherosclerotic plaques, which might induce acute myocardial infarction and stroke. Ongoing studies with IL-6 antagonists may be informative in understanding this relationship, and registries are being initiated to measure Lp(a) in subjects infected with COVID-19. If indeed an association is suggestive of being causal, consideration can be given to systematic testing of Lp(a) and prophylactic systemic anticoagulation in infected inpatients. Therapeutic lipid apheresis and pharmacotherapy for the reduction of Lp(a) levels may minimize thrombogenic potential and proinflammatory effects. We propose studies to test the hypothesis that Lp(a) may contribute to cardiovascular complications of COVID-19.


Assuntos
Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Inflamação/etiologia , Lipoproteína(a)/sangue , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Trombose/etiologia , Proteínas da Fase Aguda/análise , Proteínas da Fase Aguda/genética , Anticoagulantes/uso terapêutico , Apolipoproteína E4/genética , Aterosclerose/etiologia , Betacoronavirus , Biomarcadores/sangue , Pesquisa Biomédica , Remoção de Componentes Sanguíneos , Grupos de Populações Continentais/genética , Infecções por Coronavirus/epidemiologia , Genótipo , Humanos , Inflamação/prevenção & controle , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Lipoproteína(a)/genética , Pandemias , Pneumonia Viral/epidemiologia , Fatores Raciais , Fatores de Risco , Índice de Gravidade de Doença , Trombose/prevenção & controle
10.
FASEB J ; 34(7): 8787-8795, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32525600

RESUMO

The dynamics, such as transmission, spatial epidemiology, and clinical course of Coronavirus Disease-2019 (COVID-19) have emerged as the most intriguing features and remain incompletely understood. The genetic landscape of an individual in particular, and a population in general seems to play a pivotal role in shaping the above COVID-19 dynamics. Considering the implications of host genes in the entry and replication of SARS-CoV-2 and in mounting the host immune response, it appears that multiple genes might be crucially involved in the above processes. Herein, we propose three potentially important genetic gateways to COVID-19 infection; these could explain at least in part the discrepancies of its spread, severity, and mortality. The variations within Angiotensin-converting enzyme 2 (ACE2) gene might constitute the first genetic gateway, influencing the spatial transmission dynamics of COVID-19. The Human Leukocyte Antigen locus, a master regulator of immunity against infection seems to be crucial in influencing susceptibility and severity of COVID-19 and can be the second genetic gateway. The genes regulating Toll-like receptor and complement pathways and subsequently cytokine storm induced exaggerated inflammatory pathways seem to underlie the severity of COVID-19, and such genes might represent the third genetic gateway. Host-pathogen interaction is a complex event and some additional genes might also contribute to the dynamics of COVID-19. Overall, these three genetic gateways proposed here might be the critical host determinants governing the risk, severity, and outcome of COVID-19. Genetic variations within these gateways could be key in influencing geographical discrepancies of COVID-19.


Assuntos
Betacoronavirus/fisiologia , Ativação do Complemento/genética , Infecções por Coronavirus/genética , Antígenos HLA/genética , Interações Hospedeiro-Patógeno/genética , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Receptores Virais/genética , Receptores Toll-Like/genética , Grupos de Populações Continentais/genética , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/genética , Resistência à Doença/imunologia , Predisposição Genética para Doença , Variação Genética , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação , Metagenômica , Mutação de Sentido Incorreto , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , Prognóstico , Locos de Características Quantitativas , Receptores Virais/fisiologia , Risco , Receptores Toll-Like/imunologia , Resultado do Tratamento
11.
Anticancer Res ; 40(6): 3307-3314, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487626

RESUMO

BACKGROUND/AIM: Recent evidence has shown that African American men with prostate cancer may have more radiosensitive disease with greater overall survival (OS) with radiotherapy compared to Caucasian men. We compared OS in African American and Caucasian men receiving radiotherapy utilizing the National Cancer Database. PATIENTS AND METHODS: African American or Caucasian men with N0M0 prostate adenocarcinoma diagnosed between 2004 and 2013 were selected and grouped into favorable and unfavorable risk based on clinical T-stage, clinical Gleason score, and prostate-specific antigen. Patients with favorable risk received brachytherapy or dose-escalated external beam radiation (EBRT); those with unfavorable risk received EBRT plus anti-androgen therapy with/without brachytherapy. African American and Caucasian men in each subgroup were propensity score-matched and analyzed for survival. Sensitivity analysis used treatment-race and age-race interaction terms. RESULTS: 27,150 patients met the inclusion criteria, with a median age of 68 (range=38-90) years and median follow-up of 59.93 (range=48-142.62) months. OS was equivalent between African American and Caucasian race in favorable risk [log-rank p=0.82; hazard ratio (HR)=0.928; 95% confidence intervaI (CI)=0.583-1.477, p=0.753] and unfavorable-risk subgroups (log-rank p=0.87, HR=1.078, 95% CI=0.843-1.379, p=0.550). No significant interaction existed between treatment and race for either cohort but there was a significant interaction between race and age in those with unfavorable risk (HR=1.046, 95% CI=1.009-1.084, p=0.015), with greater OS in those of Caucasian race ≤60 years (HR=0.320, 95% CI=0.137-0.752, p=0.009). CONCLUSION: African American and Caucasian men have similar survival when treated with risk-appropriate definitive radiotherapy. However, younger (age ≤60 years) African American men with unfavorable risk have poorer survival than their Caucasian counterparts and may harbor a significantly different biology of disease.


Assuntos
Grupos de Populações Continentais/genética , Neoplasias da Próstata/etnologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/radioterapia , Análise de Sobrevida
13.
Nature ; 581(7809): 444-451, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32461652

RESUMO

Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.


Assuntos
Doença/genética , Variação Genética , Genética Médica/normas , Genética Populacional/normas , Genoma Humano/genética , Grupos de Populações Continentais/genética , Feminino , Testes Genéticos , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único/genética , Padrões de Referência , Seleção Genética , Sequenciamento Completo do Genoma
15.
Nature ; 583(7814): 83-89, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32460305

RESUMO

A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.


Assuntos
Variação Genética , Genoma Humano/genética , Sequenciamento Completo do Genoma , Alelos , Estudos de Casos e Controles , Grupos de Populações Continentais/genética , Epigênese Genética , Feminino , Dosagem de Genes/genética , Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Anotação de Sequência Molecular , Locos de Características Quantitativas , Software
16.
Sci Rep ; 10(1): 6820, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32321981

RESUMO

A major racial disparity in prostate cancer (PCa) is that African American (AA) patients have a higher mortality rate than European American (EA) patients. We filtered the SEER 2009-2011 records and divided them into four groups regarding patient races and cancer grades. On such a partition, we performed a series of statistical analyses to further clarify the aforementioned disparity. Molecular evidence for a primary result of the epidemiological analysis was obtained from gene expression data. The results include: (1) Based on the registry-specific measures, a significant linear regression of total mortality rate (as well as PCa specific mortality rate) on the percentage of (Gleason pattern-based) high-grade cancers (PHG) is demonstrated in EAs (p < 0.01) but not in AAs; (2) PHG and its racial disparity are differentiated across ages and the groups defined by patient outcomes; (3) For patients with cancers in the same grade category, i.e. the high or low grade, the survival stratification between races is not significant in most geographical areas; and (4) The genes differentially expressed between AAs' and EAs' tumors of the same grade category are relatively rare. The perception that prostate tumors are more lethal in AAs than in EAs is reasonable regarding AAs' higher PHG, while high grade alone could not imply aggressiveness. However, this perception is questionable when the comparison is focused on cases within the same grade category. Supporting observations for this conclusion hold a remarkable implication for erasing racial disparity in PCa. That is, "Equal grade, equal outcomes" is not only a verifiable hypothesis but also an achievable public health goal.


Assuntos
Grupos de Populações Continentais/genética , Análise de Dados , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Saúde Pública , Programa de SEER , Afro-Americanos/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Demografia , Grupo com Ancestrais do Continente Europeu/genética , Perfilação da Expressão Gênica , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Sistema de Registros , Análise de Regressão , Análise de Sobrevida
18.
PLoS Genet ; 16(3): e1008684, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226016

RESUMO

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.


Assuntos
Grupos de Populações Continentais/genética , Lipídeos/sangue , Lipídeos/genética , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Lipídeos/análise , Masculino , Metagenômica/métodos , Grupos Minoritários , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
19.
Sci Rep ; 10(1): 6628, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313169

RESUMO

The HLA region is responsible for almost 50% of the genetic risk of type 1 diabetes (T1D). However, haplotypes and their effects on risk or protection vary among different ethnic groups, mainly in an admixed population. We aimed to evaluate the HLA class II genetic profile of Brazilian individuals with T1D and its relationship with self-reported color/race. This was a nationwide multicenter study conducted in 10 Brazilian cities. We included 1,019 T1D individuals and 5,116 controls matched for the region of birth and self-reported color/race. Control participants belonged to the bone marrow transplant donor registry of Brazil (REDOME). HLA-class II alleles (DRB1, DQA1, and DQB1) were genotyped using the SSO and NGS methods. The most frequent risk and protection haplotypes were HLA~DRB1*03:01~DQA1*05:01 g~DQB1*02:01 (OR 5.8, p < 0.00001) and HLA~DRB1*07:01~DQA1*02:01~DQB1*02:02 (OR 0.54, p < 0.0001), respectively, regardless of self-reported color/race. Haplotypes HLA~DRB1*03:01~DQA1*05:01 g~DQB1*02:01 and HLA~DRB1*04:02~DQA1*03:01 g~DQB1*03:02 were more prevalent in the self-reported White group than in the Black group (p = 0.04 and p = 0.02, respectively). The frequency of haplotype HLA~DRB1*09:01~DQA1*03:01 g~DQB1*02:02 was higher in individuals self-reported as Black than White (p = <0.00001). No difference between the Brazilian geographical regions was found. Individuals with T1D presented differences in frequencies of haplotypes within self-reported color/race, but the more prevalent haplotypes, regardless of self-reported color/race, were the ones described previously in Europeans. We hypothesize that, in the T1D population of Brazil, although highly admixed, the disease risk alleles come mostly from Europeans as a result of centuries of colonization and migration.


Assuntos
Grupos de Populações Continentais/genética , Diabetes Mellitus Tipo 1/genética , Genes MHC da Classe II , Técnicas de Genotipagem , Autorrelato , Adulto , Alelos , Brasil , Feminino , Haplótipos/genética , Humanos , Masculino , Fatores de Risco
20.
Clin Immunol ; 214: 108385, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32173601

RESUMO

Kawasaki disease (KD) is a common vasculitis of childhood, typically affecting children under the age of five. Despite many aspects of its presentation that bear resemblence to acute infection, no causative infectious agent has been identified despite years of intense scrutiny. Unlike most infections, however, there are significant differences in racial predilection that suggest a strong genetic influence. The inflammatory response in KD specifically targets the coronary arteries, also unusual for an infectious condition. In this review, we discuss recent hypotheses on KD pathogenesis as well as new insights into the innate immune response and mechanisms behind vascular damage. The pathogenesis is complex, however, and remains inadequately understood.


Assuntos
Síndrome de Linfonodos Mucocutâneos/etiologia , Imunidade Adaptativa , Animais , Pré-Escolar , Análise por Conglomerados , Grupos de Populações Continentais/genética , Vasos Coronários/imunologia , Vasos Coronários/patologia , Modelos Animais de Doenças , Exposição Ambiental , Grupos Étnicos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Imunidade Inata , Imunoglobulina A/imunologia , Incidência , Lactente , Infecções/complicações , Inflamação , Metaloproteinases da Matriz/fisiologia , Camundongos , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Linfonodos Mucocutâneos/imunologia , Miocárdio/imunologia , Miocárdio/patologia , Inibidores de Proteases/uso terapêutico
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