RESUMO
The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing â¼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease.
Assuntos
Citometria de Fluxo/métodos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doenças do Sistema Imunitário/genética , Polimorfismo de Nucleotídeo Único , Humanos , FenótipoRESUMO
Few genome-wide association studies (GWAS) analyzing genetic regulation of morphological traits of white blood cells have been reported. We carried out a GWAS of 12 morphological traits in 869 individuals from the general population of Sardinia, Italy. These traits, included measures of cell volume, conductivity and light scatter in four white-cell populations (eosinophils, lymphocytes, monocytes, neutrophils). This analysis yielded seven statistically significant signals, four of which were novel (four novel, PRG2, P2RX3, two of CDK6). Five signals were replicated in the independent INTERVAL cohort of 11 822 individuals. The most interesting signal with large effect size on eosinophil scatter (P-value = 8.33 x 10-32, beta = -1.651, se = 0.1351) falls within the innate immunity cluster on chromosome 11, and is located in the PRG2 gene. Computational analyses revealed that a rare, Sardinian-specific PRG2:p.Ser148Pro mutation modifies PRG2 amino acid contacts and protein dynamics in a manner that could possibly explain the changes observed in eosinophil morphology. Our discoveries shed light on genetics of morphological traits. For the first time, we describe such large effect size on eosinophils morphology that is relatively frequent in Sardinian population.
Assuntos
Eosinófilos , Estudo de Associação Genômica Ampla , Humanos , Cromossomos Humanos Par 11 , Polimorfismo de Nucleotídeo Único , Imunidade InataRESUMO
Everyone carries a set of genetic variants that contribute to regulation of the levels of blood cells, with unknown clinical impact. One of them, rs445 within the cell-cycle checkpoint gene CDK6, reduces the levels of myeloid cell types including granulocytes. We treated CD3+ T cells and whole blood with palbociclib in 41 individuals, who were stratified by genotype for analyses. In T cells we assessed cell cycle and apoptosis, whereas in whole blood, apoptosis in activated (CD11b+), unactivated (CD11b-) granulocytes, cytotoxic (CD8 + CD4-), and helper (CD8-CD4+) T cells. We find that rs445 modulates the immune response of CD8+ T cells. It also increases the level of apoptotic CD11b + activated granulocytes after palbociclib treatment, which, in synergy with neutropenia, may affect drug related adverse events. These results suggest that the effect of palbociclib treatment may depend on underlying genetically encoded individual immune response as well as the direct response to the drug.
Assuntos
Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Variação Genética , Piperazinas/farmacologia , Piridinas/farmacologia , Linfócitos T/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T/fisiologiaRESUMO
Pharmacogenetics (PGx) aims to identify the genetic factors that determine inter-individual differences in response to drug treatment maximizing efficacy while decreasing the risk of adverse events. Estimating the prevalence of PGx variants involved in drug response, is a critical preparatory step for large-scale implementation of a personalized medicine program in a target population. Here, we profiled pharmacogenetic variation in fourteen clinically relevant genes in a representative sample set of 1577 unrelated sequenced Sardinians, an ancient island population that accounts for genetic variation in Europe as a whole, and, at the same time is enriched in genetic variants that are very rare elsewhere. To this end, we used PGxPOP, a PGx allele caller based on the guidelines created by the Clinical Pharmacogenetics Implementation Consortium (CPIC), to identify the main phenotypes associated with the PGx alleles most represented in Sardinians. We estimated that 99.43% of Sardinian individuals might potentially respond atypically to at least one drug, that on average each individual is expected to have an abnormal response to about 17 drugs, and that for 27 drugs the fraction of the population at risk of atypical responses to therapy is more than 40%. Finally, we identified 174 pharmacogenetic variants for which the minor allele frequency was at least 10% higher among Sardinians as compared to other European populations, a fact that may contribute to substantial interpopulation variability in drug response phenotypes. This study provides baseline information for further large-scale pharmacogenomic investigations in the Sardinian population and underlines the importance of PGx characterization of diverse European populations, such as Sardinians.
Assuntos
Farmacogenética , Medicina de Precisão , Frequência do Gene , Variação Genética , Testes Farmacogenômicos , Variantes FarmacogenômicosRESUMO
BACKGROUND: Defective alleles within the PRF1 gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines-cytokine storm. OBJECTIVE: The aim of this study was to determine the function of hypomorph PRF1:p.A91V g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D). METHODS: We cross-compare the association data for PRF1:p.A91V mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians. RESULTS: We report that PRF1:p.A91V, is associated with increase of lymphocyte levels, especially within the cytotoxic memory T-cells, at general population level with reduced interleukin 7 receptor expression on these cells. The minor allele increased risk of MS, in 2903 cases and 2880 controls from Sardinia p = 2.06 × 10-4, odds ratio OR = 1.29, replicating a previous finding, whereas it protects from T1D p = 1.04 × 10-5, OR = 0.82. CONCLUSION: Our results indicate opposing contributions of the cytotoxic T-cell compartment to MS and T1D pathogenesis.
Assuntos
Autoimunidade , Sistema Imunitário , Autoimunidade/genética , Criança , Humanos , Inflamação , Proteínas com Homeodomínio LIM , Proteínas Musculares , Mutação , Perforina/genética , Fatores de TranscriçãoRESUMO
BACKGROUND: The relationship of kidney size to ageing, kidney function and kidney disease risk factors is not fully understood. METHODS: Ultrasound length and parenchymal kidney volume were determined from a population-based sample of 3972 Sardinians (age range 18-100 years). We then identified the subset of 2256 'healthy' subjects to define age- and sex-specific reference ranges (2.5-97.5 percentile) of kidney volume. Logistic regression (accounting for family clustering) was used to identify the clinical characteristics associated with abnormally large kidneys or abnormally small kidneys. RESULTS: In the healthy subset, kidney volume and length increased up to the fourth to fifth decade of life followed by a progressive decrease in men, whereas there was a gradual kidney volume decrease throughout the lifespan of women. In the whole sample, independent predictors of lower kidney volume (<2.5 percentile for age and sex) were male sex, low body mass index, short height, low waist:hip ratio and high serum creatinine (SCr); the independent predictors of larger kidney volume (>97.5 percentile for age and sex) were younger age, female sex, diabetes, obesity, high height, high waist:hip ratio and lower SCr. Estimated heritability for kidney volume was 15%, and for length 27%; kidney volume correlated strongly with birthweight. CONCLUSIONS: Overall, in a general healthy population, kidney measures declined with age differently in men and women. The determinants of kidney parenchymal volume include genetic factors and modifiable clinical factors.
Assuntos
Envelhecimento , Peso ao Nascer , Índice de Massa Corporal , Diabetes Mellitus/fisiopatologia , Rim/anatomia & histologia , Obesidade/fisiopatologia , Insuficiência Renal Crônica/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Rim/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/epidemiologia , Fatores de Risco , Fatores Sexuais , Ultrassonografia , Relação Cintura-Quadril , Adulto JovemRESUMO
Hypoglycaemia is the most common metabolic health complication in newborns. Persistent and severe hypoglycaemia in a neonate is correlated with morbidity and could represent an early clinical manifestation of an endocrine or metabolic, genetically determined disorder. Besides this, the most common reason for neonatal hypoglycaemia is the inmature liver storage of glucose seen in preterms or children born intrauterine growth retarded. The genetic determination of hypoglycaemia is gene- and allele- heterogeneous, and thus complex to diagnose. Nevertheless its contribution to brain damage and intellectual disability in children provides a strong rationale for comprehensive and rapid testing. Hypoglycaemia may contribute directly to the phenotype of various genetic syndromes but because of their rarity, it has been not always included in differential diagnosis and its frequency has been underestimated. In clinical practice but also with the growing attention to improved neonatal helathcare and to neonatal genetic screening programmes, the detailed classification of genotype to phenotype is of great importance. This review provides a catalogue of syndromic forms of neonatal hypoglycaemia.
Assuntos
Hipoglicemia , Testes Genéticos , Genótipo , Glucose , Humanos , Recém-Nascido , FenótipoRESUMO
Sardinians are "outliers" in the European genetic landscape and, according to paleogenomic nuclear data, the closest to early European Neolithic farmers. To learn more about their genetic ancestry, we analyzed 3,491 modern and 21 ancient mitogenomes from Sardinia. We observed that 78.4% of modern mitogenomes cluster into 89 haplogroups that most likely arose in situ. For each Sardinian-specific haplogroup (SSH), we also identified the upstream node in the phylogeny, from which non-Sardinian mitogenomes radiate. This provided minimum and maximum time estimates for the presence of each SSH on the island. In agreement with demographic evidence, almost all SSHs coalesce in the post-Nuragic, Nuragic and Neolithic-Copper Age periods. For some rare SSHs, however, we could not dismiss the possibility that they might have been on the island prior to the Neolithic, a scenario that would be in agreement with archeological evidence of a Mesolithic occupation of Sardinia.
Assuntos
DNA Mitocondrial/genética , Genoma Mitocondrial/genética , DNA Antigo/análise , Demografia , Etnicidade/genética , Evolução Molecular , Variação Genética/genética , Genética Populacional/métodos , Haplótipos/genética , Humanos , Ilhas , Itália/etnologia , Filogenia , Análise de Sequência de DNA/métodos , População Branca/genéticaRESUMO
Advances in exome sequencing and the development of exome genotyping arrays are enabling explorations of association between rare coding variants and complex traits. To ensure power for these rare variant analyses, a variety of association tests that group variants by gene or functional unit have been proposed. Here, we extend these tests to family-based studies. We develop family-based burden tests, variable frequency threshold tests and sequence kernel association tests. Through simulations, we compare the performance of different tests. We describe situations where family-based studies provide greater power than studies of unrelated individuals to detect rare variants associated with moderate to large changes in trait values. Broadly speaking, we find that when sample sizes are limited and only a modest fraction of all trait-associated variants can be identified, family samples are more powerful. Finally, we illustrate our approach by analyzing the relationship between coding variants and levels of high-density lipoprotein (HDL) cholesterol in 11,556 individuals from the HUNT and SardiNIA studies, demonstrating association for coding variants in the APOC3, CETP, LIPC, LIPG, and LPL genes and illustrating the value of family samples, meta-analysis, and gene-level tests. Our methods are implemented in freely available C++ code.
Assuntos
Estudos de Associação Genética/métodos , Variação Genética/genética , Modelos Genéticos , Software , Apolipoproteína C-III/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , HDL-Colesterol/genética , Simulação por Computador , Exoma/genética , Família , Genótipo , Humanos , Lipase/genética , Lipase Lipoproteica/genética , FenótipoRESUMO
BACKGROUND: Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. METHODS: We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. RESULTS: Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 0(-6) level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10(-5), we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16 x 10(-5)), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. CONCLUSIONS: This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population.
Assuntos
Neoplasias da Mama/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptores de Progesterona/genética , Proteínas Reguladoras de Apoptose , Estudos de Casos e Controles , Feminino , Genes BRCA1 , Genes BRCA2 , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas de Grupo de Alta Mobilidade , Humanos , Itália , Penetrância , TransativadoresRESUMO
BACKGROUND: Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored. OBJECTIVE: We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians. METHODS: We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke's R(2) and the area under the Receiver Operating Characteristic (ROC) curves. RESULTS: As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles. CONCLUSIONS: The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics.
Assuntos
Predisposição Genética para Doença , Antígenos HLA/genética , Esclerose Múltipla/etnologia , Esclerose Múltipla/genética , Biomarcadores , Genótipo , Humanos , Itália/etnologia , Polimorfismo de Nucleotídeo Único , RiscoRESUMO
Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional â¼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, pâ=â2.13×10(-29)); for ESR, at the HBB (rs4910472, pâ=â2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, pâ=â8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, pâ=â7.53×10(-13)) and in CADM3 (rs3026968, pâ=â7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, pâ=â5.73×10(-21)), near DARC (rs3845624, pâ=â1.43×10(-10)), UNC119B/SPPL3 (rs11829037, pâ=â1.50×10(-14)), and ICOSLG/AIRE (rs113459440, pâ=â1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.
Assuntos
Sedimentação Sanguínea , Proteína C-Reativa/genética , Quimiocina CCL2/genética , Estudo de Associação Genômica Ampla/métodos , Inflamação/genética , Interleucina-6/genética , Locos de Características Quantitativas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Multiple sclerosis (MS) is a complex neurological disease characterized by great variability in clinical presentation, including the radiological features, and degree of disability. Both genetics and environment contribute to disease etiopathogenesis. Because MS is more common in Western countries, and diet has been proposed among the etiologic factors. However, based on the several studies published thus far, principally involving small cohorts, there is no described diet-protocol to be applied in clinical practice as a supplement to the standard immunomodulatory treatment of MS. Diet is an easily changeable factor thus the research on the diet importance in MS has been exploded in last years. Starting from the notions that diet can change lifespan and quality of life in general, and its improvement could be one of many contributing factors with effects on disease evolution, this review examines the evidence of the effects of intermittent fasting in a mouse model of MS; the evidence derived from clinical trials; and future perspectives.
Assuntos
Jejum , Esclerose Múltipla , Humanos , Esclerose Múltipla/terapia , Jejum/fisiologia , AnimaisRESUMO
Introduction: Disease-modifying therapies (DMTs) have been shown to improve disease outcomes in multiple sclerosis (MS) patients. They may also impair the immune response to vaccines, including the SARS-CoV-2 vaccine. However, available data on both the intrinsic immune effects of DMTs and their influence on cellular response to the SARS-CoV-2 vaccine are still incomplete. Methods: Here, we evaluated the immune cell effects of 3 DMTs on the response to mRNA SARS-CoV-2 vaccination by comparing MS patients treated with one specific therapy (fingolimod, dimethyl fumarate, or natalizumab) with both healthy controls and untreated patients. We profiled 23 B-cell traits, 57 T-cell traits, and 10 cytokines, both at basal level and after stimulation with a pool of SARS-CoV-2 spike peptides, in 79 MS patients, treated with DMTs or untreated, and 32 healthy controls. Measurements were made before vaccination and at three time points after immunization. Results and Discussion: MS patients treated with fingolimod showed the strongest immune cell dysregulation characterized by a reduction in all measured lymphocyte cell classes; the patients also had increased immune cell activation at baseline, accompanied by reduced specific immune cell response to the SARS-CoV-2 vaccine. Also, anti-spike specific B cells progressively increased over the three time points after vaccination, even when antibodies measured from the same samples instead showed a decline. Our findings demonstrate that repeated booster vaccinations in MS patients are crucial to overcoming the immune cell impairment caused by DMTs and achieving an immune response to the SARS-CoV-2 vaccine comparable to that of healthy controls.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Fumarato de Dimetilo , Cloridrato de Fingolimode , Esclerose Múltipla , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/prevenção & controle , Masculino , Esclerose Múltipla/imunologia , Esclerose Múltipla/tratamento farmacológico , Feminino , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Pessoa de Meia-Idade , Adulto , Cloridrato de Fingolimode/uso terapêutico , Cloridrato de Fingolimode/farmacologia , Fumarato de Dimetilo/uso terapêutico , Fumarato de Dimetilo/farmacologia , Imunossupressores/uso terapêutico , Natalizumab/uso terapêutico , Linfócitos B/imunologia , Vacinação , Linfócitos T/imunologia , Citocinas/metabolismoRESUMO
BACKGROUND: Growing evidence has suggested the involvement of gut microbiota in the pathophysiology of multiple sclerosis (MS). Disease-modifying therapies (DMTs) exert a parallel effect on the gut microenvironment with subsequent modulation of the intestinal and systemic immune system. Herein, we summarize the current literature on the effect of DMTs on the gut microbiome and possible implications for MS. METHODS: All the literature available in PubMed on the effects of DMTs on the gut microbiota composition in patients with MS was reviewed. We used multiple combinations of the following keywords: "multiple sclerosis; demyelinating disease; gut microbiome; microbiome; brain-gut axis; diet; fecal microbiome; disease modifying therapy; immunomodulator; interferon; glatiramer acetate; teriflunomide; dimethyl fumarate; natalizumab; alemtuzumab; anti-CD20; fingolimod". All the original research articles available in English were included in this narrative review. RESULTS: Ten original full-text articles were considered eligible, including seven case-control and three cohort studies. First-line DMTs, including oral and subcutaneous treatments (dimethyl fumarate, glatiramer acetate, and interferon ß 1b) were considered, while a small number of patients with MS were under natalizumab, fingolimod and anti-CD20 treatments. CONCLUSIONS: Emerging evidence reported changes in the gut microbiome during exposition to DMTs. However, the association between DMTs exposure and microbial changes was mostly indirect, and the results of the different studies needed to be more consistent. The mitigation of methodological bias is necessary for future studies to allow the identification of a "microbial signature" related to MS pathophysiology, the role of DMTs, and possible prognostic implications.
Assuntos
Microbioma Gastrointestinal , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla/tratamento farmacológico , Imunossupressores , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Acetato de Glatiramer/uso terapêutico , Natalizumab , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêuticoRESUMO
Monitoring immune responses to SARS-CoV-2 vaccination and its clinical efficacy over time in Multiple Sclerosis (MS) patients treated with disease-modifying therapies (DMTs) help to establish the optimal strategies to ensure adequate COVID-19 protection without compromising disease control offered by DMTs. Following our previous observations on the humoral response one month after two doses of BNT162b2 vaccine (T1) in MS patients differently treated, here we present a cross-sectional and longitudinal follow-up analysis six months following vaccination (T2, n=662) and one month following the first booster (T3, n=185). Consistent with results at T1, humoral responses were decreased in MS patients treated with fingolimod and anti-CD20 therapies compared with untreated patients also at the time points considered here (T2 and T3). Interestingly, a strong upregulation one month after the booster was observed in patients under every DMTs analyzed, including those treated with fingolimod and anti-CD20 therapies. Although patients taking these latter therapies had a higher rate of COVID-19 infection five months after the first booster, only mild symptoms that did not require hospitalization were reported for all the DMTs analyzed here. Based on these findings we anticipate that additional vaccine booster shots will likely further improve immune responses and COVID-19 protection in MS patients treated with any DMT.
Assuntos
COVID-19 , Esclerose Múltipla , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Estudos Transversais , Cloridrato de Fingolimode/uso terapêutico , Seguimentos , Humanos , Esclerose Múltipla/tratamento farmacológico , SARS-CoV-2 , VacinaçãoRESUMO
Objectives: Vaccination against COVID-19 is highly recommended to patients affected by multiple sclerosis (MS); however, the impact of MS disease-modifying therapies (DMTs) on the immune response following vaccination has been only partially investigated. Here, we aimed to elucidate the effect of DMTs on the humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines in MS patients. Methods: We obtained sera from 912 Sardinian MS patients and 63 healthy controls 30 days after the second dose of BNT162b2 vaccine and tested them for SARS-CoV-2 response using anti-Spike (S) protein-based serology. Previous SARS-CoV-2 infection was assessed by anti-Nucleocapsid (N) serology. Patients were either untreated or undergoing treatment with a total of 13 different DMTs. Differences between treatment groups comprised of at least 10 patients were assessed by generalized linear mixed-effects model. Demographic and clinical data and smoking status were analyzed as additional factors potentially influencing humoral immunity from COVID-19 vaccine. Results: MS patients treated with natalizumab, teriflunomide, azathioprine, fingolimod, ocrelizumab, and rituximab showed significantly lower humoral responses compared to untreated patients. We did not observe a statistically significant difference in response between patients treated with the other drugs (dimethyl fumarate, interferon, alemtuzumab and glatiramer acetate) and untreated patients. In addition, older age, male sex and active smoking were significantly associated with lower antibody titers against SARS-CoV-2. MS patients previously infected with SARS-CoV-2 had significantly higher humoral responses to vaccine than uninfected patients. Conclusion: Humoral response to BNT162b2 is significantly influenced by the specific DMTs followed by patients, as well as by other factors such as previous SARS-CoV-2 infection, age, sex, and smoking status. These results are important to inform targeted strategies to prevent clinically relevant COVID-19 in MS patients.
Assuntos
Antirreumáticos/uso terapêutico , Vacina BNT162/imunologia , COVID-19/prevenção & controle , Imunogenicidade da Vacina/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Adulto , Anticorpos Antivirais/imunologia , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Soroconversão/efeitos dos fármacosRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (P < 1.28 × 10-11) independent association signals for 459 cell traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases.