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1.
Hum Mol Genet ; 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33517400

RESUMO

Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

2.
Circ Genom Precis Med ; 13(5): 541-547, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33079603

RESUMO

BACKGROUND: The blood metabolome incorporates cues from the environment and the host's genetic background, potentially offering a holistic view of an individual's health status. METHODS: We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts. RESULTS: Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual's biological age. Exploration in independent cohorts demonstrates that being judged older by one's metabolome, as compared with one's chronological age, confers an increased risk on future cardiovascular disease, mortality, and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data. CONCLUSIONS: In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardiometabolic health.

3.
J Transl Med ; 18(1): 352, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933522

RESUMO

BACKGROUND: Understanding how HLA polymorphisms may affect both susceptibility, course and severity of Covid-19 infection could help both at the clinical level to identify individuals at higher risk from the disease and at the epidemiological one to explain the differences in the epidemic trend among countries or even within a specific country. Covid-19 disease in Italy showed a peculiar geographical distribution from the northern most affected regions to the southern ones only slightly touched. METHODS: In this study we analysed the regional frequencies for the most common Italian haplotypes from the Italian Bone Marrow Donor Registry (HLA-A, -B, -C and -DRB1 at four-digit level). Then we performed Pearson correlation analyses among regional haplotypes estimated frequency in the population and Covid-19 incidence and mortality. RESULTS: In this study we found that the two most frequent HLA haplotypes in the Italian population, HLA-A*:01:01g-B*08:01 g-C*07:01g-DRB1*03:01g and HLA-A*02.01g-B*18.01g-C*07.01g-DRB1*11.04g, had a regional distribution overlapping that of Covid-19 and showed respectively a positive (suggestive of susceptibility) and negative (suggestive of protection) significant correlation with both Covid-19 incidence and mortality. CONCLUSIONS: Based on these results, in order to define such HLA haplotypes as a factor effectively associated to the disease susceptibility, the creation of national networks that can collect patients' samples from all regions for HLA typing should be highly encouraged.


Assuntos
Betacoronavirus , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Antígenos HLA/genética , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Infecções por Coronavirus/epidemiologia , Frequência do Gene , Predisposição Genética para Doença , Genética Populacional , Geografia , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias HLA-DRB1/genética , Haplótipos , Humanos , Incidência , Itália/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Pesquisa Médica Translacional
4.
Aging Cell ; 19(10): e13216, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32860726

RESUMO

Centenarians (exceptionally long-lived individuals-ELLI) are a unique segment of the population, exhibiting long human lifespan and healthspan, despite generally practicing similar lifestyle habits as their peers. We tested disease-associated mutation burden in ELLI genomes by determining the burden of pathogenic variants reported in the ClinVar and HGMD databases using data from whole exome sequencing (WES) conducted in a cohort of ELLI, their offspring, and control individuals without antecedents of familial longevity (n = 1879), all descendent from the founder population of Ashkenazi Jews. The burden of pathogenic variants did not differ between the three groups. Additional analyses of variants subtypes and variant effect predictor (VEP) biotype frequencies did not reveal a decrease of pathogenic or loss-of-function (LoF) variants in ELLI and offspring compared to the control group. Case-control pathogenic variants enrichment analyses conducted in ELLI and controls also did not identify significant differences in any of the variants between the groups and polygenic risk scores failed to provide a predictive model. Interestingly, cancer and Alzheimer's disease-associated variants were significantly depleted in ELLI compared to controls, suggesting slower accumulation of mutation. That said, polygenic risk score analysis failed to find any predictive variants among the functional variants tested. The high similarity in the burden of pathogenic variation between ELLI and individuals without familial longevity supports the notion that extension of lifespan and healthspan in ELLI is not a consequence of pathogenic variant depletion but rather a result of other genomic, epigenomic, or potentially nongenomic properties.

5.
Mech Ageing Dev ; 191: 111316, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32693105

RESUMO

At a recent symposium on aging biology, a debate was held as to whether or not we know what biological aging is. Most of the participants were struck not only by the lack of consensus on this core question, but also on many basic tenets of the field. Accordingly, we undertook a systematic survey of our 71 participants on key questions that were raised during the debate and symposium, eliciting 37 responses. The results confirmed the impression from the symposium: there is marked disagreement on the most fundamental questions in the field, and little consensus on anything other than the heterogeneous nature of aging processes. Areas of major disagreement included what participants viewed as the essence of aging, when it begins, whether aging is programmed or not, whether we currently have a good understanding of aging mechanisms, whether aging is or will be quantifiable, whether aging will be treatable, and whether many non-aging species exist. These disagreements lay bare the urgent need for a more unified and cross-disciplinary paradigm in the biology of aging that will clarify both areas of agreement and disagreement, allowing research to proceed more efficiently. We suggest directions to encourage the emergence of such a paradigm.

6.
Nat Commun ; 11(1): 3570, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678081

RESUMO

Ageing phenotypes, such as years lived in good health (healthspan), total years lived (lifespan), and survival until an exceptional old age (longevity), are of interest to us all but require exceptionally large sample sizes to study genetically. Here we combine existing genome-wide association summary statistics for healthspan, parental lifespan, and longevity in a multivariate framework, increasing statistical power, and identify 10 genomic loci which influence all three phenotypes, of which five (near FOXO3, SLC4A7, LINC02513, ZW10, and FGD6) have not been reported previously at genome-wide significance. The majority of these 10 loci are associated with cardiovascular disease and some affect the expression of genes known to change their activity with age. In total, we implicate 78 genes, and find these to be enriched for ageing pathways previously highlighted in model organisms, such as the response to DNA damage, apoptosis, and homeostasis. Finally, we identify a pathway worthy of further study: haem metabolism.


Assuntos
Envelhecimento/genética , Heme/metabolismo , Locos de Características Quantitativas , Envelhecimento/metabolismo , Expressão Gênica , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Longevidade/genética , Herança Multifatorial , Pais , Fenótipo , Fatores Sexuais
7.
Elife ; 92020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32329715

RESUMO

A study of over 40,000 individuals suggests that carrying a small number of ultra-rare genetic variants is associated with a longer lifespan.

8.
Mol Nutr Food Res ; 64(10): e1900818, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32271991

RESUMO

SCOPE: Abdominal obesity is one of the main modifiable risk factors of age-related cardiometabolic disease. Cardiometabolic disease risk and its associated high abdominal fat mass, cholesterol, and glucose concentrations can be reduced by a healthier lifestyle. Hence, the aim is to understand the relation between lifestyle-induced changes in body composition, and specifically abdominal fat, and accompanying changes in circulating metabolic biomarkers. METHODS AND RESULTS: Data from the Growing Old Together (GOTO) study was used, which is a single arm lifestyle intervention in which 164 older adults (mean age 63 years, BMI 23-35 kg/m2 ) changed their lifestyle during 13 weeks by 12.5% caloric restriction plus 12.5% increase in energy expenditure. It is shown here that levels of circulating metabolic biomarkers, even after adjustment for body mass index, specifically associate with abdominal fat mass. The applied lifestyle intervention mainly reduces abdominal fat mass (-2.6%, SD = 3.0) and this reduction, when adjusted for general weight loss, is highly associated with decreased circulating glycerol concentrations and increased HDL diameter. CONCLUSION: The lifestyle-induced reduction of abdominal fat mass is particularly associated, independent of body mass index or general weight loss, with decreased circulating glycerol concentrations and increased HDL diameter.

9.
Sci Adv ; 6(8): eaax0301, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32128391

RESUMO

Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases.


Assuntos
Regulação da Expressão Gênica , Imunoglobulina G/metabolismo , Inflamação/genética , Inflamação/metabolismo , Algoritmos , Alelos , Biologia Computacional/métodos , Loci Gênicos , Estudo de Associação Genômica Ampla , Glicosilação , Humanos , Imunoglobulina G/imunologia , Desequilíbrio de Ligação , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Polissacarídeos/metabolismo
10.
Am J Hum Genet ; 106(3): 389-404, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109421

RESUMO

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.


Assuntos
Estudo de Associação Genômica Ampla , Leucócitos/ultraestrutura , Nucleotídeos/metabolismo , Telômero , Humanos
11.
Nat Commun ; 10(1): 3669, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413261

RESUMO

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.


Assuntos
Apolipoproteína E2/genética , Apolipoproteína E4/genética , Proteínas de Choque Térmico/genética , Longevidade/genética , Estudo de Associação Genômica Ampla , Humanos
12.
Sci Rep ; 9(1): 11623, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406173

RESUMO

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.


Assuntos
Homocisteína/metabolismo , Leucócitos/ultraestrutura , Metabolismo dos Lipídeos , Metabolômica/métodos , Telômero , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Encurtamento do Telômero
13.
Nat Commun ; 10(1): 3346, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431621

RESUMO

Predicting longer-term mortality risk requires collection of clinical data, which is often cumbersome. Therefore, we use a well-standardized metabolomics platform to identify metabolic predictors of long-term mortality in the circulation of 44,168 individuals (age at baseline 18-109), of whom 5512 died during follow-up. We apply a stepwise (forward-backward) procedure based on meta-analysis results and identify 14 circulating biomarkers independently associating with all-cause mortality. Overall, these associations are similar in men and women and across different age strata. We subsequently show that the prediction accuracy of 5- and 10-year mortality based on a model containing the identified biomarkers and sex (C-statistic = 0.837 and 0.830, respectively) is better than that of a model containing conventional risk factors for mortality (C-statistic = 0.772 and 0.790, respectively). The use of the identified metabolic profile as a predictor of mortality or surrogate endpoint in clinical studies needs further investigation.


Assuntos
Metabolômica/métodos , Mortalidade , Análise de Sobrevida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Fatores de Risco , Adulto Jovem
14.
Am J Hum Genet ; 103(5): 691-706, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388399

RESUMO

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.


Assuntos
Loci Gênicos/genética , Inflamação/genética , Redes e Vias Metabólicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Índice de Massa Corporal , Proteína C-Reativa/genética , Criança , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Inflamação/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Esquizofrenia/genética , Esquizofrenia/metabolismo , Adulto Jovem
15.
JAMA Netw Open ; 1(4): e181670, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30294719

RESUMO

IMPORTANCE: Sex differences in genetic associations with human longevity remain largely unknown; investigations on this topic are important for individualized health care. OBJECTIVE: To explore sex differences in genetic associations with longevity. DESIGN SETTING AND PARTICIPANTS: This population-based case-control study used sex-specific genome-wide association study and polygenic risk score (PRS) analyses to examine sex differences in genetic associations with longevity. Five hundred sixty-four male and 1614 female participants older than 100 years were compared with a control group of 773 male and 1526 female individuals aged 40 to 64 years. All were Chinese Longitudinal Healthy Longevity Study participants with Han ethnicity who were recruited in 1998 and 2008 to 2014. MAIN OUTCOMES AND MEASURES: Sex-specific loci and pathways associated with longevity and PRS measures of joint effects of sex-specific loci. RESULTS: Eleven male-specific and 11 female-specific longevity loci (P < 10-5) and 35 male-specific and 25 female-specific longevity loci (10-5 ≤ P < 10-4) were identified. Each of these loci's associations with longevity were replicated in north and south regions of China in one sex but were not significant in the other sex (P = .13-.97), and loci-sex interaction effects were significant (P < .05). The associations of loci rs60210535 of the LINC00871 gene with longevity were replicated in Chinese women (P = 9.0 × 10-5) and US women (P = 4.6 × 10-5) but not significant in Chinese and US men. The associations of the loci rs2622624 of the ABCG2 gene were replicated in Chinese women (P = 6.8 × 10-5) and European women (P = .003) but not significant in both Chinese and European men. Eleven male-specific pathways (inflammation and immunity genes) and 34 female-specific pathways (tryptophan metabolism and PGC-1α induced) were significantly associated with longevity (P < .005; false discovery rate < 0.05). The PRS analyses demonstrated that sex-specific associations with longevity of the 4 exclusive groups of 11 male-specific and 11 female-specific loci (P < 10-5) and 35 male-specific and 25 female-specific loci (10-5 ≤P < 10-4) were jointly replicated across north and south discovery and target samples. Analyses using the combined data set of north and south showed that these 4 groups of sex-specific loci were jointly and significantly associated with longevity in one sex (P = 2.9 × 10-70 to 1.3 × 10-39) but not jointly significant in the other sex (P = .11 to .70), while interaction effects between PRS and sex were significant (P = 4.8 × 10-50 to 1.2 × 10-16). CONCLUSION AND RELEVANCE: The sex differences in genetic associations with longevity are remarkable, but have been overlooked by previously published genome-wide association studies on longevity. This study contributes to filling this research gap and provides a scientific basis for further investigating effects of sex-specific genetic variants and their interactions with environment on healthy aging, which may substantially contribute to more effective and targeted individualized health care for male and female elderly individuals.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Longevidade/genética , Adulto , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , China/etnologia , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Caracteres Sexuais , Fatores Sexuais
16.
Nat Commun ; 9(1): 4455, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367059

RESUMO

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.


Assuntos
2-Aminoadipato Transaminase/metabolismo , Regulação da Expressão Gênica/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo I/metabolismo , Hormônios Tireóideos/genética , Tireotropina/metabolismo , 2-Aminoadipato Transaminase/genética , Animais , Transporte Biológico , Células COS , Chlorocebus aethiops , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Humanos , Hipertireoidismo/genética , Hipertireoidismo/fisiopatologia , Hipotireoidismo/genética , Hipotireoidismo/fisiopatologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Proteínas Cotransportadoras de Sódio-Fosfato Tipo I/genética , Glândula Tireoide/metabolismo , Glândula Tireoide/fisiopatologia , Hormônios Tireóideos/metabolismo
17.
Nature ; 561(7721): 45-56, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30185958

RESUMO

Longer human lives have led to a global burden of late-life disease. However, some older people experience little ill health, a trait that should be extended to the general population. Interventions into lifestyle, including increased exercise and reduction in food intake and obesity, can help to maintain healthspan. Altered gut microbiota, removal of senescent cells, blood factors obtained from young individuals and drugs can all improve late-life health in animals. Application to humans will require better biomarkers of disease risk and responses to interventions, closer alignment of work in animals and humans, and increased use of electronic health records, biobank resources and cohort studies.


Assuntos
Envelhecimento , Internacionalidade , Idoso , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Biomarcadores , Senescência Celular , Pessoas com Deficiência/estatística & dados numéricos , Registros Eletrônicos de Saúde , Estudo de Associação Genômica Ampla , Humanos , Estilo de Vida , Longevidade/genética , Modelos Animais , Países Baixos/epidemiologia , Fenótipo
18.
Front Immunol ; 9: 277, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535710

RESUMO

Immunoglobulin G (IgG), a glycoprotein secreted by plasma B-cells, plays a major role in the human adaptive immune response and are associated with a wide range of diseases. Glycosylation of the Fc binding region of IgGs, responsible for the antibody's effector function, is essential for prompting a proper immune response. This study focuses on the general genetic impact on IgG glycosylation as well as corresponding subclass specificities. To identify genetic loci involved in IgG glycosylation, we performed a genome-wide association study (GWAS) on liquid chromatography electrospray mass spectrometry (LC-ESI-MS)-measured IgG glycopeptides of 1,823 individuals in the Cooperative Health Research in the Augsburg Region (KORA F4) study cohort. In addition, we performed GWAS on subclass-specific ratios of IgG glycans to gain power in identifying genetic factors underlying single enzymatic steps in the glycosylation pathways. We replicated our findings in 1,836 individuals from the Leiden Longevity Study (LLS). We were able to show subclass-specific genetic influences on single IgG glycan structures. The replicated results indicate that, in addition to genes encoding for glycosyltransferases (i.e., ST6GAL1, B4GALT1, FUT8, and MGAT3), other genetic loci have strong influences on the IgG glycosylation patterns. A novel locus on chromosome 1, harboring RUNX3, which encodes for a transcription factor of the runt domain-containing family, is associated with decreased galactosylation. Interestingly, members of the RUNX family are cross-regulated, and RUNX3 is involved in both IgA class switching and B-cell maturation as well as T-cell differentiation and apoptosis. Besides the involvement of glycosyltransferases in IgG glycosylation, we suggest that, due to the impact of variants within RUNX3, potentially mechanisms involved in B-cell activation and T-cell differentiation during the immune response as well as cell migration and invasion involve IgG glycosylation.


Assuntos
Glicosilação , Imunoglobulina G/metabolismo , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Estudo de Associação Genômica Ampla , Glicosiltransferases/genética , Humanos
20.
PLoS One ; 13(1): e0189886, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29293525

RESUMO

Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin secretion.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insulina/metabolismo , Animais , Humanos , Secreção de Insulina , Camundongos
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