Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 210
Filtrar
1.
Sci Rep ; 9(1): 16972, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31740739

RESUMO

The objective of the study was to identify associations of longitudinal trajectories of traditional cardiometabolic risk factors with abdominal and ectopic adipose tissue depots measured by magnetic resonance imaging (MRI). We measured total abdominal, visceral, and subcutaneous adipose tissue in liter and intrahepatic, intrapancreatic and renal sinus fat as fat fractions by MRI in 325 individuals free of cardiovascular disease at Exam 3 of a population-based cohort. We related these MRI measurements at Exam 3 to longitudinal risk profile trajectory clusters, based on risk factor measurements from Exam 3, Exam 2 (seven years prior to MRI) and Exam 1 (14 years prior to MRI). Based on the levels and longitudinal trajectories of several risk factors (blood pressure, lipid profile, anthropometric measurements, HbA1c), we identified three different trajectory clusters. These clusters displayed a graded association with all adipose tissue traits after adjustment for potential confounders (e.g. visceral adipose tissue: ßClusterII = 1.30 l, 95%-CI:[0.84 l;1.75 l], ßClusterIII = 3.32 l[2.74 l;3.90 l]; intrahepatic: EstimateClusterII = 1.54[1.27,1.86], EstimateClusterIII = 2.48[1.93,3.16]. Associations remained statistically significant after additional adjustment for the risk factor levels at Exam 1 or Exam 3, respectively. Trajectory clusters provided additional information in explaining variation in the different fat compartments beyond risk factor profiles obtained at individual exams. In conclusion, sustained high risk factor levels and unfavorable trajectories are associated with high levels of adipose tissue; however, the association with cardiometabolic risk factors varies substantially between different ectopic adipose tissues. Trajectory clusters, covering longitudinal risk profiles, provide additional information beyond single-point risk profiles. This emphasizes the need to incorporate longitudinal information in cardiometabolic risk estimation.

2.
Int J Cancer ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745977

RESUMO

Protein kinase D3 (PKD3) is upregulated in triple-negative breast cancer (TNBC) and associated with cell proliferation and metastasis development but its precise pro-oncogenic function is unknown. Here we show that PKD3 is required for the maintenance of the TNBC stem cell population. Depletion of PKD3 in MDA-MB-231 cells reduced the cancer stem cell frequency in vitro and tumor initiation potential in vivo. We further provide evidence that the RhoGEF GEF-H1 is upstream of PKD3 activation in TNBC stem cells. Most importantly, pharmacological PKD inhibition in combination with paclitaxel synergistically decreased oncosphere and colony formation efficiency in vitro and tumor recurrence in vivo. Based on our results we propose that targeting the GEF-H1/PKD3 signaling pathway in combination with chemotherapy might provide an effective therapeutic option for TNBC. This article is protected by copyright. All rights reserved.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31707051

RESUMO

BACKGROUND: 15% of atopic dermatitis liability-scale heritability could be attributed to 31 susceptibility loci identified by genome-wide association studies, with only three of them (IL13, IL6R, and FLG) resolved to protein-coding variants. OBJECTIVE: We examined whether a significant portion of unexplained atopic dermatitis heritability is further explained by low-frequency and rare variants in gene coding sequence. METHODS: We evaluated common, low-frequency and rare protein-coding variants using exome chip and replication genotype data of 15,574 patients and 377,839 controls, combined with whole transcriptome data on lesional, non-lesional and healthy skin samples of 27 patients and 38 controls. RESULTS: Additional 12.56% (s.e. 0.74%) of atopic dermatitis heritability is explained by rare protein-coding variation. We identified Docking protein 2 (DOK2) and CD200 Receptor 1 (CD200R1) as novel genome-wide significant susceptibility genes. Rare coding variants associated with atopic dermatitis are further enriched in five genes (IL4R, IL13, JAK1, JAK2, TYK2) of the IL13 pathway, all of which are targets for novel systemic atopic dermatitis therapeutics. Multiomics-based network and RNA-Sequencing analysis revealed DOK2 as a central hub interacting, among others, with CD200R1, IL6R and STAT3. Multi-tissue gene expression profile analysis for 53 tissue types from GTEx showed that disease-associated protein-coding variants exert their greatest effect in skin tissues. CONCLUSION: Our discoveries highlight a major role of rare coding variants in atopic dermatitis acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility.

5.
Cell ; 178(6): 1299-1312.e29, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474368

RESUMO

Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT.

6.
Eur J Hum Genet ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31485028

RESUMO

Gallstones Disease (GSD) is one of the most common digestive diseases requiring hospitalization and surgical procedures in the world. GSD has a high prevalence in populations with European or Amerindian ancestry (10-20%) and the influence of genetic factors is broadly acknowledged. However, known genetic variants do not entirely explain the disease heritability suggesting that additional genetic variants remain to be identified. Here, we examined the association of copy number variants (CNVs) with GSD in a sample of 4778 individuals (1929 GSD cases and 2849 controls) including two European cohorts from Germany (n = 3702) and one admixed Latin American cohort from Chile (n = 1076). We detected 2936 large and rare CNVs events (size > 100 kb, frequency < 1%). Case-control burden analysis and generalized linear regression models revealed significant association of CNVs with GSD in men, with the strongest effect observed with CNVs overlapping lipid metabolism genes (p-value = 6.54 × 10-4; OR = 2.76; CI 95% = 1.53-4.89). Our results indicate a clear link between CNVs and GSD in men and provides additional evidence that the genetic components of risk for GSD are complex, can be sex specific and include CNVs affecting genes involved in lipid metabolism.

7.
Nat Commun ; 10(1): 3669, 2019 Aug 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.

8.
Cell Host Microbe ; 26(2): 252-264.e10, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31399369

RESUMO

Obesity and type 2 diabetes (T2D) are metabolic disorders that are linked to microbiome alterations. However, their co-occurrence poses challenges in disentangling microbial features unique to each condition. We analyzed gut microbiomes of lean non-diabetic (n = 633), obese non-diabetic (n = 494), and obese individuals with T2D (n = 153) from German population and metabolic disease cohorts. Microbial taxonomic and functional profiles were analyzed along with medical histories, serum metabolomics, biometrics, and dietary data. Obesity was associated with alterations in microbiome composition, individual taxa, and functions with notable changes in Akkermansia, Faecalibacterium, Oscillibacter, and Alistipes, as well as in serum metabolites that correlated with gut microbial patterns. However, microbiome associations were modest for T2D, with nominal increases in Escherichia/Shigella. Medications, including antihypertensives and antidiabetics, along with dietary supplements including iron, were significantly associated with microbiome variation. These results differentiate microbial components of these interrelated metabolic diseases and identify dietary and medication exposures to consider in future studies.

9.
Aliment Pharmacol Ther ; 50(5): 580-589, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250469

RESUMO

BACKGROUND: Single-centre studies reported alterations of faecal microbiota in patients with primary sclerosing cholangitis (PSC). As regional factors may affect microbial communities, it is unclear if a microbial signature of PSC exists across different geographical regions. AIM: To identify a robust microbial signature of PSC independent of geography and environmental influences. METHODS: We included 388 individuals (median age, 47 years; range, 15-78) from Germany and Norway in the study, 137 patients with PSC (n = 75 with colitis), 118 with ulcerative colitis (UC) and 133 healthy controls. Faecal microbiomes were analysed by 16S rRNA gene sequencing (V1-V2). Differences in relative abundances of single taxa were subjected to a meta-analysis. RESULTS: In both cohorts, microbiota composition (beta-diversity) differed between PSC patients and controls (P < 0.001). Random forests classification discriminated PSC patients from controls in both geographical cohorts with an average area under the curve of 0.88. Compared to healthy controls, many new cohort-spanning alterations were identified in PSC, such as an increase of Proteobacteria and the bile-tolerant genus Parabacteroides, which were detected independent from geographical region. Associated colitis only had minor effects on microbiota composition, suggesting that PSC itself drives the faecal microbiota changes observed. CONCLUSION: Compared to healthy controls, numerous microbiota alterations are reproducible in PSC patients across geographical regions, clearly pointing towards a microbiota composition that is shaped by the disease itself and not by environmental factors. These reproducibly altered microbial populations might provide future insights into the pathophysiology of PSC.

10.
Gut ; 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243055

RESUMO

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its interplay with bile acid metabolism in PSC. METHODS: Patients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1-V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20). RESULTS: The bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen Enterococcus faecalis (FDR=4.18×10-5) in PSC. Enterococcus abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021). CONCLUSION: PSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid.

11.
Mov Disord ; 34(7): 1049-1059, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31059154

RESUMO

BACKGROUND: Progressive supranuclear palsy is a neurodegenerative tauopathy manifesting clinically as a progressive akinetic-rigid syndrome. In this study, we sought to identify genetic variants influencing PSP susceptibility through a genome-wide association analysis of a cohort of well-characterized patients who had participated in the Neuroprotection and Natural History in Parkinson Plus Syndromes and Blood Brain Barrier in Parkinson Plus Syndromes studies. METHODS: We genotyped single-nucleotide polymorphisms in 283 PSP cases from the United Kingdom, Germany, and France and compared these with genotypes from 4472 controls. Copy number variants were identified from genotyping data. RESULTS: We observed associations on chromosome 17 within or close to the MAPT gene and explored the genetic architecture at this locus. We confirmed the previously reported association of rs1768208 in the MOBP gene (P = 3.29 × 10-13 ) and rs1411478 in STX6 (P = 3.45 × 10-10 ). The population-attributable risk from the MAPT, MOBP, and STX6 single-nucleotide polymorphisms was found to be 0.37, 0.26, and 0.08, respectively. In addition, we found 2 instances of copy number variants spanning the MAPT gene in patients with PSP. These copy number variants include tau but few other genes within the chromosome 17 haplotype region, providing additional support for the direct pathogenicity of MAPT in PSP. CONCLUSIONS: Clinicians should also be aware of MAPT duplication as a possible genetic cause of PSP, especially in patients presenting with young age at onset. © 2019 International Parkinson and Movement Disorder Society.

12.
Eur J Nutr ; 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31115681

RESUMO

PURPOSE: The aim of the present study was to derive overall and sex-specific dietary patterns associated with inflammatory biomarkers in a general population sample from Northern Germany. METHODS: The present analysis included 1158 participants (477 men, 681 women, mean age: 53.1 years; mean body mass index: 26.2 kg/m2) of the Food Chain Plus (FoCus) cohort in Kiel, Germany. Participants completed a semi-quantitative food frequency questionnaire and provided blood samples. Reduced rank regression with C-reactive protein (CRP) and Interleukin 6 (IL-6) as response variables was used to derive dietary patterns. After a mean follow-up of 1.7 years, a second blood sample was obtained in a subsample of 112 individuals. Multiple regression models were used to examine the association between dietary patterns at baseline and inflammatory biomarkers at follow-up. RESULTS: The overall pattern characterised by high intakes of soft drinks, meat, potatoes and sauce, and low intakes of other cereals (except pasta/rice), wine, nuts, seeds, vegetarian dishes, vegetable oil, and fish was positively associated with CRP (OR 2.20; 95% CI 1.12, 4.35) and IL-6 (OR 3.14; 95% CI 1.26, 7.87) at follow-up. In men, the dietary pattern was higher in soft drinks, processed meat and low in cereals and plant-based fats. In women, the pattern was characterised by soft drinks, meat, vegetables and low in other cereals, wine, nuts, and seeds. The association between sex-specific patterns with inflammatory biomarkers was weaker for CRP. CONCLUSION: We identified dietary patterns positively associated with established biomarkers of chronic low-grade inflammation.

13.
Sci Rep ; 9(1): 7306, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086276

RESUMO

Signaling of the pleiotropic cytokine Interleukin-6 (IL-6) via its soluble IL-6R (sIL-6R) has been termed trans-signaling and is thought to be responsible for the pro-inflammatory properties of IL-6. The sIL-6R can be generated by alternative mRNA splicing or proteolytic cleavage of the membrane-bound IL-6R. However, which stimuli induce sIL-6R release and which endogenous signaling pathways are required for this process is poorly understood. Here, we show that activation of Toll-like receptor 2 (TLR2) on primary human peripheral blood mononuclear cells (PBMCs) and on the monocytic cell line THP-1 induces expression and secretion of IL-6 and the generation of sIL-6R. We show by flow cytometry that monocytes are a PBMC subset that expresses TLR2 in conjunction with the IL-6R and are the major cellular source for both IL-6 and sIL-6R. Mechanistically, we find that the metalloproteases ADAM10 and ADAM17 are responsible for cleavage of the IL-6R and therefore sIL-6R generation. Finally, we identify the Extracellular-signal Regulated Kinase (ERK) cascade as a critical pathway that differentially regulates both IL-6 and sIL-6R generation in monocytes.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31034016

RESUMO

CONTEXT: CD36 is a class B scavenger-receptor involved in the uptake of fatty acids in liver and adipose tissue. It is unknown whether plasma CD36 levels are related to liver fat content or adipose tissue in the general population. METHODS: We measured plasma CD36 from 575 participants of the community-based PopGen-cohort who underwent magnetic resonance imaging (MRI) to quantify visceral (VAT) and subcutaneous (SAT) adipose tissue and liver signal intensity (LSI), a proxy for liver fat content. Non-alcoholic fatty liver disease (NAFLD) was defined as LSI ≥3.0 in the absence of high alcohol intake. The relations between plasma CD36 and body mass index (BMI), VAT, SAT, LSI, and NAFLD were evaluated using multivariable-adjusted linear and logistic regression analysis. RESULTS: Plasma CD36 concentrations were correlated with BMI (r=0.11; P=0.01), SAT (r=0.16; P<0.001), and VAT (r=0.15, P<0.001), but not with LSI (P=0.44). In multivariable-adjusted regression models, mean BMI values rose across CD36-quartiles (Q1: 27.8 kg/m2; Q4: 28.9 kg/m2; P-trend=0.013). Similarly, VAT (Q1: 4.13 dm3; Q4: 4.71 dm3; P-trend<0.001) and SAT (Q1: 7.61 dm3; Q4: 8.74 dm3; P-trend<0.001) rose across CD36 quartiles. Plasma CD36 concentrations were unrelated to LSI (P-trend=0.36), and NAFLD (P-trend=0.64). Participants with NAFLD and elevated alanine aminotransferase (ALT), a marker for liver damage, had higher CD36 compared to NAFLD participants with normal ALT. CONCLUSIONS: Higher plasma concentrations of CD36 were associated with greater general and abdominal adiposity, but not with liver fat content or NAFLD in this community-based sample. However, plasma CD36 may reflect more severe liver damage in NAFLD.

15.
J Community Genet ; 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30927239

RESUMO

The significance of human biorepositories for modern medical research, particularly for comprehensive population-based genetic analyses, is constantly growing. While large and centralized institutions are usually considered best suited to meet the increasing demand for high-quality "biobanks," most medical research institutions still host rather heterogeneous and fragmented biobanking activities, undertaken by clinical departments with oftentimes rather different scientific scope. Undoubtedly, most clinicians and medical researchers would appreciate infrastructural support in terms of the storage and handling of their biosamples, but they are also likely to expect access to their samples avoiding extensive formal requirements. We report on the establishment of the PopGen 2.0 Network (P2N), an overarching alliance of initially seven biobanks from Northern Germany which adopted a joint but lean governance structure and use-and-access policy for their samples and data. In addition, the members of P2N have pursued an intense collaboration on ethical, legal and social issues and maintain a common IT infrastructure. The implementation of P2N has substantially improved the prospects of biobank-based research at the participating institutions. The network may thus serve as a role model for similar initiatives geared at linking pre-existing biorepositories for the benefit of research quality, efficiency, and transparency.

16.
J Am Heart Assoc ; 8(7): e011426, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30890055

RESUMO

Background Tissue inhibitor of metalloproteinases-1 ( TIMP -1) and procollagen type III aminoterminal peptide are established circulating markers of extracellular matrix remodeling and associated with cardiovascular disease. The association of both biomarkers with incident congestive heart failure and chronic kidney disease ( CKD ) in the community is not well studied. Methods and Results We measured plasma total TIMP -1 and procollagen type III aminoterminal peptide levels in 922 Framingham participants (mean age, 57 years; 57% women) and related both biomarkers to the risk of incident CKD and congestive heart failure in multivariable-adjusted Cox regression models. Plasma total TIMP -1 levels were positively associated with risk of incident CKD (164 events; hazard ratio per 1 SD in log-biomarker, 1.90; 95% CI , 1.53-2.37) in multivariable models, including adjustments for left ventricular mass, C-reactive protein, and B-type natriuretic peptide levels. The association of total TIMP -1 with risk of congestive heart failure was statistically significant in an age- and sex-adjusted model, but was attenuated upon adjustment for conventional risk factors. Blood procollagen type III aminoterminal peptide levels were not related to the risk of CKD or congestive heart failure. Conclusions Higher baseline levels of total TIMP -1 conferred an increased risk for incident CKD , independent of conventional risk factors and circulating biomarkers of chronic systemic inflammation and neurohormonal activation. Our prospective observations in a large community-based sample support the role of matrix remodeling in the pathogenesis of CKD .

17.
BMC Infect Dis ; 19(1): 99, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30700258

RESUMO

BACKGROUND: Until now, herpes zoster (HZ)-related disease burden in Germany has been estimated based on health insurance data and clinical findings. However, the validity of self-reported HZ is unclear. This study investigated the validity of self-reported herpes zoster (HZ) and its complication postherpetic neuralgia (PHN) using data from the pretest studies of the German National Cohort (GNC) in comparison with estimates based on health insurance data. METHODS: Data of 4751 participants aged between 20 and 69 years from two pretest studies of the GNC carried out in 2011 and 2012 were used. Based on self-reports of physician-diagnosed HZ and PHN, age- and sex-specific HZ incidence rates and PHN proportions were estimated. For comparison, estimates based on statutory health insurance data from the German population were considered. RESULTS: Eleven percent (95%-CI, 10.4 to 12.3, n = 539) of the participants reported at least one HZ episode in their lifetime. Our estimated age-specific HZ incidence rates were lower than previous estimates based on statutory health insurance data. The PHN proportion in participants older than 50 years was 5.9% (1.9 to 13.9%), which was in line with estimates based on health insurance data. CONCLUSION: As age- and sex-specific patterns were comparable with that in health insurance data, self-reported diagnosis of HZ seems to be a valid instrument for overall disease trends. Possible reasons for observed differences in incidence rates are recall bias in self-reported data or overestimation in health insurance data.


Assuntos
Herpes Zoster/epidemiologia , Neuralgia Pós-Herpética/epidemiologia , Autorrelato , Adulto , Fatores Etários , Idoso , Estudos de Coortes , Feminino , Alemanha/epidemiologia , Herpes Zoster/etiologia , Herpes Zoster/prevenção & controle , Herpes Zoster/virologia , Herpesvirus Humano 3 , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neuralgia Pós-Herpética/etiologia , Neuralgia Pós-Herpética/prevenção & controle , Neuralgia Pós-Herpética/virologia , Reprodutibilidade dos Testes , Fatores Sexuais , Inquéritos e Questionários , Adulto Jovem
18.
J Clin Periodontol ; 46(5): 522-528, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30762911

RESUMO

AIM: Recombinant secreted frizzled-related protein 5 (sFRP5) improved periodontal status in mice. Thus, this study aimed to investigate this finding in human periodontitis using an epidemiological approach. MATERIALS AND METHODS: sFRP5 and wnt5a concentrations were determined in human serum from the Food Chain Plus cohort using ELISAs. A total of 128 patients with periodontitis and tooth loss and 245 patients with periodontitis without tooth loss were compared to 373 sex-, smoker-, age- and BMI-matched individuals in a nested case-control design. RESULTS: Systemic sFRP5 serum levels were significantly lower in patients with periodontitis and tooth loss (2.5 [0.0-10.4] ng/ml, median [IQR]) compared to patients with periodontitis without tooth loss (6.0 [2.5-15.8] ng/ml, median [IQR], p = 0.04] and matched controls (7.0 [2.5-18.3] ng/ml, median [IQR], p = 0.02). No significant differences in sFRP5 serum levels were found among patients with periodontitis without tooth loss (6.0 [2.5-15.8] ng/ml, median [IQR]) and controls (3.1 [0.0-10.6] ng/ml, median [IQR], p = 0.06). CONCLUSIONS: sFRP5 might serve as a novel biomarker for periodontitis severity. Modulating the inflammatory background of severe forms of periodontitis, in the time of precision medicine, needs to be revealed in further studies.

19.
Sci Rep ; 9(1): 772, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30692554

RESUMO

Latin Americans and Chilean Amerindians have the highest prevalence of gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however, they only explain a small portion of the genetic component of the disease. Here, we performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Chilean Latinos with Mapuche Native American ancestry. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Top-10 candidate variants surpassing the suggestive cutoff of P < 1 × 10-5 in the discovery cohort were genotyped in an independent replication sample composed of 1,643 individuals. Variants with positive replication were further examined in two European GSD populations and a Chilean GBC cohort. We consistently replicated the association of ABCG8 gene with GSD (rs11887534, P = 3.24 × 10-8, OR = 1.74) and identified TRAF3 (rs12882491, P = 1.11 × 10-7, OR = 1.40) as a novel candidate gene for the disease in admixed Chilean Latinos. ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 was significantly decreased in gallbladder (P = 0.015) and duodenal mucosa (P = 0.001) of GSD individuals compared to healthy controls, where according to GTEx data in the small intestine, the presence of the risk allele contributes to the observed effect. We conclude that ABCG8 and TRAF3 genes are associated with GSD and GBC in admixed Latinos and that decreased TRAF3 levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.

20.
Eur J Clin Nutr ; 73(11): 1480-1491, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30647440

RESUMO

BACKGROUND/OBJECTIVES: The aim of the study was to describe a novel dietary assessment strategy based on two instruments complemented by information from an external population applied to estimate usual food intake in the large-scale multicenter German National Cohort (GNC). As proof of concept, we applied the assessment strategy to data from a pretest study (2012-2013) to assess the feasibility of the novel assessment strategy. SUBJECTS/METHODS: First, the consumption probability for each individual was modeled using three 24 h food lists (24h-FLs) and frequencies from one food frequency questionnaire (FFQ). Second, daily consumed food amounts were estimated from the representative German National Nutrition Survey II (NVS II) taking the characteristics of the participants into account. Usual food intake was estimated using the product of consumption probability and amounts. RESULTS: We estimated usual intake of 41 food groups in 318 men and 377 women. The participation proportion was 100, 84.4, and 68.5% for the first, second, and third 24h-FL, respectively. We observed no associations between the probability of participating and lifestyle factors. The estimated distributions of usual food intakes were plausible and total energy was estimated to be 2707 kcal/day for men and 2103 kcal/day for women. The estimated consumption frequencies did not differ substantially between men and women with only few exceptions. The differences in energy intake between men and women were mostly due to differences in estimated daily amounts. CONCLUSIONS: The combination of repeated 24h-FLs, a FFQ, and consumption-day amounts from a reference population represents a user-friendly dietary assessment approach having generated plausible, but not yet validated, food intake values in the pretest study.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA