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p66Shc regulates migration of castration-resistant prostate cancer cells.

Biobank publications - 1 hour 31 min ago

p66Shc regulates migration of castration-resistant prostate cancer cells.

Cell Signal. 2018 Feb 17;:

Authors: Ingersoll MA, Chou YW, Lin JS, Yuan TC, Miller D, Xie Y, Tu Y, Oberley-Deegan RE, Batra SK, Lin MF

Abstract
Metastatic castration-resistant (CR) prostate cancer (PCa) is a lethal disease for which no effective treatment is currently available. p66Shc is an oxidase previously shown to promote androgen-independent cell growth through generation of reactive oxygen species (ROS) and elevated in clinical PCa and multiple CR PCa cell lines. We hypothesize p66Shc also increases the migratory activity of PCa cells through ROS and investigate the associated mechanism. Using the transwell assay, our study reveals that the level of p66Shc protein correlates with cell migratory ability across several PCa cell lines. Furthermore, we show peroxide treatment induces migration of PCa cells that express low levels of p66Shc in a dose-dependent manner, while antioxidants inhibit migration. Conversely, PCa cells that express high levels of endogenous p66Shc or by cDNA transfection possess increased cell migration which is mitigated upon p66Shc shRNA transfection or expression of oxidase-deficient dominant-negative p66Shc W134F mutant. Protein microarray and immunoblot analyses reveal multiple proteins, including ErbB-2, AKT, mTOR, ERK, FOXM1, PYK2 and Rac1, are activated in p66Shc-elevated cells. Their involvement in PCa migration was examined using respective small-molecule inhibitors. The role of Rac1 was further validated using cDNA transfection and, significantly, p66Shc is found to promote lamellipodia formation through Rac1 activation. In summary, the results of our current studies clearly indicate p66Shc also regulates PCa cell migration through ROS-mediated activation of migration-associated proteins, notably Rac1.

PMID: 29462661 [PubMed - as supplied by publisher]

The relationship between alcohol use and long-term cognitive decline in middle and late life: a longitudinal analysis using UK Biobank.

Biobank publications - 1 hour 31 min ago

The relationship between alcohol use and long-term cognitive decline in middle and late life: a longitudinal analysis using UK Biobank.

J Public Health (Oxf). 2018 Feb 16;:

Authors: Piumatti G, Moore S, Berridge D, Sarkar C, Gallacher J

PMID: 29462350 [PubMed - as supplied by publisher]

Patients' Attitudes Towards the Return of Incidental Findings After Research with Residual Tissue: A Mixed Methods Study.

Biobank publications - 1 hour 31 min ago

Patients' Attitudes Towards the Return of Incidental Findings After Research with Residual Tissue: A Mixed Methods Study.

Genet Test Mol Biomarkers. 2018 Feb 20;:

Authors: Vermeulen E, Rebers S, Aaronson NK, Brandenburg AP, van Leeuwen FE, Schmidt MK

Abstract
AIMS: To investigate the attitudes of patients toward the return of individual research results from scientific research with residual tissue.
METHODS AND FINDINGS: We recruited 1319 patients from 6 Dutch hospitals. In total, 673 patients (51% response rate) completed the questionnaire and 146 were interviewed. Based on the questionnaire data, the majority of respondents (92%) wanted to be informed of incidental findings about both a curable (92%) and an incurable (76%) disease. Respondents' wishes to be informed about incidental findings did not vary significantly as a function of patient demographics or type of disease. The interview data show that respondents wished to be informed about incidental findings because they considered it to be normal practice; they expected the information to be of benefit for their health. Information should be provided by their physician. Yet, most respondents (84%) would consent to research even if they would not be informed about incidental findings, primarily because they recognized that there might be practical problems in providing such information, and because they valued scientific research highly.
CONCLUSIONS: We conclude that, while the majority of patients want to be informed about incidental findings, they also recognize that this may be difficult.

PMID: 29461872 [PubMed - as supplied by publisher]

Occupational exposure to pesticides is associated with differential DNA methylation.

Biobank publications - 1 hour 31 min ago
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Occupational exposure to pesticides is associated with differential DNA methylation.

Occup Environ Med. 2018 Feb 19;:

Authors: van der Plaat DA, de Jong K, de Vries M, van Diemen CC, Nedeljković I, Amin N, Kromhout H, Biobank-based Integrative Omics Study Consortium, Vermeulen R, Postma DS, van Duijn CM, Boezen HM, Vonk JM

Abstract
OBJECTIVES: Occupational pesticide exposure is associated with a wide range of diseases, including lung diseases, but it is largely unknown how pesticides influence airway disease pathogenesis. A potential mechanism might be through epigenetic mechanisms, like DNA methylation. Therefore, we assessed associations between occupational exposure to pesticides and genome-wide DNA methylation sites.
METHODS: 1561 subjects of LifeLines were included with either no (n=1392), low (n=108) or high (n=61) exposure to any type of pesticides (estimated based on current or last held job). Blood DNA methylation levels were measured using Illumina 450K arrays. Associations between pesticide exposure and 420 938 methylation sites (CpGs) were assessed using robust linear regression adjusted for appropriate confounders. In addition, we performed genome-wide stratified and interaction analyses by gender, smoking and airway obstruction status, and assessed associations between gene expression and methylation for genome-wide significant CpGs (n=2802).
RESULTS: In total for all analyses, high pesticide exposure was genome-wide significantly (false discovery rate P<0.05) associated with differential DNA methylation of 31 CpGs annotated to 29 genes. Twenty of these CpGs were found in subjects with airway obstruction. Several of the identified genes, for example, RYR1, ALLC, PTPRN2, LRRC3B, PAX2 and VTRNA2-1, are genes previously linked to either pesticide exposure or lung-related diseases. Seven out of 31 CpGs were associated with gene expression levels.
CONCLUSIONS: We show for the first time that occupational exposure to pesticides is genome-wide associated with differential DNA methylation. Further research should reveal whether this differential methylation plays a role in the airway disease pathogenesis induced by pesticides.

PMID: 29459480 [PubMed - as supplied by publisher]

Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease.

Biobank publications - 1 hour 31 min ago
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Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease.

Alzheimers Res Ther. 2018 Feb 20;10(1):23

Authors: Rhodius-Meester HFM, Liedes H, Koene T, Lemstra AW, Teunissen CE, Barkhof F, Scheltens P, van Gils M, Lötjönen J, van der Flier WM

Abstract
BACKGROUND: Survival after dementia diagnosis varies considerably. Previous studies were focused mainly on factors related to demographics and comorbidity rather than on Alzheimer's disease (AD)-related determinants. We set out to answer the question whether markers with proven diagnostic value also have prognostic value. We aimed to identify disease-related determinants associated with mortality in patients with AD.
METHODS: We included 616 patients (50% female; age 67 ± 8 years; mean Mini Mental State Examination score 22 ± 3) with dementia due to AD from the Amsterdam Dementia Cohort. Information on mortality was obtained from the Dutch Municipal Register. We used age- and sex-adjusted Cox proportional hazards analysis to study associations of baseline demographics, comorbidity, neuropsychology, magnetic resonance imaging (MRI) (medial temporal lobe, global cortical and parietal atrophy, and measures of small vessel disease), and cerebrospinal fluid (CSF) (β-amyloid 1-42, total tau, and tau phosphorylated at threonine 181 [p-tau]) with mortality (outcome). In addition, we built a multivariate model using forward selection.
RESULTS: After an average of 4.9 ± 2.0 years, 213 (35%) patients had died. Age- and sex-adjusted Cox models showed that older age (HR 1.29 [95% CI 1.12-1.48]), male sex (HR 1.60 [95% CI 1.22-2.11]), worse scores on cognitive functioning (HR 1.14 [95% CI 1.01-1.30] to 1.31 [95% CI 1.13-1.52]), and more global and hippocampal atrophy on MRI (HR 1.18 [95% CI 1.01-1.37] and HR 1.18 [95% CI 1.02-1.37]) were associated with increased risk of mortality. There were no associations with comorbidity, level of activities of daily living, apolipoprotein E (APOE) ε4 status, or duration of disease. Using forward selection, the multivariate model included a panel of age, sex, cognitive tests, atrophy of the medial temporal lobe, and CSF p-tau.
CONCLUSIONS: In this relatively young sample of patients with AD, disease-related determinants were associated with an increased risk of mortality, whereas neither comorbidity nor APOE genotype had any prognostic value.

PMID: 29458426 [PubMed - in process]

The antibiotic resistome and microbiota landscape of refugees from Syria, Iraq and Afghanistan in Germany.

Biobank publications - 1 hour 31 min ago
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The antibiotic resistome and microbiota landscape of refugees from Syria, Iraq and Afghanistan in Germany.

Microbiome. 2018 Feb 20;6(1):37

Authors: Häsler R, Kautz C, Rehman A, Podschun R, Gassling V, Brzoska P, Sherlock J, Gräsner JT, Hoppenstedt G, Schubert S, Ferlinz A, Lieb W, Laudes M, Heinsen FA, Scholz J, Harmsen D, Franke A, Eisend S, Kunze T, Fickenscher H, Ott S, Rosenstiel P, Schreiber S

Abstract
BACKGROUND: Multidrug-resistant bacteria represent a substantial global burden for human health, potentially fuelled by migration waves: in 2015, 476,649 refugees applied for asylum in Germany mostly as a result of the Syrian crisis. In Arabic countries, multiresistant bacteria cause significant problems for healthcare systems. Currently, no data exist describing antibiotic resistances in healthy refugees. Here, we assess the microbial landscape and presence of antibiotic resistance genes (ARGs) in refugees and German controls. To achieve this, a systematic study was conducted in 500 consecutive refugees, mainly from Syria, Iraq, and Afghanistan and 100 German controls. Stool samples were subjected to PCR-based quantification of 42 most relevant ARGs, 16S ribosomal RNA gene sequencing-based microbiota analysis, and culture-based validation of multidrug-resistant microorganisms.
RESULTS: The fecal microbiota of refugees is substantially different from that of resident Germans. Three categories of resistance profiles were found: (i) ARGs independent of geographic origin of individuals comprising BIL/LAT/CMA, ErmB, and mefE; (ii) vanB with a high prevalence in Germany; and (iii) ARGs showing substantially increased prevalences in refugees comprising CTX-M group 1, SHV, vanC1, OXA-1, and QnrB. The majority of refugees carried five or more ARGs while the majority of German controls carried three or less ARGs, although the observed ARGs occurred independent of signatures of potential pathogens.
CONCLUSIONS: Our results, for the first time, assess antibiotic resistance genes in refugees and demonstrate a substantially increased prevalence for most resistances compared to German controls. The antibiotic resistome in refugees may thus require particular attention in the healthcare system of host countries.

PMID: 29458422 [PubMed - in process]

Identification of genetic variants for clinical management of familial colorectal tumors.

Biobank publications - 1 hour 31 min ago
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Identification of genetic variants for clinical management of familial colorectal tumors.

BMC Med Genet. 2018 Feb 20;19(1):26

Authors: Dominguez-Valentin M, Nakken S, Tubeuf H, Vodak D, Ekstrøm PO, Nissen AM, Morak M, Holinski-Feder E, Martins A, Møller P, Hovig E

Abstract
BACKGROUND: The genetic mechanisms for families who meet the clinical criteria for Lynch syndrome (LS) but do not carry pathogenic variants in the mismatch repair (MMR) genes are still undetermined. We aimed to study the potential contribution of genes other than MMR genes to the biological and clinical characteristics of Norwegian families fulfilling Amsterdam (AMS) criteria or revised Bethesda guidelines.
METHODS: The Hereditary Cancer Biobank of the Norwegian Radium Hospital was interrogated to identify individuals with a high risk of developing colorectal cancer (CRC) for whom no pathogenic variants in MMR genes had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by using our in-house designed TruSeq amplicon-based assay for targeted sequencing. RNA splicing- and protein-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as likely to affect splicing were experimentally analyzed by resorting to minigene assays.
RESULTS: We identified a patient who met the revised Bethesda guidelines and carried a likely pathogenic variant in CHEK2 (c.470 T > C, p.I157T). In addition, 25 unique VUS were identified in 18 individuals, of which 2 exonic variants (MAP3K1 c.764A > G and NOTCH3 c.5854G >A) were analyzed in the minigene splicing assay and found not to have an effect on RNA splicing.
CONCLUSIONS: Among high-risk CRC patients that fulfill the AMS criteria or revised Bethesda guidelines, targeted gene sequencing identified likely pathogenic variant and VUS in other genes than the MMR genes (CHEK2, NOTCH3 and MAP3K1). Our study suggests that the analysis of genes currently excluded from routine molecular diagnostic screens may confer cancer susceptibility.

PMID: 29458332 [PubMed - in process]

Assessing the clinical value of microRNAs in formalin-fixed paraffin-embedded liposarcoma tissues: Overexpressed miR-155 is an indicator of poor prognosis.

Biobank publications - 1 hour 31 min ago
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Assessing the clinical value of microRNAs in formalin-fixed paraffin-embedded liposarcoma tissues: Overexpressed miR-155 is an indicator of poor prognosis.

Oncotarget. 2017 Jan 24;8(4):6896-6913

Authors: Kapodistrias N, Mavridis K, Batistatou A, Gogou P, Karavasilis V, Sainis I, Briasoulis E, Scorilas A

Abstract
Liposarcoma (LPS) is a malignancy with extreme heterogeneity and thus optimization towards personalizing patient prognosis and treatment is essential. Here, we evaluated miR-155, miR-21, miR-143, miR-145 and miR-451 that are implicated in LPS, as novel FFPE tissue biomarkers.A total of 83 FFPE tissue specimens from primary LPS and lipomas (LPM) were analyzed. A proteinase K incubation-Trizol treatment coupled protocol was used for RNA isolation. After polyadenylation of total RNA and reverse transcription, expression analysis of 9 candidate reference and 5 target miRNAs was performed by qPCR. Genorm and NormFinder were used for finding the most suitable molecules for normalization. Survival analyses were performed in order to evaluate the prognostic potential of miRNAs.MiR-103 and miR-191 are most suitable for normalization of miRNA expression in LPS. MiR-155 and miR-21 are clearly overexpressed (P<0.001) in LPS compared with LPM specimens, whereas miR-145 (P<0.001), miR-143 (P =0.008) and miR-451 (P=0.037) are underexpressed. MiR-155 (P=0.007) and miR-21 (P=0.029) are differentially expressed between well-differentiated, dedifferentiated, myxoid/round cell and pleomorphic LPs tumor subtypes. MiR-155 represents a novel independent indicator of unfavorable prognosis in LPS (HR = 2.97, 95% CI = 1.23-7.17, P = 0.016).

PMID: 28036291 [PubMed - indexed for MEDLINE]

Positive feedback loop of IL-1β/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma.

Biobank publications - 1 hour 31 min ago
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Positive feedback loop of IL-1β/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma.

Oncotarget. 2017 Jan 24;8(4):6718-6729

Authors: Ren HY, Liu F, Huang GL, Liu Y, Shen JX, Zhou P, Liu WM, Shen DY

Abstract
Abnormal expression and function of retinoic acid receptor α (RARα) have been reported to be associated with various cancers including acute promyelocytic leukemia and hepatocellular carcinoma. However, the role and the mechanism of RARα in gastric carcinoma (GC) were unknown. Here, the expression of RARα was frequently elevated in human GC tissues and cell lines, and its overexpression was closely correlated with tumor size, lymph node metastasis and clinical stages in GC patients. Moreover, RARα overexpression was related with pathological differentiation. Functionally, RARα knockdown inhibited the proliferation and metastasis of GC cells, as well as enhanced drug susceptibility both in vitro and in vivo. Additionally, RARα knockdown suppressed GC progression through regulating the expression of cell proliferation, cell cycle, invasion and drug resistance associated proteins, such as PCNA, CyclinB1, CyclinD2, CyclinE, p21, MMP9 and MDR1. Mechanistically, the above oncogenic properties of RARα in GC were closely associated with Akt signaling activation. Moreover, overexpression of RARα was induced by IL-1β/Akt signaling activation, which suggested a positive feedback loop of IL-1β/Akt/RARα/Akt signaling in GC. Taken together, we demonstrated that RARα was frequently elevated in GC and exerted oncogenic properties. It might be a potential molecular target for GC treatment.

PMID: 28035062 [PubMed - indexed for MEDLINE]

Established BMI-associated genetic variants and their prospective associations with BMI and other cardiometabolic traits: the GLACIER Study.

Biobank publications - 1 hour 31 min ago
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Established BMI-associated genetic variants and their prospective associations with BMI and other cardiometabolic traits: the GLACIER Study.

Int J Obes (Lond). 2016 Sep;40(9):1346-52

Authors: Ahmad S, Poveda A, Shungin D, Barroso I, Hallmans G, Renström F, Franks PW

Abstract
BACKGROUND: Recent cross-sectional genome-wide scans have reported associations of 97 independent loci with body mass index (BMI). In 3541 middle-aged adult participants from the GLACIER Study, we tested whether these loci are associated with 10-year changes in BMI and other cardiometabolic traits (fasting and 2-h glucose, triglycerides, total cholesterol, and systolic and diastolic blood pressures).
METHODS: A BMI-specific genetic risk score (GRS) was calculated by summing the BMI-associated effect alleles at each locus. Trait-specific cardiometabolic GRSs comprised only the loci that show nominal association (P⩽0.10) with the respective trait in the original cross-sectional study. In longitudinal genetic association analyses, the second visit trait measure (assessed ~10 years after baseline) was used as the dependent variable and the models were adjusted for the baseline measure of the outcome trait, age, age(2), fasting time (for glucose and lipid traits), sex, follow-up time and population substructure.
RESULTS: The BMI-specific GRS was associated with increased BMI at follow-up (β=0.014 kg m(-2) per allele per 10-year follow-up, s.e.=0.006, P=0.019) as were three loci (PARK2 rs13191362, P=0.005; C6orf106 rs205262, P=0.043; and C9orf93 rs4740619, P=0.01). Although not withstanding Bonferroni correction, a handful of single-nucleotide polymorphisms was nominally associated with changes in blood pressure, glucose and lipid levels.
CONCLUSIONS: Collectively, established BMI-associated loci convey modest but statistically significant time-dependent associations with long-term changes in BMI, suggesting a role for effect modification by factors that change with time in this population.

PMID: 27121252 [PubMed - indexed for MEDLINE]

Reshaping a multimode laser beam into a constructed Gaussian beam for generating a thin light sheet.

Biobank publications - Tue, 02/20/2018 - 13:44

Reshaping a multimode laser beam into a constructed Gaussian beam for generating a thin light sheet.

J Biophotonics. 2018 Feb 19;:

Authors: Saghafi S, Haghi-Danaloo N, Becker K, Sabdyusheva I, Foroughipour M, Hahn C, Pende M, Wanis M, Bergmann M, Stift J, Hegedus B, Dome B, Dodt HU

Abstract
Based on the modal analysis method, we developed a model that describes the output beam of a diode pumped solid state (DPSS) laser emitting a multimode beam. Measuring the output beam profile in the near field and at the constructed far field the individual modes, their respective contributions, and their optical parameters are determined. Using this information, the beam is optically reshaped into a quasi-Gaussian beam by the interference and superposition of the various modes. This process is controlled by a mode modulator unit that includes different meso-aspheric elements and a soft-aperture. The converted beam is guided into a second optical unit comprising achromatic-aspheric elements to produce a thin light sheet for ultramicroscopy. We found that this light sheet is markedly thinner and exhibits less side shoulders compared with a light sheet directly generated from the output of a DPSS multimode laser.

PMID: 29457696 [PubMed - as supplied by publisher]

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

Biobank publications - Tue, 02/20/2018 - 13:44
Related Articles

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

Am J Hum Genet. 2018 Feb 13;:

Authors: Sung YJ, Winkler TW, de Las Fuentes L, Bentley AR, Brown MR, Kraja AT, Schwander K, Ntalla I, Guo X, Franceschini N, Lu Y, Cheng CY, Sim X, Vojinovic D, Marten J, Musani SK, Li C, Feitosa MF, Kilpeläinen TO, Richard MA, Noordam R, Aslibekyan S, Aschard H, Bartz TM, Dorajoo R, Liu Y, Manning AK, Rankinen T, Smith AV, Tajuddin SM, Tayo BO, Warren HR, Zhao W, Zhou Y, Matoba N, Sofer T, Alver M, Amini M, Boissel M, Chai JF, Chen X, Divers J, Gandin I, Gao C, Giulianini F, Goel A, Harris SE, Hartwig FP, Horimoto ARVR, Hsu FC, Jackson AU, Kähönen M, Kasturiratne A, Kühnel B, Leander K, Lee WJ, Lin KH, 'an Luan J, McKenzie CA, Meian H, Nelson CP, Rauramaa R, Schupf N, Scott RA, Sheu WHH, Stančáková A, Takeuchi F, van der Most PJ, Varga TV, Wang H, Wang Y, Ware EB, Weiss S, Wen W, Yanek LR, Zhang W, Zhao JH, Afaq S, Alfred T, Amin N, Arking D, Aung T, Barr RG, Bielak LF, Boerwinkle E, Bottinger EP, Braund PS, Brody JA, Broeckel U, Cabrera CP, Cade B, Caizheng Y, Campbell A, Canouil M, Chakravarti A, CHARGE Neurology Working Group, Chauhan G, Christensen K, Cocca M, COGENT-Kidney Consortium, Collins FS, Connell JM, de Mutsert R, de Silva HJ, Debette S, Dörr M, Duan Q, Eaton CB, Ehret G, Evangelou E, Faul JD, Fisher VA, Forouhi NG, Franco OH, Friedlander Y, Gao H, GIANT Consortium, Gigante B, Graff M, Gu CC, Gu D, Gupta P, Hagenaars SP, Harris TB, He J, Heikkinen S, Heng CK, Hirata M, Hofman A, Howard BV, Hunt S, Irvin MR, Jia Y, Joehanes R, Justice AE, Katsuya T, Kaufman J, Kerrison ND, Khor CC, Koh WP, Koistinen HA, Komulainen P, Kooperberg C, Krieger JE, Kubo M, Kuusisto J, Langefeld CD, Langenberg C, Launer LJ, Lehne B, Lewis CE, Li Y, Lifelines Cohort Study, Lim SH, Lin S, Liu CT, Liu J, Liu J, Liu K, Liu Y, Loh M, Lohman KK, Long J, Louie T, Mägi R, Mahajan A, Meitinger T, Metspalu A, Milani L, Momozawa Y, Morris AP, Mosley TH, Munson P, Murray AD, Nalls MA, Nasri U, Norris JM, North K, Ogunniyi A, Padmanabhan S, Palmas WR, Palmer ND, Pankow JS, Pedersen NL, Peters A, Peyser PA, Polasek O, Raitakari OT, Renström F, Rice TK, Ridker PM, Robino A, Robinson JG, Rose LM, Rudan I, Sabanayagam C, Salako BL, Sandow K, Schmidt CO, Schreiner PJ, Scott WR, Seshadri S, Sever P, Sitlani CM, Smith JA, Snieder H, Starr JM, Strauch K, Tang H, Taylor KD, Teo YY, Tham YC, Uitterlinden AG, Waldenberger M, Wang L, Wang YX, Wei WB, Williams C, Wilson G, Wojczynski MK, Yao J, Yuan JM, Zonderman AB, Becker DM, Boehnke M, Bowden DW, Chambers JC, Chen YI, de Faire U, Deary IJ, Esko T, Farrall M, Forrester T, Franks PW, Freedman BI, Froguel P, Gasparini P, Gieger C, Horta BL, Hung YJ, Jonas JB, Kato N, Kooner JS, Laakso M, Lehtimäki T, Liang KW, Magnusson PKE, Newman AB, Oldehinkel AJ, Pereira AC, Redline S, Rettig R, Samani NJ, Scott J, Shu XO, van der Harst P, Wagenknecht LE, Wareham NJ, Watkins H, Weir DR, Wickremasinghe AR, Wu T, Zheng W, Kamatani Y, Laurie CC, Bouchard C, Cooper RS, Evans MK, Gudnason V, Kardia SLR, Kritchevsky SB, Levy D, O'Connell JR, Psaty BM, van Dam RM, Sims M, Arnett DK, Mook-Kanamori DO, Kelly TN, Fox ER, Hayward C, Fornage M, Rotimi CN, Province MA, van Duijn CM, Tai ES, Wong TY, Loos RJF, Reiner AP, Rotter JI, Zhu X, Bierut LJ, Gauderman WJ, Caulfield MJ, Elliott P, Rice K, Munroe PB, Morrison AC, Cupples LA, Rao DC, Chasman DI

Abstract
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

PMID: 29455858 [PubMed - as supplied by publisher]

Roundtable on etiology of familial chylomicronemia syndrome.

Biobank publications - Sun, 02/18/2018 - 17:21
Related Articles

Roundtable on etiology of familial chylomicronemia syndrome.

J Clin Lipidol. 2018 Jan - Feb;12(1):5-11

Authors: Brown WV, Gaudet D, Goldberg I, Hegele R

PMID: 29452917 [PubMed - in process]

Survival Impact of Stations of Pathological Lymph Nodes in N2 Non-small Cell Lung Cancer in a French Hospital.

Biobank publications - Sat, 02/17/2018 - 15:26
Related Articles

Survival Impact of Stations of Pathological Lymph Nodes in N2 Non-small Cell Lung Cancer in a French Hospital.

Ann Surg Oncol. 2018 Feb 14;:

Authors: Clément-Duchêne C, Luc A, Casse JM, Vignaud JM, Lacomme S, Anne V, Siat J, Ménard O, Martinet Y

Abstract
BACKGROUND: The prognosis of lung cancer remains poor; only 20% of patients can undergo surgery. N2 non-small cell lung cancer (NSCLC) is a heterogeneous disease. We conducted a retrospective study to analyze the impact of N2 location on survival.
METHODS: This study included 342 NSCLC with N2 involvement between 1988 and 2014. Patient-related data were collected through the CRB biobank and included demographic, therapeutic, and survival data. Survival was analyzed according to Kaplan-Maier method. Cox's regression analysis and analysis of variance (ANOVA) were used to determine factors significantly associated with survival.
RESULTS: The population average age was 61.6 years; 82.2% were men, a majority were former smokers (87.1%), and 45.3% had adenocarcinoma. The main prognostic factors were male gender (p = 0.01), number of nodes (p < 0.0001), and tumor size (p < 0.0001). N2 disease had a poor survival (16 months) compared with N0 (32 months) and N1 (21.1 months) disease (p < 0.0001). The patients with involvement of station 4 (survival = 17.8 months) seemed to have a prognosis between those with station 7 (survival = 10.5 months) and N1 (survival = 22.6 months), p = 0.0005.
CONCLUSIONS: N2 location has a prognostic impact in surgically NSCLC, and station 4 involvement has a better prognostic than station 7.

PMID: 29450750 [PubMed - as supplied by publisher]

A human-specific switch of alternatively spliced AFMID isoforms contributes to TP53 mutations and tumor recurrence in hepatocellular carcinoma.

Biobank publications - Sat, 02/17/2018 - 15:26
Related Articles

A human-specific switch of alternatively spliced AFMID isoforms contributes to TP53 mutations and tumor recurrence in hepatocellular carcinoma.

Genome Res. 2018 Feb 15;:

Authors: Lin KT, Ma WK, Scharner J, Liu YR, Krainer AR

Abstract
Pre-mRNA splicing can contribute to the switch of cell identity that occurs in carcinogenesis. Here, we analyze a large collection of RNA-seq data sets and report that splicing changes in hepatocyte-specific enzymes, such as AFMID and KHK, are associated with HCC patients' survival and relapse. The switch of AFMID isoforms is an early event in HCC development and is associated with driver mutations in TP53 and ARID1A The switch of AFMID isoforms is human-specific and not detectable in other species, including primates. Finally, we show that overexpression of the full-length AFMID isoform leads to a higher NAD+ level, lower DNA-damage response, and slower cell growth in HepG2 cells. The integrative analysis uncovered a mechanistic link between splicing switches, de novo NAD+ biosynthesis, driver mutations, and HCC recurrence.

PMID: 29449409 [PubMed - as supplied by publisher]

Collection of human biological samples for research purpose: Key challenges and patients’ perspectives.

Biobank publications - Sat, 02/17/2018 - 15:26
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Collection of human biological samples for research purpose: Key challenges and patients’ perspectives.

Therapie. 2018 Feb 12;:

Authors: Verstuyft C, Antoun Z, Deplanque D, Participants to Round Table Biological collections of Giens XXXIII

Abstract
The development and the access to collections of human biological samples is one of the major challenges for health research. In recent years, biological resource centres (BRCs) have developed in such a way that they provide all activities relating to the handling of samples. In this context, France is undoubtedly a pioneering country, because most of the biological collections available were created on the basis of themed research projects, which involved a particular donor phenotype. The round table was an opportunity to emphasise the persistence of some pitfalls particularly in relation to ensuring the consistency of different regulatory pathways. It also gave the opportunity to question and make recommendations on aspects of governance of biological collections and the BRCs, to state the challenges linked to scientific and economic valorisation and to consider the place of patients and the general public. The development of specific education in public health and research is essential to underline that these initiatives are necessary for developing new diagnostic and therapeutic procedures.

PMID: 29449028 [PubMed - as supplied by publisher]

Using structural equation modelling to jointly estimate maternal and fetal effects on birthweight in the UK Biobank.

Biobank publications - Fri, 02/16/2018 - 14:16

Using structural equation modelling to jointly estimate maternal and fetal effects on birthweight in the UK Biobank.

Int J Epidemiol. 2018 Feb 13;:

Authors: Warrington NM, Freathy RM, Neale MC, Evans DM

Abstract
Background: To date, 60 genetic variants have been robustly associated with birthweight. It is unclear whether these associations represent the effect of an individual's own genotype on their birthweight, their mother's genotype, or both.
Methods: We demonstrate how structural equation modelling (SEM) can be used to estimate both maternal and fetal effects when phenotype information is present for individuals in two generations and genotype information is available on the older individual. We conduct an extensive simulation study to assess the bias, power and type 1 error rates of the SEM and also apply the SEM to birthweight data in the UK Biobank study.
Results: Unlike simple regression models, our approach is unbiased when there is both a maternal and a fetal effect. The method can be used when either the individual's own phenotype or the phenotype of their offspring is not available, and allows the inclusion of summary statistics from additional cohorts where raw data cannot be shared. We show that the type 1 error rate of the method is appropriate, and that there is substantial statistical power to detect a genetic variant that has a moderate effect on the phenotype and reasonable power to detect whether it is a fetal and/or a maternal effect. We also identify a subset of birthweight-associated single nucleotide polymorphisms (SNPs) that have opposing maternal and fetal effects in the UK Biobank.
Conclusions: Our results show that SEM can be used to estimate parameters that would be difficult to quantify using simple statistical methods alone.

PMID: 29447406 [PubMed - as supplied by publisher]

Dietary pattern associated with selenoprotein P and MRI-derived body fat volumes, liver signal intensity, and metabolic disorders.

Biobank publications - Fri, 02/16/2018 - 14:16
Related Articles

Dietary pattern associated with selenoprotein P and MRI-derived body fat volumes, liver signal intensity, and metabolic disorders.

Eur J Nutr. 2018 Feb 14;:

Authors: di Giuseppe R, Plachta-Danielzik S, Koch M, Nöthlings U, Schlesinger S, Borggrefe J, Both M, Müller HP, Kassubek J, Jacobs G, Lieb W

Abstract
PURPOSE: The association of complex dietary patterns with circulating selenoprotein P (SELENOP) levels in humans is unknown. In a general population sample, we aimed to identify a dietary pattern explaining inter-individual variation in circulating SELENOP concentrations and to study this pattern in relation to prevalent diabetes, metabolic syndrome (MetS), MRI-determined total volumes of visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue, and liver signal intensity/fatty liver disease.
METHODS: In this cross-sectional study, serum SELENOP levels were measured in 853 individuals. In a subsample of 553 participants, whole-body MRI was performed to assess body fat distribution and liver fat. Dietary intake was assessed by a self-administered food frequency questionnaire and the dietary pattern identified using reduced-rank regression (RRR). Multivariable linear and logistic regressions were used to investigate associations between dietary pattern score and metabolic traits.
RESULTS: Characterized by high intake of fruit, vegetables and antioxidant beverages, the RRR-derived dietary pattern displayed inverse associations with VAT, SAT, MetS, and prevalent diabetes in multivariable-adjusted restricted cubic splines. Each unit increase in dietary pattern score was associated with 31% higher SELENOP levels, 12% lower VAT (95% CI: - 19%; - 5%), 13% (95% CI: - 20%; - 6%) lower SAT values and 46% (95% CI: 27%; 60%) and 53% (95% CI: 22%; 72%) lower odds of having MetS or diabetes, respectively. No meaningful relations were observed between the dietary pattern and liver traits.
CONCLUSIONS: Our observations propose diet-related regulation in SELENOP levels and that the identified dietary pattern is inversely related to VAT, SAT, MetS, and prevalent diabetes.

PMID: 29445913 [PubMed - as supplied by publisher]

Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer's Disease: Analytical and Diagnostic Characterization.

Biobank publications - Fri, 02/16/2018 - 14:16
Related Articles

Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer's Disease: Analytical and Diagnostic Characterization.

J Alzheimers Dis. 2017;55(1):159-170

Authors: Lewczuk P, Lelental N, Lachmann I, Holzer M, Flach K, Brandner S, Engelborghs S, Teunissen CE, Zetterberg H, Molinuevo JL, Mroczko B, Blennow K, Popp J, Parnetti L, Chiasserini D, Perret-Liaudet A, Spitzer P, Maler JM, Kornhuber J

Abstract
BACKGROUND: Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF).
OBJECTIVE: To establish and analytically and clinically characterize the first assay capable to measure concentrations of Non-P-Tau in human CSF.
METHODS: An antibody (1G2) was developed that selectively binds to the Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method.
RESULTS: The 1G2 antibody shows decreasing reactivity to tau peptides containing phosphorylation mainly at positions T175 and T181. Detection limit of the assay is 25 pg/ml; the coefficients of variation (CVs) of the optical densities of the repeated standard curves were between 3.6-15.9%. Median intra-assay imprecision of double measurements was 4.8%; inter-assay imprecision was in the range of 11.2% - 15.3%. Non-P-Tau concentrations are stable in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in patients with Alzheimer's disease in stage of mild cognitive impairment or dementia (AD/MCI, n = 58, 109.2±32.0 pg/mL) compared to the non-demented Controls (n = 42, 62.1±9.3 pg/mL, p < 0.001). At the cut-off of 78.3 pg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively.
CONCLUSION: For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF.

PMID: 27662295 [PubMed - indexed for MEDLINE]

EEG Dominant Frequency Peak Differentiates Between Alzheimer's Disease and Frontotemporal Lobar Degeneration.

Biobank publications - Fri, 02/16/2018 - 14:16
Related Articles

EEG Dominant Frequency Peak Differentiates Between Alzheimer's Disease and Frontotemporal Lobar Degeneration.

J Alzheimers Dis. 2017;55(1):53-58

Authors: Goossens J, Laton J, Van Schependom J, Gielen J, Struyfs H, Van Mossevelde S, Van den Bossche T, Goeman J, De Deyn PP, Sieben A, Martin JJ, Van Broeckhoven C, van der Zee J, Engelborghs S, Nagels G

Abstract
We investigated the power of EEG as biomarker in differential diagnosis of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). EEG was recorded from 106 patients with AD or FTLD, of which 37 had a definite diagnosis, and 40 controls. Dominant frequency peaks were extracted for all 19 channels, for each subject. The average frequency of the largest dominant frequency peaks (maxpeak) was significantly lower in AD than FTLD patients and controls. Based on ROC analysis, classification could be made with diagnostic accuracy of 78.9%. Our findings show that quantitative analysis of EEG maxpeak frequency is an easy and useful measure for differential dementia diagnosis.

PMID: 27636837 [PubMed - indexed for MEDLINE]