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A new mass spectrometry-based method for the quantification of histones in plasma from septic shock patients.

Fri, 09/08/2017 - 12:19
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A new mass spectrometry-based method for the quantification of histones in plasma from septic shock patients.

Sci Rep. 2017 Sep 06;7(1):10643

Authors: García-Giménez JL, Romá-Mateo C, Carbonell N, Palacios L, Peiró-Chova L, García-López E, García-Simón M, Lahuerta R, Gimenez-Garzó C, Berenguer-Pascual E, Mora MI, Valero ML, Alpízar A, Corrales FJ, Blanquer J, Pallardó FV

Abstract
The aim of this study was to develop a novel method to detect circulating histones H3 and H2B in plasma based on multiple reaction monitoring targeted mass spectrometry and a multiple reaction monitoring approach (MRM-MS) for its clinical application in critical bacteriaemic septic shock patients. Plasma samples from 17 septic shock patients with confirmed bacteraemia and 10 healthy controls were analysed by an MRM-MS method, which specifically detects presence of histones H3 and H2B. By an internal standard, it was possible to quantify the concentration of circulating histones in plasma, which were significantly higher in patients, and thus confirmed their potential as biomarkers for diagnosing septic shock. After comparing surviving patients and non-survivors, a correlation was found between higher levels of circulating histones and unfavourable outcome. Indeed, histone H3 proved a more efficient and sensitive biomarker for septic shock prognosis. In conclusion, these findings suggest the accuracy of the MRM-MS technique and stable isotope labelled peptides to detect and quantify circulating plasma histones H2B and H3. This method may be used for early septic shock diagnoses and for the prognosis of fatal outcomes.

PMID: 28878320 [PubMed - in process]

Inflammation biomarkers in blood as mortality predictors in community-acquired pneumonia admitted patients: Importance of comparison with neutrophil count percentage or neutrophil-lymphocyte ratio.

Fri, 09/08/2017 - 12:19
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Inflammation biomarkers in blood as mortality predictors in community-acquired pneumonia admitted patients: Importance of comparison with neutrophil count percentage or neutrophil-lymphocyte ratio.

PLoS One. 2017;12(3):e0173947

Authors: Curbelo J, Luquero Bueno S, Galván-Román JM, Ortega-Gómez M, Rajas O, Fernández-Jiménez G, Vega-Piris L, Rodríguez-Salvanes F, Arnalich B, Díaz A, Costa R, de la Fuente H, Lancho Á, Suárez C, Ancochea J, Aspa J

Abstract
INTRODUCTION: The increase and persistence of inflammation in community-acquired pneumonia (CAP) patients can lead to higher mortality. Biomarkers capable of measuring this inadequate inflammatory response are likely candidates to be related with a bad outcome. We investigated the association between concentrations of several inflammatory markers and mortality of CAP patients.
MATERIAL AND METHODS: This was a prospective study of hospitalised CAP patients in a Spanish university hospital. Blood tests upon admittance and in the early-stage evolution (72-120 hours) were carried out, where C-reactive protein, procalcitonin, proadrenomedullin, copeptin, white blood cell, Lymphocyte Count Percentage (LCP), Neutrophil Count Percentage (NCP) and Neutrophil/Lymphocyte Ratio (NLR) were measured. The outcome variable was mortality at 30 and 90 days. Statistical analysis included logistic regression, ROC analysis and area-under-curve test.
RESULTS: 154 hospitalised CAP patients were included. Patients who died during follow-up had higher levels of procalcitonin, copeptin, proadrenomedullin, lower levels of LCP, and higher of NCP and NLR. Remarkably, multivariate analysis showed a relationship between NCP and mortality, regardless of age, severity of CAP and comorbidities. AUC analysis showed that NLR and NCP at admittance and during early-stage evolution achieved a good diagnostic power. ROC test for NCP and NLR were similar to those of the novel serum biomarkers analysed.
CONCLUSIONS: NLR and NCP, are promising candidate predictors of mortality for hospitalised CAP patients, and both are cheaper, easier to perform, and at least as reliable as the new serum biomarkers. Future implementation of new biomarkers would require comparison not only with classic inflammatory parameters like White Blood Cell count but also with NLR and NCP.

PMID: 28301543 [PubMed - indexed for MEDLINE]

Inflammatory bowel diseases in Faroese-born Danish residents and their offspring: further evidence of the dominant role of environmental factors in IBD development.

Fri, 09/08/2017 - 12:19
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Inflammatory bowel diseases in Faroese-born Danish residents and their offspring: further evidence of the dominant role of environmental factors in IBD development.

Aliment Pharmacol Ther. 2017 Apr;45(8):1107-1114

Authors: Hammer T, Lophaven SN, Nielsen KR, von Euler-Chelpin M, Weihe P, Munkholm P, Burisch J, Lynge E

Abstract
BACKGROUND: The incidence of inflammatory bowel disease (IBD) is record high in the Faroe Islands, and many Faroese emigrate to Denmark, where the IBD incidence is considerably lower.
AIM: To study the IBD incidence in first-, second- and third-generation immigrants from the Faroe Islands to Denmark to assess the extent to which the immigrants adopt the lower IBD incidence of their new home country.
METHODS: Data on Faroese-born Danish residents and their children were retrieved from the Danish Central Population Register for 1980-2014. Incident IBD cases were identified from the Danish National Patient Register. Standardised Incidence Ratios (SIRs) were used to compare the IBD risk in immigrants with that of Danes. 95% confidence intervals (CI) were calculated using the square-root transform.
RESULTS: First-generation Faroese immigrants had a higher IBD incidence than Danes, SIR 1.25 (95% CI, 0.97-1.59) for men and 1.28 (95% CI, 1.05-1.53) for women. This excess risk derived from ulcerative colitis (UC), SIR 1.44 (95% CI, 1.10-1.87) for men and 1.36 (95% CI, 1.09-1.68) for women. No excess risk was found for Crohn's disease (CD). The UC risk was nearly doubled during the immigrants' first 10 years in Denmark; SIR 2.13 (95% CI, 1.52-2.92) for men and 1.63 (95% CI, 1.19-2.18) for women.
CONCLUSIONS: Although some impact of genetic dilution cannot be excluded, our findings indicate importance of gene-environment interplay in UC, as the excess UC risk in Faroese immigrants to Denmark disappeared over time and over one generation in men and over two generations in women.

PMID: 28176348 [PubMed - indexed for MEDLINE]

Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis.

Fri, 09/08/2017 - 12:19
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Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis.

Cancer Res. 2017 Mar 15;77(6):1408-1415

Authors: Späth F, Wibom C, Krop EJ, Johansson AS, Bergdahl IA, Vermeulen R, Melin B

Abstract
The B-cell activation markers CXCL13, sCD23, sCD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of marker-disease association hampers interpretation. In this study, we identified 170 individuals who had donated two prediagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lymphoma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope = 28, Ptrend = 7.279 × 10(-10)). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Furthermore, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients. Cancer Res; 77(6); 1408-15. ©2017 AACR.

PMID: 28108506 [PubMed - indexed for MEDLINE]

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Fri, 09/08/2017 - 12:19
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Nat Genet. 2016 Sep;48(9):1043-8

Authors: van Rheenen W, Shatunov A, Dekker AM, McLaughlin RL, Diekstra FP, Pulit SL, van der Spek RA, Võsa U, de Jong S, Robinson MR, Yang J, Fogh I, van Doormaal PT, Tazelaar GH, Koppers M, Blokhuis AM, Sproviero W, Jones AR, Kenna KP, van Eijk KR, Harschnitz O, Schellevis RD, Brands WJ, Medic J, Menelaou A, Vajda A, Ticozzi N, Lin K, Rogelj B, Vrabec K, Ravnik-Glavač M, Koritnik B, Zidar J, Leonardis L, Grošelj LD, Millecamps S, Salachas F, Meininger V, de Carvalho M, Pinto S, Mora JS, Rojas-García R, Polak M, Chandran S, Colville S, Swingler R, Morrison KE, Shaw PJ, Hardy J, Orrell RW, Pittman A, Sidle K, Fratta P, Malaspina A, Topp S, Petri S, Abdulla S, Drepper C, Sendtner M, Meyer T, Ophoff RA, Staats KA, Wiedau-Pazos M, Lomen-Hoerth C, Van Deerlin VM, Trojanowski JQ, Elman L, McCluskey L, Basak AN, Tunca C, Hamzeiy H, Parman Y, Meitinger T, Lichtner P, Radivojkov-Blagojevic M, Andres CR, Maurel C, Bensimon G, Landwehrmeyer B, Brice A, Payan CA, Saker-Delye S, Dürr A, Wood NW, Tittmann L, Lieb W, Franke A, Rietschel M, Cichon S, Nöthen MM, Amouyel P, Tzourio C, Dartigues JF, Uitterlinden AG, Rivadeneira F, Estrada K, Hofman A, Curtis C, Blauw HM, van der Kooi AJ, de Visser M, Goris A, Weber M, Shaw CE, Smith BN, Pansarasa O, Cereda C, Del Bo R, Comi GP, D'Alfonso S, Bertolin C, Sorarù G, Mazzini L, Pensato V, Gellera C, Tiloca C, Ratti A, Calvo A, Moglia C, Brunetti M, Arcuti S, Capozzo R, Zecca C, Lunetta C, Penco S, Riva N, Padovani A, Filosto M, Muller B, Stuit RJ, PARALS Registry, SLALOM Group, SLAP Registry, FALS Sequencing Consortium, SLAGEN Consortium, NNIPPS Study Group, Blair I, Zhang K, McCann EP, Fifita JA, Nicholson GA, Rowe DB, Pamphlett R, Kiernan MC, Grosskreutz J, Witte OW, Ringer T, Prell T, Stubendorff B, Kurth I, Hübner CA, Leigh PN, Casale F, Chio A, Beghi E, Pupillo E, Tortelli R, Logroscino G, Powell J, Ludolph AC, Weishaupt JH, Robberecht W, Van Damme P, Franke L, Pers TH, Brown RH, Glass JD, Landers JE, Hardiman O, Andersen PM, Corcia P, Vourc'h P, Silani V, Wray NR, Visscher PM, de Bakker PI, van Es MA, Pasterkamp RJ, Lewis CM, Breen G, Al-Chalabi A, van den Berg LH, Veldink JH

Abstract
To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

PMID: 27455348 [PubMed - indexed for MEDLINE]

Exosomes secreted from mutant-HIF-1α-modified bone-marrow-derived mesenchymal stem cells attenuate early steroid-induced avascular necrosis of femoral head in rabbit.

Thu, 09/07/2017 - 14:12
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Exosomes secreted from mutant-HIF-1α-modified bone-marrow-derived mesenchymal stem cells attenuate early steroid-induced avascular necrosis of femoral head in rabbit.

Cell Biol Int. 2017 Sep 06;:

Authors: Li H, Liu D, Li C, Zhou S, Tian D, Xiao D, Zhang H, Gao F, Huang J

Abstract
Mesenchymal stem cells (MSCs)-derived exosomes exhibit protective effects on damaged or diseased tissues. Hypoxia-inducible factor 1α (HIF-1α) plays a critical role in bone development. However, HIF-1α is easily biodegradable under normoxic conditions. The bone-marrow-derived mesenchymal stem cells (BMSCs) were transfected with adenovirus carrying triple point-mutations (amino acids 402, 564, and 803) in the HIF-1α coding sequence (CDS). The mutant HIF-1α can efficiently express functional proteins under normoxic conditions. To date, no study has reported the role of exosomes secreted by mutant HIF-1α modified BMSCs in the recovery of the early steroid-induced avascular necrosis of femoral head (SANFH). In this study, we firstly analyzed exosomes derived from BMSCs modified by mutant (BMSC-Exos(MU) ) or wild-type HIF-1α (BMSC-Exos(WT) ). In vitro, we investigated the osteogenic differentiation capacity of BMSCs modified by BMSC-Exos(MU) or BMSC-Exos(WT) , and the angiogenesis effects of BMSC-Exos(MU) and BMSC-Exos(WT) on human umbilical vein endothelial cells (HUVECs). Besides, the healing of the femoral head was also assessed in vivo. We found that the potential of osteogenic differentiation of BMSCs treated with BMSC-Exos(MU) was higher than the wild-type group In vitro. In addition, BMSC-Exos(MU) stimulated the proliferation, migration and tube formation of HUVECs in a dose-dependent manner. Compared with the BMSC-Exos(WT) or PBS control group, the injection of BMSC-Exos(MU) into the necrosis region markedly accelerated the bone regeneration and angiogenesis, which were indicated by the increased trabecular reconstruction and microvascular density. Taken together, our data suggest that BMSC-Exos(MU) facilitates the repair of SANFH by enhancing osteogenesis and angiogenesis.

PMID: 28877384 [PubMed - as supplied by publisher]

The impact of FLT3 mutations on treatment response and survival in Chinese de novo AML patients.

Thu, 09/07/2017 - 14:12
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The impact of FLT3 mutations on treatment response and survival in Chinese de novo AML patients.

Hematology. 2017 Sep 06;:1-8

Authors: Qiu QC, Wang C, Bao XB, Yang J, Shen HJ, Ding ZX, Liu H, He J, Yao H, Chen SN, Li Z, Xue SL, Liu SB

Abstract
OBJECTIVE: Two distinct forms of FMS-like tyrosine kinase 3 (FLT3) mutations, internal tandem duplication (ITD) in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain (TKD), have been identified in considerable number of patients with AML. This study was aimed to analyze the impacts of these mutations on clinical outcomes, and assess the efficacy of different therapeutic regimens (allo-HSCT, sorafenib, or conventional chemotherapy) for AML patients with FLT3 mutations after the standard induction therapy.
MATERIALS AND METHODS: We analyzed DNA samples from 158 consecutive de novo AML patients (18-60 years, excluding APL) with FLT3 mutations between July 2010 and October 2015.
RESULTS: We found that AML patients with FLT3-TKD mutations have more favorable clinical outcomes than those with FLT3-ITD mutations. We also found that allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients (p < 0.001, p = 0.071). However, compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients. Further study on a large scale is still recommended.
CONCLUSIONS: FLT3-TKD-mutated AML patients have more favorable clinical outcomes than those with FLT3-ITD mutations. Allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients. Compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients.

PMID: 28876197 [PubMed - as supplied by publisher]

Penetrance and the Healthy Elderly.

Thu, 09/07/2017 - 14:12
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Penetrance and the Healthy Elderly.

Genet Test Mol Biomarkers. 2017 Sep 06;:

Authors: Lacaze P, Winship I, McNeil J

Abstract
The variable penetrance of pathogenic variants (PVs) represents a major challenge to the field of human genetics, often complicating clinical decision-making and risk management. Nonpenetrance, the detection of PVs in the absence of disease manifestation, is a common phenomenon, yet, we know very little about the underlying factors, which may protect some individuals and not others. Placing a new focus on the genomic study of the healthy elderly may be pivotal for advancing our understanding of penetrance. Studying those who remain unaffected late into life, despite harboring known genetic risk variants, could provide important insights into disease mechanisms and ultimately inform clinical care, yet, it has received relatively little attention as a research strategy. The ever increasing use of sequencing technology is further driving the requirement to understand the penetrance of ascertained variants. The ASPREE Biobank of Healthy Ageing provides a unique opportunity to address this area of need. DNA has been collected from a cohort of over 14,000 healthy elderly individuals aged 70 years or older enrolled in an aspirin clinical trial. The ASPREE cohort represents a healthy reference population ascertained without the typical biases of a genetic study. The cohort is depleted of expressed monogenetic disease, yet will contain hundreds of elderly individuals with known PVs in clinically actionable genes. Investigating this population along with other cohorts of the healthy elderly will provide critical new knowledge into the penetrance of actionable variants as a foundation for informing clinical care.

PMID: 28876137 [PubMed - as supplied by publisher]

Pregnancy-Associated Plasma Protein-A2 and Anthropometry, Lifestyle, and Biochemical Factors in a Human Adult Population.

Thu, 09/07/2017 - 14:12
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Pregnancy-Associated Plasma Protein-A2 and Anthropometry, Lifestyle, and Biochemical Factors in a Human Adult Population.

Sci Rep. 2017 Sep 05;7(1):10455

Authors: Steinbrecher A, Janke J, Poy MN, Oxvig C, Pischon T

Abstract
Pregnancy-associated plasma protein-A2 (PAPP-A2), a metalloproteinase purportedly related to pregnancy, foetal growth and development, has recently been described essential for pre-adult growth. Thus, we measured PAPP-A2 in plasma of a non-pregnant population and determined its associations with lifestyle, anthropometric or biochemical factors. In this cross-sectional study of 387 participants (20-70 years) randomly drawn from registration offices near Berlin, Germany, socio-economic and lifestyle factors were assessed by questionnaires, and anthropometric measures and blood samples were taken by trained personnel. Blood was analysed for standard clinical parameters. PAPP-A2 concentration was measured by ELISA. Generalized linear models were used to estimate associations with anthropometric and biochemical factors adjusted for age, sex, and weight. Adjusted mean PAPP-A2 concentration was slightly higher in women (283 pg/mL) than in men (261 pg/mL, p = 0.05) and positively correlated with age (r = 0.17, p = 0.001). PAPP-A2 concentration was inversely associated with body mass index (-2.7 pg/mL per kg/m(2), p = 0.03) and weight (-1.0 pg/mL per kg, p = 0.01) and positively associated with γ-glutamyl transferase (13.6 pg/mL per SD, p = 0.02), aspartate transaminase (18.5 pg/mL per SD, p = 0.002) and lactate dehydrogenase (14.9 pg/mL per SD, p = 0.02). Our results support that PAPP-A2, beyond its established role in early growth and development is relevant in adult metabolisms.

PMID: 28874827 [PubMed - in process]

The PF4/PPBP/CXCL5 Gene Cluster Is Associated with Periodontitis.

Thu, 09/07/2017 - 14:12
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The PF4/PPBP/CXCL5 Gene Cluster Is Associated with Periodontitis.

J Dent Res. 2017 Jul;96(8):945-952

Authors: Shusterman A, Munz M, Richter G, Jepsen S, Lieb W, Krone B, Hoffman P, Laudes M, Wellmann J, Berger K, Kocher T, Offenbacher S, Divaris K, Franke A, Schreiber S, Dommisch H, Weiss E, Schaefer AS, Houri-Haddad Y, Iraqi FA

Abstract
Periodontitis is a common dysbiotic inflammatory disease with an estimated heritability of 50%. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWAS) of chronic periodontitis (CP) have been unsuccessful in discovering susceptibility factors. A strategy that combines agnostic GWAS with a well-powered candidate-gene approach has the potential to discover novel loci. We combined RNA-seq data from gingival tissues with quantitative trait loci (QTLs) that were identified in a F2-cross of mice resistant and susceptible to infection with oral bacterial pathogens. Four genes, which were located within the mapped QTLs, showed differential expression. The chromosomal regions across the human orthologous were interrogated for putative periodontitis-associated variants using existing GWAS data from a German case-control sample of aggressive periodontitis (AgP; 651 cases, 4,001 controls), the most severe and early onset form of periodontitis. Two haplotype blocks, one upstream to the coding region of UGT2A1 (rs146712414, P = 9.1 × 10(-5); odds ratio [OR], 1.34; 95% confidence interval [CI], 1.16-1.56) and one downstream of the genes PF4/PPBP/CXCL5 (rs1595009, P = 1.3 × 10(-4); OR, 1.32; 95% CI, 1.15-1.52), were associated with AgP. The association of rs1595009 was validated in an independent cohort of CP of European Americans (1,961 cases and 1,864 controls; P = 0.03; OR, 1.45; 95% CI, 1.01-1.29). This association was further replicated in another sample of 399 German CP cases (disease onset <60 y of age) and 1,633 controls ( P = 0.03; OR, 1.75; 95% CI, 1.06-2.90). The combined estimates of association from all samples were P = 2.9 × 10(-5) (OR, 1.2; 95% CI, 1.1-1.3). This study shows the strength of combining QTL mapping and RNA-Seq data from a mouse model with association studies in human case-control samples to identify genetic risk variants of periodontitis.

PMID: 28467728 [PubMed - indexed for MEDLINE]

Evaluating genetic variants associated with breast cancer risk in high and moderate-penetrance genes in Asians.

Thu, 09/07/2017 - 14:12
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Evaluating genetic variants associated with breast cancer risk in high and moderate-penetrance genes in Asians.

Carcinogenesis. 2017 May 01;38(5):511-518

Authors: Han MR, Zheng W, Cai Q, Gao YT, Zheng Y, Bolla MK, Michailidou K, Dennis J, Wang Q, Dunning AM, Brennan P, Chen ST, Choi JY, Hartman M, Ito H, Lophatananon A, Matsuo K, Miao H, Muir K, Sangrajrang S, Shen CY, Teo SH, Tseng CC, Wu AH, Yip CH, Kang D, Xiang YB, Easton DF, Shu XO, Long J

Abstract
Over the past 20 years, high-penetrance pathogenic mutations in genes BRCA1, BRCA2, TP53, PTEN, STK11 and CDH1 and moderate-penetrance mutations in genes CHEK2, ATM, BRIP1, PALB2, RAD51C, RAD50 and NBN have been identified for breast cancer. In this study, we investigated whether there are additional variants in these 13 genes associated with breast cancer among women of Asian ancestry. We analyzed up to 654 single nucleotide polymorphisms (SNPs) from 6269 cases and 6624 controls of Asian descent included in the Breast Cancer Association Consortium (BCAC), and up to 236 SNPs from 5794 cases and 5529 controls included in the Shanghai Breast Cancer Genetics Study (SBCGS). We found three missense variants with minor allele frequency (MAF) <0.05: rs80358978 (Gly2508Ser), rs80359065 (Lys2729Asn) and rs11571653 (Met784Val) in the BRCA2 gene, showing statistically significant associations with breast cancer risk, with P-values of 1.2 × 10-4, 1.0 × 10-3 and 5.0 × 10-3, respectively. In addition, we found four low-frequency variants (rs8176085, rs799923, rs8176173 and rs8176258) in the BRCA1 gene, one common variant in the CHEK2 gene (rs9620817), and one common variant in the PALB2 gene (rs13330119) associated with breast cancer risk at P < 0.01. Our study identified several new risk variants in BRCA1, BRCA2, CHEK2, and PALB2 genes in relation to breast cancer risk in Asian women. These results provide further insights that, in addition to the high/moderate penetrance mutations, other low-penetrance variants in these genes may also contribute to breast cancer risk.

PMID: 28419251 [PubMed - indexed for MEDLINE]

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Thu, 09/07/2017 - 14:12
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Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Nat Genet. 2017 Feb;49(2):269-273

Authors: Ji SG, Juran BD, Mucha S, Folseraas T, Jostins L, Melum E, Kumasaka N, Atkinson EJ, Schlicht EM, Liu JZ, Shah T, Gutierrez-Achury J, Boberg KM, Bergquist A, Vermeire S, Eksteen B, Durie PR, Farkkila M, Müller T, Schramm C, Sterneck M, Weismüller TJ, Gotthardt DN, Ellinghaus D, Braun F, Teufel A, Laudes M, Lieb W, Jacobs G, Beuers U, Weersma RK, Wijmenga C, Marschall HU, Milkiewicz P, Pares A, Kontula K, Chazouillères O, Invernizzi P, Goode E, Spiess K, Moore C, Sambrook J, Ouwehand WH, Roberts DJ, Danesh J, Floreani A, Gulamhusein AF, Eaton JE, Schreiber S, Coltescu C, Bowlus CL, Luketic VA, Odin JA, Chopra KB, Kowdley KV, Chalasani N, Manns MP, Srivastava B, Mells G, Sandford RN, Alexander G, Gaffney DJ, Chapman RW, Hirschfield GM, de Andrade M, UK-PSC Consortium, International IBD Genetics Consortium, International PSC Study Group, Rushbrook SM, Franke A, Karlsen TH, Lazaridis KN, Anderson CA

Abstract
Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10(-15)). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10(-15)). Our study represents a substantial advance in understanding of the genetics of PSC.

PMID: 27992413 [PubMed - indexed for MEDLINE]

Oncogenic retinoic acid receptor α promotes human colorectal cancer growth through simultaneously regulating p21 transcription and GSK3β/β-catenin signaling.

Thu, 09/07/2017 - 14:12
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Oncogenic retinoic acid receptor α promotes human colorectal cancer growth through simultaneously regulating p21 transcription and GSK3β/β-catenin signaling.

Cancer Lett. 2017 Mar 01;388:118-129

Authors: Huang GL, Zhang W, Ren HY, Zhou P, Chen Y, Chen QX, Shen DY

Abstract
Retinoic acid receptor α (RARα) plays important roles in the progression of several cancers such as leukemia, breast cancer, and lung cancer. In this study, we demonstrated that RARα protein was frequently overexpressed in human CRC specimens and CRC cell lines. RARα knockdown decreased cell survival, proliferation, and colony formation in vitro and tumorigenic potential in nude mice. Specifically, RARα knockdown inhibited cell cycle progression at G1 phase through upregulation of cell cycle inhibitor p21, and downregulation of cyclinD1. Furthermore, RARα was directly recruited to the p21 promoter to inhibit the expression of p21. Simultaneously, RARα contributed to the progression of CRC cells in part due to upregulation of cyclinD1 via activation of GSK3β/β-catenin pathway. Molecular mechanism studies revealed RARα interacted with GSK3β and led to decreased expression of GSK3β at ser9, followed by increased β-catenin expression. Taken together, our results signified the importance of RARα in CRC and demonstrated that RARα promotes CRC progression through suppressing p21 transcription and enhancing GSK3β/β-catenin signaling. RARα might become a potential molecular target for the treatment of CRC.

PMID: 27932034 [PubMed - indexed for MEDLINE]

Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status.

Wed, 09/06/2017 - 13:19

Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status.

PLoS Genet. 2017 Sep 05;13(9):e1006977

Authors: Rask-Andersen M, Karlsson T, Ek WE, Johansson Å

Abstract
Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GSBMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GSBMI, of which alcohol intake frequency, usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10-29, p = 3.83*10-26, p = 4.66*10-11, respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone and controlled experiments are required to fully characterise the causal factors.

PMID: 28873402 [PubMed - as supplied by publisher]

Long-term intra-individual reproducibility of heart rate dynamics during exercise and recovery in the UK Biobank cohort.

Wed, 09/06/2017 - 13:19

Long-term intra-individual reproducibility of heart rate dynamics during exercise and recovery in the UK Biobank cohort.

PLoS One. 2017;12(9):e0183732

Authors: Orini M, Tinker A, Munroe PB, Lambiase PD

Abstract
BACKGROUND: The heart rate (HR) response to exercise provides useful information about the autonomic function and has prognostic value, but its reproducibility over a long period of time, a critical requirement for using it as a clinical biomarker, is undetermined.
AIM: To determine the intra-individual reproducibility of HR dynamics during sub-maximum exercise and one minute recovery.
METHODS: 1187 individuals from the Cardio physical fitness assessment test of the UK Biobank repeated a standard exercise stress test twice (recall time 34.2 ± 2.8 months) and were prospectively studied.
RESULTS: 821 individuals complied with inclusion criteria for reproducibility analysis, including peak workload differences between assessments ≤10 W. Intra-individual correlation between HR profile during the first and the second assessment was very high and higher than inter-individual correlation (0.92±0.08 vs 0.87±0.11, p<0.01). Intra-individual correlation of indices describing HR dynamics was: ρ = 0.81 for maximum HR during exercise; ρ = 0.71 for minimum HR during recovery; ρ = 0.70 for HR changes during both exercise and recovery; Intra-individual correlation was higher for these indices of HR dynamics than for resting HR (ρ = 0.64). Bland-Altman plots demonstrated good agreement between HR indices estimated during the first and second assessment. A small but consistent bias was registered for all repeated measurements. The intra-individual consistency of abnormal values was about 60-70%.
CONCLUSIONS: The HR dynamics during exercise and recovery are reproducible over a period of 3 years, with moderate to strong intra-individual reproducibility of abnormal values.

PMID: 28873397 [PubMed - in process]

Identifying genetic variants that affect viability in large cohorts.

Wed, 09/06/2017 - 13:19

Identifying genetic variants that affect viability in large cohorts.

PLoS Biol. 2017 Sep;15(9):e2002458

Authors: Mostafavi H, Berisa T, Day FR, Perry JRB, Przeworski M, Pickrell JK

Abstract
A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10-6 for fathers and P~2.0 × 10-3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10-3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.

PMID: 28873088 [PubMed - in process]

Impact of Preanalytical Variations in Blood-Derived Biospecimens on Omics Studies: Toward Precision Biobanking?

Wed, 09/06/2017 - 13:19

Impact of Preanalytical Variations in Blood-Derived Biospecimens on Omics Studies: Toward Precision Biobanking?

OMICS. 2017 Sep 05;:

Authors: Lee JE, Kim YY

Abstract
Research data and outcomes do vary across populations and persons, but this is not always due to experimental or true biological variation. Preanalytical components of experiments, be they biospecimen acquisition, preparation, storage, or transportation to the laboratory, may all contribute to apparent variability in research data, outcomes, and interpretation. The present review article and biobanking innovation analysis offer new insights with a summary of such preanalytical variables, for example, the type of blood collection tube, centrifugation conditions, long-term sample storage temperature, and duration, on output of omics analyses of blood-derived biospecimens: whole blood, serum, plasma, buffy coat, and peripheral blood mononuclear cells. Furthermore, we draw parallels from the field of precision medicine in this study, with a view to the future of "precision biobanking" wherein such preanalytical variations are carefully taken into consideration so as to minimize their influence on outcomes of omics data, analyses, and sensemaking, particularly in clinical omics applications. We underscore the need for using broadly framed, critical, independent, social and political science, and humanities research so as to understand the multiple possible future trajectories of, and the motivations and values embedded in, precision biobanking that is increasingly relevant in the current age of Big Data.

PMID: 28873014 [PubMed - as supplied by publisher]

Nylon Mesh Device for Vitrification of Large Quantities of Rat Pancreatic Islets.

Wed, 09/06/2017 - 13:19

Nylon Mesh Device for Vitrification of Large Quantities of Rat Pancreatic Islets.

Biopreserv Biobank. 2017 Sep 05;:

Authors: Yamanaka T, Goto T, Hirabayashi M, Hochi S

Abstract
The practical requirements of islet transplantation necessitate that a large quantity of pancreatic islets be cryopreserved for a long period of time in a simple and convenient manner. We cryopreserved rat islets (size range 101-150 μm in mean diameter) by vitrification with either a Cryotop(®) device or a ø = 57-μm nylon mesh device in units of 10 islets, or by conventional freezing with a Bicell(®) vessel in units of 50 islets. Postwarm/thaw survival rates of the islets were 68.1% ± 5.9%, 64.1% ± 3.5%, and 47.7 ± 1.2% following Cryotop vitrification, nylon mesh vitrification, and Bicell freezing, respectively (p < 0.05). Glucose-stimulated insulin secretion in the two vitrification groups (stimulus index [SI] = 3.1-3.9) was superior to that in the freezing group (SI = 0.8). Additional experiments involved scaling-up the cryopreservation process using the nylon mesh device in units of 10, 50, or 100 islets. Increased numbers of islets per device had no adverse effects on cryosurvival (58.6%-68.5%) or insulin secretion potential (SI = 2.8-4.2). As the nylon mesh device does not require the handling of individual islets with glass pipettes, pre- and postvitrification islet treatment is less complicated. Therefore, nylon mesh can serve as a simple cryodevice for the vitrification of large quantities of rat pancreatic islets.

PMID: 28872901 [PubMed - as supplied by publisher]

Genome-Wide Association Study of Blood Pressure Traits by Hispanic/Latino Background: the Hispanic Community Health Study/Study of Latinos.

Wed, 09/06/2017 - 13:19
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Genome-Wide Association Study of Blood Pressure Traits by Hispanic/Latino Background: the Hispanic Community Health Study/Study of Latinos.

Sci Rep. 2017 Sep 04;7(1):10348

Authors: Sofer T, Wong Q, Hartwig FP, Taylor K, Warren HR, Evangelou E, Cabrera CP, Levy D, Kramer H, Lange LA, Horta BL, COGENT-BP consortium, Kerr KF, Reiner AP, Franceschini N

Abstract
Hypertension prevalence varies between ethnic groups, possibly due to differences in genetic, environmental, and cultural determinants. Hispanic/Latino Americans are a diverse and understudied population. We performed a genome-wide association study (GWAS) of blood pressure (BP) traits in 12,278 participants from the Hispanics Community Health Study/Study of Latinos (HCHS/SOL). In the discovery phase we identified eight previously unreported BP loci. In the replication stage, we tested these loci in the 1982 Pelotas Birth Cohort Study of admixed Southern Brazilians, the COGENT-BP study of African descent, women of European descent from the Women Health Initiative (WHI), and a sample of European descent from the UK Biobank. No loci met the Bonferroni-adjusted level of statistical significance (0.0024). Two loci had marginal evidence of replication: rs78701042 (NGF) with diastolic BP (P = 0.008 in the 1982 Pelotas Birth Cohort Study), and rs7315692 (SLC5A8) with systolic BP (P = 0.007 in European ancestry replication). We investigated whether previously reported loci associated with BP in studies of European, African, and Asian ancestry generalize to Hispanics/Latinos. Overall, 26% of the known associations in studies of individuals of European and Chinese ancestries generalized, while only a single association previously discovered in a people of African descent generalized.

PMID: 28871152 [PubMed - in process]

Polygenic determinants in extremes of high-density lipoprotein cholesterol.

Wed, 09/06/2017 - 13:19
Related Articles

Polygenic determinants in extremes of high-density lipoprotein cholesterol.

J Lipid Res. 2017 Sep 04;:

Authors: Dron JS, Wang J, Low-Kam C, Khetarpal SA, Robinson JF, McIntyre AD, Ban MR, Cao H, Rhainds D, Dubé MP, Rader DJ, Lettre G, Tardif JC, Hegele RA

Abstract
HDL cholesterol (HDL-C) remains a superior biochemical predictor of cardiovascular disease risk, but its genetic basis is incompletely defined. In patients with extreme HDL-C concentrations, we concurrently evaluated the contributions of multiple large- and small-effect genetic variants. In a discovery sample of 255 unrelated lipid clinic patients with extreme HDL-C levels, we used a targeted next-generation sequencing panel to evaluate rare variants in known HDL metabolism genes, simultaneously with common variants bundled into a polygenic trait score. Two additional cohorts were used for validation, and included 1,746 individuals from the Montreal Heart Institute Biobank, and 1,048 individuals from the University of Pennsylvania. Findings were consistent between cohorts: we found rare heterozygous large-effect variants in 18.7% and 10.9% of low and high HDL-C patients, respectively. We also found common variant accumulation - indicated by extreme polygenic trait scores - in an additional 12.8% and 19.3% of overall cases of low and high HDL-C extremes, respectively. Thus, the genetic basis of extreme HDL-C concentrations encountered clinically is frequently polygenic, with contributions from both rare large-effect and common small-effect variants. Multiple types of genetic variants should be considered as contributing factors in patients with extreme dyslipidemia.

PMID: 28870971 [PubMed - as supplied by publisher]