Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration

Background High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ −6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. Methods The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. Findings In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17–21%), 2% (1–3%), 8% (7–10%) and 6% (3–9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75–0.81), 0.58 (0.53–0.64), 0.71 (0.69–0.74) and 0.67 (0.62–0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92–1.24). Interpretation Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted fo

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH

Effects of spice oil treatment of rice on moulding and mycotoxin contamination

Moulding and mycotoxin production have been studied during storage of rice at 85 and 90% relative humidity (r.h.) following treatment with cinnamon and clove oils. The clove oil-treated rice was artificially inoculated with Aspergillus flavus. Aflatoxin B1 and ochratoxin A were determined by monoclonal antibody-based enzyme-linked immunosorbent assay. Both moulding and mycotoxin were inhibited by 9 mul cinnamon oil g-1 but, with smaller doses, fungi could be isolated during the early part of storage, but not subsequently. Thus, following treatment with 3 or 6 mul cinnamon oil g-1, fungi were isolated from direct plated grains after 30 days but not after 45 days. Fungi were also isolated from washings of grain up to 30 days after treatment with 3 or 6 mul g-1, although fewer than from untreated grain. Propagules could also be detected up to 15 days after treatment with 9 mul g-1. Clove oil was much less effective than cinnamon oil in preventing moulding. After treatment with 8 mul g-1, the proportion of seeds infected with fungi and numbers of propagules in washings decreased only after 60 days' storage and with 4 mul g-1 after 90 days at both relative humidities. However, aflatoxin contamination could not be detected 90, 60 and 60 days after treatment with, respectively, 2, 4 and 8 mul g-1 at 85% r.h., although ochratoxin A was present in all treatments. At 90% r.h. aflatoxin was absent only after 90 days from treatment with 4 and 8 mul g-1. No T2 toxin was detected

Fungal colonization and mycotoxin contamination of developing rice grain

Fungal colonization and mycotoxin contamination of developing rice grains of two cultivars (IR-20 and Gowrisanna) were studied during the 1990 and 1991 crop seasons. Field and storage fungi invaded florets while they were still concealed within the boot leaf. Field fungi were most numerous from GS 65 to 77 and then decreased towards GS 91 (fully ripe). Storage fungi also decreased towards harvest. Aflatoxin B1 was detected at early growth stages but then decreased with decreasing water content. T-2 toxin increased steadily during grain development, and at harvest there was up to 210 ng toxin g-1 grain. Ochratoxin A was not detected until harvest, The incidence of toxigenic A. flavus isolates in fields of the two cultivars differed slightly, but their growth and toxin-producing ability differed greatly between seasons. A. flavus isolates collected during the 1991 crop season produced 26000 ng aflatoxin B1 ml-1 medium, much more than was produced by isolates collected during the 1990 crop season

Effect of spice essential oils on growth and aflatoxin B1 production by Aspergillus flavus

Aflatoxin B1 production by Aspergillus flavus was studied in yeast extract sucrose broth in the presence of cinnamon, clove, almond and cardamom oils. Growth and aflatoxin B1 production was inhibited by 0.5 mul cinnamon oil ml-1 medium and by 1 mul clove oil ml-1. Almond and cardamom oils only affected growth when their concentration exceeded 1.25 mul ml-1 medium. Aflatoxin B1 production was stimulated by 0.75 and 1 mul almond oil ml-1 medium or by 0.25 and 0.5 mul cardamom oil ml-1

Analysis of the vascular responses in a murine model of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of the reproductive age, but the exact pathophysiological mechanisms involved remain unclear. Cardiovascular disease risk is increased in PCOS patients and endothelial damage has been observed. We recently developed a mouse model of PCOS with reproductive and metabolic characteristics resembling those observed in women with PCOS. In this model we studied vascular function with particular emphasis on markers of vascular endothelial function. Animals were treated for 90 days with dihydrotestosterone (DHT; 27.5 μg/day) or placebo using subcutaneous continuous-release pellets. Aortas were isolated for isometric force recordings in organ baths to investigate endothelial and vascular smooth muscle characteristics. Lungs were used to analyze endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Asymmetric dimethylarginine (ADMA) levels were investigated in serum to assess endothelial damage. Expression of androgen receptor (Ar) mRNA was studied in aortas. DHT treatment (compared with placebo) induced i) a significantdecrease in acetylcholine-induced aortic relaxations, with no change in calcitonin generelated peptide- or sodium nitroprusside-induced relaxations, as well as 5-hydroxytryptamine-induced contractions; ii) no change in eNOS expression/phosphorylation in lungs or in plasma ADMA levels; and iii) a twofold increase in aortic AR expression. Our results suggest that, in DHT-exposed mice, hyperandrogenemia specifically decreases endotheliumdependent vasorelaxation without deterioration of smooth muscle function. This study may initiate further investigations to elucidate underlying mechanism for the phenotype that is present in these animals, as well as in PCOS patients