Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction.

BACKGROUND: Coronary artery calcification (CAC) detected by computed tomography is a noninvasive measure of coronary atherosclerosis, which underlies most cases of myocardial infarction (MI). We sought to identify common genetic variants associated with CAC and further investigate their associations with MI. METHODS AND RESULTS: Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was performed in 9961 men and women from 5 independent community-based cohorts, with replication in 3 additional independent cohorts (n=6032). We examined the top single-nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049; P=7.58×10(-19)) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene; P=2.65×10(-11)) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene). CONCLUSIONS: SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.

Protection of pancreatic beta-cells by high density lipoproteins

SUMMARYThe incidence of type 2 diabetes (T2D) is increasing worldwide and is linked to the enhancement of obesity. The principal cause of T2D development is insulin resistance, which lead to the increase of insulin production by the pancreatic beta-cells. In a pathological environment, namely dyslipidaemia, hyperglycaemia and inflammation, beta-cell compensation will fail in more vulnerable cells and diabetes will occur. High Density Lipoproteins (HDLs), commonly named "good cholesterol" are known to be atheroprotective. Low levels of HDLs are associated with increased prevalence of cardiovascular disease but are also an independent risk factor for the development of T2D. HDLs were demonstrated to protect pancreatic beta-cells against several stresses. However the molecular mechanisms of the protection are unknown and the objectives of this work were to try to elucidate the way how HDLs protect. The first approach was a broad screening of genes regulated by the stress and HDLs. A microarray analysis was performed on beta-cells stressed by serum deprivation and rescued by HDLs. Among the genes regulated, we focused on 4E-BP1, a cap-dependent translational inhibitor. In addition, HDLs were also found to protect against several other stresses.Endoplasmic reticulum (ER) stress is a mechanism that may play a role in the onset of T2D. The unfolded protein response (UPR) is a physiological process that aims at maintaining ER homeostasis in conditions where the protein folding and secretion is perturbed. Specific signalling pathways are involved in the increase of folding, export and degradation capacity of the ER. However, in case where the stress is prolonged, this mechanism turns to be pathological, by inducing cell death effector pathways, leading to beta-cell apoptosis. In our study, we discovered that HDLs were protective against ER stress induced by drugs and physiological stresses such as saturated free fatty acids. HDLs protected beta-cells by promoting ER homeostasis via the improvement of the folding and trafficking od proteins from the ER to the Golgi apparatus.Altogether our results suggest that HDLs are important for beta-cell function and survival, by protecting them from several stresses and acting on ER homeostasis. This suggests that attempt in keeping normal HDLs levels or function in patients is crucial to lessen the development of T2D.RÉSUMÉL'incidence du diabète de type 2 est en constante augmentation et est fortement liée à l'accroissement du taux d'obésité. La cause principale du diabète de type 2 est la résistance à l'insuline, qui entraîne une surproduction d'insuline par les cellules bêta pancréatiques. Dans un environnement pathologique associé à l'obésité (dyslipidémie, hyperglycémie et inflammation), les cellules bêta les plus vulnérables ne sont plus capables de compenser en augmentant leur production d'insuline, dysfonctionnent, ce qui conduit à leur mort par apoptose. Les lipoprotéines de hautes densités (HDLs), communément appelées (( bon cholestérol », sont connues pour leurs propriétés protectrices contre l'athérosclérose. Des niveaux bas de HDLs sanguins sont associés au risque de développer un diabète de type 2. Les HDLs ont également montré des propriétés protectrices contre divers stresses dans la cellule bêta. Cependant, les mécanismes de protection restent encore inconnus et l'objectif de ce travail a été d'investiguer les mécanismes moléculaires de protection des HDLs. La première approche choisie a été une étude du profil d'expression génique par puce à ADN afin d'identifier les gènes régulés par le stress et les HDLs. Parmi les gènes régulés, notre intérêt s'est porté sur 4E-BP1, un inhibiteur de la traduction coiffe- dépendante, dont l'induction par le stress était corrélée avec une augmentation de l'apoptose. Suite à cette étude, les HDLs ont également montrés un rôle protecteur contre d'autres stresses. Il s'agit particulièrement du stress du réticulum endoplasmique (RE), qui est un mécanisme qui semble jouer un rôle clé dans le développement du diabète. L'UPR (« Unfolded Protein Response ») est un processus physiologique tendant à maintenir l'homéostasie du réticulum endoplasmique, organelle prépondérante pour la fonction des cellules sécrétrices, notamment lorsqu'elle est soumise à des conditions extrêmes telles que des perturbations de la conformation tertiaire des protéines ou de la sécrétion. Dans ces cas, des voies de signalisation moléculaires sont activées, ce qui mène à l'exportation des protéines mal repliées, à leur dégradation et à l'augmentation de l'expression de chaperonnes capables d'améliorer le repliement des protéines mal formées. Toutefois, en cas de stress persistant, ce mécanisme de protection s'avère être pathologique. En induisant des voies de signalisation effectrices de l'apoptose, il conduit finalement au développement du diabète. Dans cette étude, nous avons démontré que les HDLs étaient capables de protéger la cellule bêta contre le stress du RE induits par des inhibiteurs (thapsigargine, tunicamycine) ou des stresses physiologiques tels que les acides gras libres. Les HDLs ont la capacité d'améliorer l'homéostasie du RE, notamment en favorisant le repliement et le transfert des protéines du RE à l'appareil de Golgi.En résumé, ces données suggèrent que les HDLs sont bénéfiques pour la survie des cellules bêta soumises à des stresses impliqués dans le développement du diabète, notamment en restaurant l'homéostasie du RE. Ces résultats conduisent à soutenir que le maintien des taux de cholestérol joue un rôle important dans la limitation de l'incidence du diabète.

Situación de los recursos anchoveta, sardina, jurel y caballa a junio de 1978

Analiza la situación actual de los recursosa partir de los datos colectados por un crucero integral a lo largo de la costa con el SNP-1

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Estructura del subsistema demersal durante el crucero de evaluación del recurso Merluza, BIC Humboldt 9705-06, Callao a Puerto Pizarro

Presenta la estructura especiológica, distribución, espacio temporal y captura de peces e invertebrados accesibles a redes tipo Granton 130/400 y Engel 998/400, empleadas durante el Crucero de Evaluación del recurso merluza BIC Humboldt 9705-06. Así como el análisis de comunidades de peces del fondo de la fauna acompañante. Se capturó 134 especies: 99 fueron peces, 19 crustáceos, 12 moluscos, 2 equinodermos, 1 cnidario, 1 sipuncúlido y un cordado. En comparación con los dos últimos cruceros BIC SNP-1 9505-06 y 9607-08, la diversidad íctica se incrementó hasta 43%, aún sin haberse constatado presencia de la típica diversidad íctica tropical costera y estuarina. Al sur de los 6°S se encontró distribuida más del 50% de la riqueza íctica. La captura total fue 45.368,59 kg, de los cuales 40.106,04 se obtuvo en 63 lances de fondo y 5.262,55 kg con 20 lances de media agua. El falso volador Prionotus stephanophrys y la merluza Merluccius gayi peruanus fueron las especies más frecuentes y abundantes con 21.259,21 kg y 14.190,51 kg de captura total, respectivamente.

Otros recursos de importancia durante el crucero de evaluación de la Merluza, BIC Humboldt 9705-06, Callao a Puerto Pizarro

Se presentan los resultados del Crucero de Evaluación del recurso merluza BIC Humboldt 9705-06, referentes a otros recursos pesqueros en el otoño de 1997, obtenidos con lances de arrastre de fondo y arrastre pelágico entre Puerto Pizarro (3°30 'S) y Callao (12°3 'S), del 15 de mayo al 8 de junio de 1997. Prionotus stephanophrys (falso volador) fue la especie más importante, después de la merluza, con una distribución latitudinal de Puerto Pizarro a Callao, y hasta las 65 millas de la costa. La estructura por tallas muestra la predominancia de ejemplares adultos. En Paralabrax humeralis (cabrilla), se observaron tallas de hasta 55 cm (subárea E), situación diferente a la reportada en el Crucero BIC SNP-1 9607-08. Engraulis ringens (anchoveta) se distribuyó desde el Callao hasta Paita entre 1 y 55 millas de la costa con predominancia de la categoría dispersa. Sciaena deliciosa (lorna) presentó una distribución vertical en las subáreas C, D y E entre los 95 a 180 metros de profundidad. Otra especies cuya distribución se analizó fueron: Cynoscion analis (cachema), Galeichthys peruvianus (bagre), Trachurus picturarus murphyi (jurel) y Scomber japonicus (caballa). Loligo gahi (calamar) se ubicó en profundidades de 14 a 158 m y a 65 mn de la costa entre las subáreas E, F, G e I. El análisis de la condición sexual evidencia la evolución del proceso reproductivo en las especies cabrilla, lorna y falso volador con porcentajes considerables de ejemplares madurantes (grado de madurez sexual III, IV y V).

Evaluación de los principales recursos pelágicos en la costa peruana

Presenta los resultados sobre estimados de biomasa de anchoveta, sardinas, jurel y caballa, así como las características biológicas y poblacionales de estos recursos en relación con las condiciones oceanográficas, interpretándose la distribución y comportamiento de estas especies pelágicas con mayor detalle; lo que permite hacer un seguimiento de la situación de estas poblaciones, para actualizar las cifras dadas en el informe del crucero de evaluación de recursos pelágicos 8911-12

Operación Eureka XXIX, 28-30 de Mayo 1974

Expone los resultados de la Operación Eureka XXIX, realizada del 28 al 30 de Mayo con 51 embarcaciones, tomando además algunos elementos provenientes de los cruceros del SNP-1 (Mayo-Junio) y de la pesca comercial (Marzo-Mayo) para fines comparativos

Situación de los recursos anchoveta, sardina, jurel y caballa a junio 1987

Análisis de la información concerniente a un crucero integral a lo largo de toda la costa con el SNP-1, y cuatro bolicheras, entre abril y mayo, de los registros estadísticos de la pesca y los estudios biológicos correspondientes.

Aspectos biológicos pesqueros de algunos recursos pelágicos entre Punta Falsa y Tambo de Mora en el invierno 2000

Este trabajo se refiere a algunas especies pelagicas capturadas durante el Crucero de Evaluaci6n de Biomasa Desovante de la Anchoveta BICs Jose Olaya Balandra y SNP-2 ooo8c09, entre del 25 de agosto y el 23 al septiembre del 2000, entre Punta Falsa y Tambo de Mora.

Condiciones oceanográficas frente a las costas del Perú en mayo 2000

Se analizan las condiciones oceanográficas observadas durante el III Crucero Regional Conjunto de Investigación Oceanografía en el Pacifico Sudeste, Perú, realizado a bordo de los BICs Humboldt (12 - 25 mayo) y SNP-2 (15 mayo - I junio 2000).

Información básica sobre muestras de bentos, sedimentos y factores abioticos de la plataforma continental del Perú entre 1976 y 1987

Se presenta la información básica sobre un total de 455 estaciones en la plataforma continental peruana en las cuales se tomaron muestras de macrobentos. La información fue obtenida durante 13 cruceros con los barcos de investigación científica Humboldt, SNP-1 y Tareq-II así como con bolichera. Aparte de las informaciones básicas de las estaciones y los muestreos se proporcionan datos sobre el sedimento y factores abióticos de las aguas cercanas del fondo marino.

Global Genomic Diversity of Human Papillomavirus 6 Based on 724 Isolates and 190 Complete Genome Sequences.

Human papillomavirus type 6 (HPV6) is the major etiological agent of anogenital warts and laryngeal papillomas and has been included in both the quadrivalent and nonavalent prophylactic HPV vaccines. This study investigated the global genomic diversity of HPV6, using 724 isolates and 190 complete genomes from six continents, and the association of HPV6 genomic variants with geographical location, anatomical site of infection/disease, and gender. Initially, a 2,800-bp E5a-E5b-L1-LCR fragment was sequenced from 492/530 (92.8%) HPV6-positive samples collected for this study. Among them, 130 exhibited at least one single nucleotide polymorphism (SNP), indel, or amino acid change in the E5a-E5b-L1-LCR fragment and were sequenced in full. A global alignment and maximum likelihood tree of 190 complete HPV6 genomes (130 fully sequenced in this study and 60 obtained from sequence repositories) revealed two variant lineages, A and B, and five B sublineages: B1, B2, B3, B4, and B5. HPV6 (sub)lineage-specific SNPs and a 960-bp representative region for whole-genome-based phylogenetic clustering within the L2 open reading frame were identified. Multivariate logistic regression analysis revealed that lineage B predominated globally. Sublineage B3 was more common in Africa and North and South America, and lineage A was more common in Asia. Sublineages B1 and B3 were associated with anogenital infections, indicating a potential lesion-specific predilection of some HPV6 sublineages. Females had higher odds for infection with sublineage B3 than males. In conclusion, a global HPV6 phylogenetic analysis revealed the existence of two variant lineages and five sublineages, showing some degree of ethnogeographic, gender, and/or disease predilection in their distribution. IMPORTANCE: This study established the largest database of globally circulating HPV6 genomic variants and contributed a total of 130 new, complete HPV6 genome sequences to available sequence repositories. Two HPV6 variant lineages and five sublineages were identified and showed some degree of association with geographical location, anatomical site of infection/disease, and/or gender. We additionally identified several HPV6 lineage- and sublineage-specific SNPs to facilitate the identification of HPV6 variants and determined a representative region within the L2 gene that is suitable for HPV6 whole-genome-based phylogenetic analysis. This study complements and significantly expands the current knowledge of HPV6 genetic diversity and forms a comprehensive basis for future epidemiological, evolutionary, functional, pathogenicity, vaccination, and molecular assay development studies.

Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats.

We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.

Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development

BACKGROUND: Vitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODOLOGY/PRINCIPAL FINDINGS: Associations between CYP2R1, GC, and DHCR7 genotypes that are determinants of reduced 25-hydroxyvitamin D (25[OH]D3) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between CYP2R1 (rs1993116, rs10741657), GC (rs2282679), and DHCR7 (rs7944926, rs12785878) genotypes and 25(OH)D3 serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D3 serum levels were found to be associated with HCV-related HCC (P = 0.07 [OR = 1.13, 95% CI = 0.99-1.28] for CYP2R1, P = 0.007 [OR = 1.56, 95% CI = 1.12-2.15] for GC, P = 0.003 [OR = 1.42, 95% CI = 1.13-1.78] for DHCR7; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (P>0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (P>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D3 serum levels on hepatocarcinogenesis. CONCLUSIONS/SIGNIFICANCE: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis.