Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Linfadenitis por Mycobacterium incluyendo pacientes infectados por el Virus de Inmunodefi ciencia Humana Mycobacterium lymphadenitis including patients infected with Human Inmunodefi cient Virus

El g&eacute;nero Mycobacterium provoca infecciones pulmonares y extrapulmonares, de estas &uacute;ltimas predomina la infecci&oacute;n ganglionar. Mientras Mycobacterium tuberculosis es el agente causal m&aacute;s importante, en las &uacute;ltimas d&eacute;cadas aumenta la incidencia de otras especies micobacterianas que se han hecho prevalentes en los pacientes positivos al virus de la inmunodeficiencia humana (VIH +) tanto en pa&iacute;ses desarrollados como en v&iacute;as de desarrollo.Durante el per&iacute;odo enero 2007 hasta diciembre 2009 se proces&oacute; en nuestro laboratorio 6540 muestras, 210 muestras fueron obtenidas por biopsia ganglionar, precisamente este constituy&oacute; nuestro universo de estudio, 190 (90.4%) muestras se obtuvieron por ex&eacute;resis quir&uacute;rgica, 20 (9.5%) por punci&oacute;n espirativa;17 proced&iacute;an de pacientes VIH&ndash; (8.1%) y 193 procedentes de pacientes VIH+(91.9%). En solo 16 muestras (7.6%) el cultivo BAAR fue positivo; 4 procedentes de pacientes VIH&ndash; (25%) y 12 VIH+(75%). La clasificaci&oacute;n e identificaci&oacute;n micobacteriana demostr&oacute; la presencia de Mycobacterium tuberculosis en 13 de los casos (81.25%), mientras Mycobacterium avium-intracellulare fue aislado en 3 (18.7%).En los pacientes inmunodeprimidos con linfadenopat&iacute;a incluidos los pacientes VIH/sida, es muy importante la b&uacute;squeda activa de la presencia de BAAR como coinfecci&oacute;n oportunista, donde Mycobacterium tuberculosis se mantiene como el agente infeccioso m&aacute;s frecuente, sin embargo la posibilidad de que otras especies micobacterianas tambi&eacute;n est&eacute;n presentes no se debe descartar.Nuestro objetivo en este estudio como Laboratorio Nacional de Referencia de TB- Micobacterias fue lograr la caracterizaci&oacute;n etiol&oacute;gica de linfadenopat&iacute;as en pacientes en que se sospechaba cl&iacute;nicamente la participaci&oacute;n del g&eacute;nero Mycobacterium.Mycobacterium tuberculosis is the most important etiological agent producing pulmonary as well as extrapulmonary infection.During these last decades, the increase in the incidence of infection due to other mycobacteria species is evident.Lymphadenopathy is the most frequent extrapulmonary presentation form of Mycobacterium Genera infection among HIV positive patients either in developed or underdeveloped countries.The aim of this work is to analyze the results obtained during January 2007 - December 2009 in our laboratory.Two hundred ten tissue samples were studied; 190 (90.4%) samples were lymph node biopsied tissues and 20 (9.5%) samples were obtained by fine needle aspiration; 17 were from HIV - patients (8.1%) and 193 from HIV + (91.9%). A total of 16 (7.6%) samples produced a positive culture for BAAR, 4 VIH- (25%) and 12 VIH+ (75%). Classification and identification for mycobacteria confirmed Mycobacterium tuberculosis in 13 of the cases (81.25%), and Mycobacterium avium-intracellulare in three patients (18.7%). The present study once again confirms that BAAR culture has more sensitivity and specificity than histopathologhic studies have.Lymphadenopathy in immunosuppressed patients should by studied for the presence of an BAAR coinfection where M.tuberculosis is still the agent most frequently found, nevertheless, other species of Mycobacteria may be causing infection and should be searched for. Our objective as National Reference Laboratory of Tuberculosis and Mycobacterial was to obtain the etiological characterization of Mycobacterium lymphadenopathy in clinically suspect patients

Micobacteriosis sistémica por Mycobacterium avium en paciente con SIDA Systemic mycobacteriosis for Mycobacterium avium in a AIDS patient

Se analizaron repetidas muestras procedentes de un paciente cubano con SIDA, para descartar la presencia de bacilos &aacute;cido alcohol resistente (BAAR), pasadas 2-3 semana en las muestras de esputo, l&iacute;quido cefalorraqu&iacute;deo y de hemocultivo que hab&iacute;an sido procesadas y cultivadas se detecta la presencia de algunas colonias, como resultado se obtuvo el aislamiento de una cepa micobacteriana no pigmentada, de crecimiento lento perteneciente al Grupo III de Runyon, esta cepas fueron clasificadas como Mycobacterium avium por los m&eacute;todos convencionales establecidos para la identificaci&oacute;n de cepas micobacterianas, como t&eacute;cnica confirmativa diagn&oacute;stica se utiliz&oacute; el an&aacute;lisis de las fracciones de &aacute;cido mic&oacute;licos por la t&eacute;cnica de cromatograf&iacute;a en capa delgada bidimensional. El objetivo fundamental de este estudio ha sido reportar el primer caso de micobacteriosis sist&eacute;mica en un paciente cubano con SIDA.Several sputum and blood culture simples from a Cuban HIV/AIDS patient were analyzed to discard the presence of alcohol acid resistant bacillus. After 2-3 weeks the culture revealed in both kinds of samples some colonies from non-pigmented mycobacterium strain with slow growth and belonging to III Runyon Group. This strain was classified as Mycobacterium avium by conventional methods established for mycobacterium identification. To diagnostic confirmative method was used the analysis of fraction mycolic acid by bi-dimensional thin layer chromatography. The main objective of this study was to report the first case of systemic mycobacteriosisin a Cuban HIV/AIDS patient

Linfadenitis por Mycobacterium incluyendo pacientes infectados por el Virus de Inmunodefi ciencia Humana Mycobacterium lymphadenitis including patients infected with Human Inmunodefi cient Virus

El g&eacute;nero Mycobacterium provoca infecciones pulmonares y extrapulmonares, de estas &uacute;ltimas predomina la infecci&oacute;n ganglionar. Mientras Mycobacterium tuberculosis es el agente causal m&aacute;s importante, en las &uacute;ltimas d&eacute;cadas aumenta la incidencia de otras especies micobacterianas que se han hecho prevalentes en los pacientes positivos al virus de la inmunodeficiencia humana (VIH +) tanto en pa&iacute;ses desarrollados como en v&iacute;as de desarrollo.Durante el per&iacute;odo enero 2007 hasta diciembre 2009 se proces&oacute; en nuestro laboratorio 6540 muestras, 210 muestras fueron obtenidas por biopsia ganglionar, precisamente este constituy&oacute; nuestro universo de estudio, 190 (90.4%) muestras se obtuvieron por ex&eacute;resis quir&uacute;rgica, 20 (9.5%) por punci&oacute;n espirativa;17 proced&iacute;an de pacientes VIH&ndash; (8.1%) y 193 procedentes de pacientes VIH+(91.9%). En solo 16 muestras (7.6%) el cultivo BAAR fue positivo; 4 procedentes de pacientes VIH&ndash; (25%) y 12 VIH+(75%). La clasificaci&oacute;n e identificaci&oacute;n micobacteriana demostr&oacute; la presencia de Mycobacterium tuberculosis en 13 de los casos (81.25%), mientras Mycobacterium avium-intracellulare fue aislado en 3 (18.7%).En los pacientes inmunodeprimidos con linfadenopat&iacute;a incluidos los pacientes VIH/sida, es muy importante la b&uacute;squeda activa de la presencia de BAAR como coinfecci&oacute;n oportunista, donde Mycobacterium tuberculosis se mantiene como el agente infeccioso m&aacute;s frecuente, sin embargo la posibilidad de que otras especies micobacterianas tambi&eacute;n est&eacute;n presentes no se debe descartar.Nuestro objetivo en este estudio como Laboratorio Nacional de Referencia de TB- Micobacterias fue lograr la caracterizaci&oacute;n etiol&oacute;gica de linfadenopat&iacute;as en pacientes en que se sospechaba cl&iacute;nicamente la participaci&oacute;n del g&eacute;nero Mycobacterium.Mycobacterium tuberculosis is the most important etiological agent producing pulmonary as well as extrapulmonary infection.During these last decades, the increase in the incidence of infection due to other mycobacteria species is evident.Lymphadenopathy is the most frequent extrapulmonary presentation form of Mycobacterium Genera infection among HIV positive patients either in developed or underdeveloped countries.The aim of this work is to analyze the results obtained during January 2007 - December 2009 in our laboratory.Two hundred ten tissue samples were studied; 190 (90.4%) samples were lymph node biopsied tissues and 20 (9.5%) samples were obtained by fine needle aspiration; 17 were from HIV - patients (8.1%) and 193 from HIV + (91.9%). A total of 16 (7.6%) samples produced a positive culture for BAAR, 4 VIH- (25%) and 12 VIH+ (75%). Classification and identification for mycobacteria confirmed Mycobacterium tuberculosis in 13 of the cases (81.25%), and Mycobacterium avium-intracellulare in three patients (18.7%). The present study once again confirms that BAAR culture has more sensitivity and specificity than histopathologhic studies have.Lymphadenopathy in immunosuppressed patients should by studied for the presence of an BAAR coinfection where M.tuberculosis is still the agent most frequently found, nevertheless, other species of Mycobacteria may be causing infection and should be searched for. Our objective as National Reference Laboratory of Tuberculosis and Mycobacterial was to obtain the etiological characterization of Mycobacterium lymphadenopathy in clinically suspect patients

Micobacteriosis sistémica por Mycobacterium avium en paciente con SIDA Systemic mycobacteriosis for Mycobacterium avium in a AIDS patient

Se analizaron repetidas muestras procedentes de un paciente cubano con SIDA, para descartar la presencia de bacilos &aacute;cido alcohol resistente (BAAR), pasadas 2-3 semana en las muestras de esputo, l&iacute;quido cefalorraqu&iacute;deo y de hemocultivo que hab&iacute;an sido procesadas y cultivadas se detecta la presencia de algunas colonias, como resultado se obtuvo el aislamiento de una cepa micobacteriana no pigmentada, de crecimiento lento perteneciente al Grupo III de Runyon, esta cepas fueron clasificadas como Mycobacterium avium por los m&eacute;todos convencionales establecidos para la identificaci&oacute;n de cepas micobacterianas, como t&eacute;cnica confirmativa diagn&oacute;stica se utiliz&oacute; el an&aacute;lisis de las fracciones de &aacute;cido mic&oacute;licos por la t&eacute;cnica de cromatograf&iacute;a en capa delgada bidimensional. El objetivo fundamental de este estudio ha sido reportar el primer caso de micobacteriosis sist&eacute;mica en un paciente cubano con SIDA.Several sputum and blood culture simples from a Cuban HIV/AIDS patient were analyzed to discard the presence of alcohol acid resistant bacillus. After 2-3 weeks the culture revealed in both kinds of samples some colonies from non-pigmented mycobacterium strain with slow growth and belonging to III Runyon Group. This strain was classified as Mycobacterium avium by conventional methods established for mycobacterium identification. To diagnostic confirmative method was used the analysis of fraction mycolic acid by bi-dimensional thin layer chromatography. The main objective of this study was to report the first case of systemic mycobacteriosisin a Cuban HIV/AIDS patient

Safety and immunogenicity of the Cuban heptavalent pneumococcal conjugate vaccine in healthy infants. Results from a double-blind randomized control trial Phase I

Background: Cuba has a new pneumococcal conjugate vaccine candidate (PCV7-TT). This study evaluates the safety and immunogenicity in healthy infants using 2p+1 vaccination schedule. Methods: A phase I, controlled, randomized and double blind clinical trial was designed. 30 unvaccinated healthy infants were included. 20 subjects were assigned to study group (PCV7-TT) and 10 to control group (Synflorix®) to receive the vaccines at 7, 8 months of age (primary series) and 11 months (booster dose). Blood samples were collected 30 days after second dose and post booster for antibodies measure analysis by ELISA and OPA. The statistics analysis included the frequency of occurrence for adverse events and the immune response. Non-parametric tests were used to compare the immune response. The clinical trial was published in the Cuban Public Register of Clinical Trials with code RPCEC00000173 available at http://registroclinico.sld.cu. Results: Overall, the safety profile of PCV7-TT was similar to Synflorix®. Local reactions were predominant and systemic events were mild in severity. Swelling and redness were frequently associated with PCV7-TT mainly after the first dose (50% and 40% respectively). 15% and 10% of subject reported severe swelling after first dose with PCV7-TT and after second dose with Synflorix®. Mild fever (≥38–≤39), vomiting and sleep disturb were the systemic events reported. 100% of infants achieved pneumococcal IgG antibody concentrations ≥0.35 µg/ml after booster dose for serotypes 1, 14, 18C and 19F in each vaccine group. For serotypes 5, 6B and 23F, more than 80% infants vaccinated with Synflorix® or PCV7-TT achieved protective IgG GMC ≥ 0.35 µg/ml after booster dose. OPA proportion’s responders to the seven common serotypes were 89.5% or more after the primary dose and 100% after booster dose in vaccinated with PCV7-TT. Conclusions: The Cuban PCV7-TT is safe, well tolerated and immunogenic in healthy infants