Dissection of the Complex Genetic Architecture of Human Stature and Osteoporosis

Osteoporosis is a common complex disease mostly characterized by decreased bone mineral density (BMD). In this thesis we show that hundreds of variants affect adult height and it is the same case for many other complex traits such as bone mineral density. We have applied the novel hypothesis-free approach of Genome-wide Association Study (GWAS) to identify those loci harboring at least one variant affecting these osteoporosis-related traits

Association of a Genetic Risk Score With Body Mass Index Across Different Birth Cohorts

Importance Many genetic variants are associated with body mass index (BMI). Associations may have changed with the 20th century obesity epidemic and may differ for black vs white individuals. Objective Using birth cohort as an indicator for exposure to obesogenic environment, to evaluate whether genetic predisposition to higher BMI has a larger magnitude of association among adults from more recent birth cohorts, who were exposed to the obesity epidemic at younger ages. Design, Setting, and Participants Observational study of 8788 adults in the US national Health and Retirement Study who were aged 50 years and older, born between 1900 and 1958, with as many as 12 BMI assessments from 1992 to 2014. Exposures A multilocus genetic risk score for BMI (GRS-BMI), calculated as the weighted sum of alleles of 29 single nucleotide polymorphisms associated with BMI, with weights equal to the published per-allele effects. The GRS-BMI represents how much each person’s BMI is expected to differ, based on genetic background (with respect to these 29 loci), from the BMI of a sample member with median genetic risk. The median-centered GRS-BMI ranged from −1.68 to 2.01. Main Outcomes and Measures BMI based on self-reported height and weight. Results GRS-BMI was significantly associated with BMI among white participants (n = 7482; mean age at first assessment, 59 years; 3373 [45%] were men; P \u3c.001) and among black participants (n = 1306; mean age at first assessment, 57 years; 505 [39%] were men; P \u3c.001) but accounted for 0.99% of variation in BMI among white participants and 1.37% among black participants. In multilevel models accounting for age, the magnitude of associations of GRS-BMI with BMI were larger for more recent birth cohorts. For example, among white participants, each unit higher GRS-BMI was associated with a difference in BMI of 1.37 (95% CI, 0.93 to 1.80) if born after 1943, and 0.17 (95% CI, −0.55 to 0.89) if born before 1924 (P = .006). For black participants, each unit higher GRS-BMI was associated with a difference in BMI of 3.70 (95% CI, 2.42 to 4.97) if born after 1943, and 1.44 (95% CI, −1.40 to 4.29) if born before 1924. Conclusions and Relevance For participants born between 1900 and 1958, the magnitude of association between BMI and a genetic risk score for BMI was larger among persons born in later cohorts. This suggests that associations of known genetic variants with BMI may be modified by obesogenic environments

Los costos de operación en los servicios turísticos Santuario Histórico Machupicchu en la modalidad de Pool y la fijación de precios y tarifas en la Empresa Andean World Expedition´s E.I.R.L, periodo 2016

El trabajo de investigación intitulada: LOS COSTOS DE OPERACIÓN EN LOS SERVICIOS TURÍSTICOS SANTUARIO HISTÓRICO MACHUPICCHU EN LA MODALIDAD DE POOL Y LA FIJACIÓN DE PRECIOS Y TARIFAS EN LA EMPRESA ANDEAN WORLD EXPEDITION´S E.I.R.L., PERIODO 2016, desarrollado en el departamento de Cusco, distrito Wanchaq. La investigación desarrolla la variable: Los costos de operación en los servicios turísticos en la modalidad de pool, fijación de precios y tarifas, existiendo la modalidad de pool en los servicios turísticos en la ciudad de Cusco, donde la investigación tendrá énfasis en los Servicios Turísticos del Santuario Histórico Machupicchu. En la ciudad del Cusco y como consecuencia al incremento acelerado de la actividad turística en los últimos años, se ha podido observar que existe mucha competencia en las agencias de turismo, en la clase de Operador turístico, con el afán de abaratar costos, precios y tarifas algunas empresas han creado en los servicios denominado sistema Pool y combinada, Valle Sagrado y Santuario Histórico de Machupicchu que consiste en este caso el que realiza la operadora Empresa Andean World Expedition´S E.I.R.L. recibiendo el endose de otras agencias y/o pasajeros libres técnicamente conocidas como FITS o individuales el número que oscile entre 1 a 5 amigos o familiares quienes pagan sus costos de operaciones es decir el traslado de ida y vuelta cusco Ollanta, la compra de pasajes de Peru Rail o Inka Rail, ingresos, bus CONSETUR y los servicios de guía oficial de turismo en el tren local o de pasajeros, adiciona su utilidad y vende directamente al turista en counter y lo más importante es que recibe endoses de otras agencias y free lances o vendedores libres mucho de ellos informales. El principal objetivo fue identificar los costos de operación de los servicios turísticos en la modalidad pool de la Empresa Andean World Expedition´S E.I.R.L, se planteó como hipótesis general Los costos de operación en los servicios turísticos santuario histórico Machupicchu en la modalidad de pool y la fijación de precios y tarifas en la empresa Andean World Expedition´s E.I.R.L. Periodo 2016. El tipo de investigación desde el punto de vista cuantitativo tiene la finalidad de estudiar los costos de operación y como es la situación actual en la modalidad pool de la Empresa Andean World Expedition´S E.I.R.L. en la ciudad del Cusco.Tesi

Association of a Low-Frequency Variant in HNF1A With Type 2 Diabetes in a Latino Population

Importance: Latino populations have one of the highest prevalences of type 2 diabetes worldwide. Objectives: To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. Design, Setting, and Participants: Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14 276 participants and characterized in experimental assays. Main Outcome and Measures: Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. Results: A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10−7) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). Conclusions and Relevance: Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.publishedVersio

GRIMP: A web- and grid-based tool for high-speed analysis of large-scale genome-wide association using imputed data.

The current fast growth of genome-wide association studies (GWAS) combined with now common computationally expensive imputation requires the online access of large user groups to high-performance computing resources capable of analyzing rapidly and efficiently millions of genetic markers for ten thousands of individuals. Here, we present a web-based interface—called GRIMP—to run publicly available genetic software for extremely large GWAS on scalable super-computing grid infrastructures. This is of major importance for the enlargement of GWAS with the availability of whole-genome sequence data from the 1000 Genomes Project and for future whole-population efforts

Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behçet disease

The etiology of Behçet's disease (BD) is unknown, but widely considered an excessive T-cell mediated inflammatory response in a genetically susceptible host. Recent genome-wide association studies (GWAS) have shown limited number of novel loci-associations. The rarity and unequal distribution of the disease prevalence amongst different ethnic backgrounds have hampered the use of GWAS in cohorts of mixed ethnicity and sufficient sample size. However, novel statistical approaches have now enabled GWAS in admixed cohorts.We ran a GWAS on 336 BD cases and 5,843 controls. The cases consisted of Western Europeans, Middle Eastern and Turkish individuals. Participants from the Generation R study, a multiethnic birth cohort in Rotterdam, The Netherlands were used as controls. All samples were genotyped and data was combined. Linear regression models were corrected for population stratification using Genomic Principal Components and Linear Mixed Modelling. Meta-analysis was performed on selected results previously published.We identified SNPs associated at genome-wide significant level mapping to the 6p21.33 (HLA) region. In addition to this known signal two potential novel associations on chromosomes 6 and 18 were identified, yet with low minor allele frequencies. Extended meta-analysis reveal a GWS association with the IL12A variant rs17810546 on chromosome 3.We demonstrate that new statistical techniques enable GWAS analyses in a limited sized cohort of mixed ethnicity. After implementation, we confirmed the central role of the HLA region in the disease and identified new regions of interest. Moreover, we validated the association of a variant in the IL2A gene by meta-analysis with previous work. These findings enhance our knowledge of genetic associations and BD, and provide further justification for pursuing collective initiatives in genetic studies given the low prevalence of this and other rare diseases

Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behçet Disease

Introduction: The etiology of Behçet's disease (BD) is unknown, but widely considered an excessive T-cell mediated inflammatory response in a genetically susceptible host. Recent genomewide association studies (GWAS) have shown limited number of novel loci-associations. The rarity and unequal distribution of the disease prevalence amongst different ethnic backgrounds have hampered the use of GWAS in cohorts of mixed ethnicity and sufficient sample size. However, novel statistical approaches have now enabled GWAS in admixed cohorts. Methods: We ran a GWAS on 336 BD cases and 5,843 controls. The cases consisted of Western Europeans, Middle Eastern and Turkish individuals. Participants from the Generation R study, a multiethnic birth cohort in Rotterdam, The Netherlands were used as controls. All samples were genotyped and data was combined. Linear regression models were corrected for population stratification using Genomic Principal Components and Linear Mixed Modelling. Meta-analysis was performed on selected results previously published. Results: We identified SNPs associated at genome-wide significant level mapping to the 6p21.33 (HLA) region. In addition to this known signal two potential novel associations on chromosomes 6 and 18 were identified, yet with low minor allele frequencies. Extended metaanalysis reveal a GWS association with the IL12A variant rs17810546 on chromosome 3. Discussion: We demonstrate that new statistical techniques enable GWAS analyses in a limited sized cohort of mixed ethnicity. After implementation, we confirmed the central role of the HLA region in the disease and identified new regions of interest. Moreover, we validated the association of a variant in the IL2A gene by meta-analysis with previous work. These findings enhance our

Casos de Seguridad en el Trabajo y Ambiente

Este primer volumen del libro «Casos de Seguridad en el Trabajo y Ambiente» editada por los docentes de la Facultad de Ingeniería Industrial de la UNMSM, inaugura la primera serie de nuestra publicación. Nos propusimos dar a conocer fundamentalmente las investigaciones y una selección de casos, elaborados y desarrollados, en el dictado de los diferentes cursos, que tienen relación con el tema. En la presente selección de casos y lecturas, se recogen materiales teóricos prácticos, en los cuales se realiza: estudio de casos, su contenido y las actividades a desarrollar en los casos. Como es natural, el presente libro «Casos de Seguridad en el Trabajo y Ambiente» surge con la finalidad básica de dar a conocer los resultados de los estudios de casos de investigación realizados en el campo de la Ingeniería, con énfasis en las especialidades de Ingeniería en Seguridad, Salud en el Trabajo y Medio Ambiente. El presente libro servirá para que el estudiante o el profesional pueda profundizar en los aspectos teóricos y metodológicos del estudio de caso, así como proveer al docente, casos modelos de estudio, en los cuales se realiza una integración de diversas disciplinas