Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely-imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (Stage 1, n=59,771) and generalized our findings in 9 additional studies (HISLA Stage 2, n=10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA Stage 1 and existing consortia of European and African ancestries. In our HISLA Stage 1+2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified three secondary signals for BMI, 28 for height, and two for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification

Adenoamigdalectomía para la apnea obstructiva del sueño en niños

Antecedentes: El tratamiento actual de la apnea del sueño en niños consiste principalmente en tratamientos quirúrgicos. La adenoamigdalectomía es la intervención que se usa con más frecuencia para tratar la apnea del sueño en niños. Objetivos: Determinar la eficacia de la adenoamigdalectomía en el tratamiento de la apnea obstructiva del sueño en niños. Estrategia de búsqueda: Se hicieron búsquedas en el registro especializado del Grupo Cochrane de Vías Respiratorias (Cochrane Airways Group) usando términos ya especificados. Las búsquedas actuales se realizaron hasta agosto de 2008. Criterios de selección: Ensayos con asignación al azar en niños con diagnóstico de apnea obstructiva del sueño. Obtención y análisis de los datos: Dos revisores examinaron los resultados de la búsqueda y recopilaron los datos de los estudios en cuanto a sus características antes de decidir cuáles incluir en la revisión. Resultados principales: Un estudio cumplió los criterios de inclusión. Este estudio abordó los méritos relativos de dos técnicas quirúrgicas para tratar la apnea obstructiva del sueño en niños (adenoidectomía y amigdalectomía por radiofrecuencia controlada con temperatura y adenoidectomía y amigdalectomía total). No se evidenció ninguna diferencia significativa para los síntomas o el índice de dificultad respiratoria. Más niños en el grupo de adenoidectomía y amigdalectomía por radiofrecuencia controlada con temperatura pudieron retornar a la dieta normal a los siete días en comparación con adenoidectomía y amigdalectomía total. No se observaron complicaciones significativas en el estudio. Conclusiones de los autores: Un estudio pequeño no logró encontrar una diferencia entre dos técnicas quirúrgicas, aunque el retorno a la dieta fue más frecuente en el grupo tratado con adenoidectomía y amigdalectomía por radiofrecuencia controlada con temperatura. En la actualidad, aún se discute sobre los criterios requeridos para diagnosticar la apnea obstructiva del sueño significativa en niños. Además, la historia natural de la enfermedad no se ha delineado por completo. Faltan ensayos controlados aleatorios que investiguen la eficacia del tratamiento de la apnea obstructiva del sueño confirmada con amigdaloadenoidectomía en niños. Se necesitan más estudios antes de efectuar recomendaciones para el tratamiento de la apnea obstructiva del sueño en niños. La calidad de la investigación en esta área podría mejorarse con el uso de estudios del sueño al inicio para determinar el grado de gravedad de la apnea del sueño en niños que se incorporan a los estudios en esta área. También se necesita un seguimiento a largo plazo para explorar el efecto de la amigdaloadenoidectomía en la apnea del sueño pediátrica