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 < 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 \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

Simplified PET Quantitation of Myocardial Glucose Utilization

The purpose of this study was to validate experimentally a simple method to quantify tissue glucose utilization with the brain reference index(BRI) using 14C-deoxyglucose and assess its clinical feasibility for myocardial PET. Methods: To validate the BRI method, glucose utilization in myocardial and skeletal muscle was studied in rats with 14C-deoxyglucose after increasing doses of oral glucose loading. To assess clinical feasibility of the method, the BRI was applied to nine patients undergoing myocardial PET and compared to rMGU measured by the deoxyglucose model of Sokoloff et al. and by Patlak graphical analysis. The normal range of myocardial FDG uptake expressed as the BRI was estimated with four normal volunteers.Results: In skeletal muscle, a dose-dependent increase of glucose utilization was observed during oral glucose loading with doses up to 4 mg/g. In the myocardium, glucose utilization increased with a glucose loading dose of up to 1 mg/g without increasing further at greater glucose doses. Ratios of maximal glucose utilizatio nin glucose-loaded rats to 19-hr fasted rats (controls), expressed as the BRI for left and right ventricular myocardium and skeletal muscle were 4.16, 3.74 and 7.39, respectively. Glucose utilization of right ventricular myocardium was approximately 70% of left ventricular myocardium for all glucose-loaded conditions. For patients, the BRI correlated with rMGU; four of these patients had a constant plasma glucose concentration. Conclusion: Myocardial BRI is a sensitive indicator of rMGU that does not require dynamic data acquisition or constant plasma glucose concentratios

Incidence of Skin Cancer among Nagasaki Atomic Bomb Survivors (Preliminary Report)

Among a total of 65, 268 Nagasaki atomic bomb survivors recorded in the Scientific Data Center of Atomic Bomb Disaster, Nagasaki University School of Medicine, 140 cases with skin cancer were collected from 31 hospitals in Nagasaki City from 1961 through 1987. Subsequently, these cases of skin cancer in Nagasaki atomic bomb survivors were statistically analyzed in relation to the estimated distance from the hypocenter by age, sex, histology and latent period. The results were as follows: 1. A high correlation was observed between the incidence of skin cancer and the distance from the hypocenter. 2. The incidence of skin cancer in Nagasaki atomic bomb survivors now appears to be increasing in relation to exposure distance. 3. Among 140 cases, basal cell epithelioma was observed in 67 cases (47. 9%) and squamous cell carcinoma in 43 cases (30. 7%)

Incidence of Skin Cancer among Nagasaki Atomic Bomb Survivors (Preliminary Report)

Among a total of 65, 268 Nagasaki atomic bomb survivors recorded in the Scientific Data Center of Atomic Bomb Disaster, Nagasaki University School of Medicine, 140 cases with skin cancer were collected from 31 hospitals in Nagasaki City from 1961 through 1987. Subsequently, these cases of skin cancer in Nagasaki atomic bomb survivors were statistically analyzed in relation to the estimated distance from the hypocenter by age, sex, histology and latent period. The results were as follows: 1. A high correlation was observed between the incidence of skin cancer and the distance from the hypocenter. 2. The incidence of skin cancer in Nagasaki atomic bomb survivors now appears to be increasing in relation to exposure distance. 3. Among 140 cases, basal cell epithelioma was observed in 67 cases (47. 9%) and squamous cell carcinoma in 43 cases (30. 7%)