Heterogeneity in phenotype, disease progression and drug response in type 2 diabetes

TY - JOUR

T1 - Heterogeneity in phenotype, disease progression and drug response in type 2 diabetes

AU - Thakarakkattil Narayanan Nair, Anand

AU - Wesolowska-Andersen, Agata

AU - Brorsson, Caroline A.

AU - Lathika Rajendrakumar, Aravind

AU - Hapca, Simona

AU - Gan, Sushrima

AU - Dawed, Adem Y.

AU - Donnelly, Louise A.

AU - McCrimmon, Rory

AU - Doney, Alexander S. F.

AU - Palmer, Colin N. A.

AU - Mohan, Viswanathan

AU - Anjana, Ranjit M.

AU - Hattersley, Andrew T.

AU - Dennis, John M.

AU - Pearson, Ewan R.

N1 - We thank all personnel at Health Informatics Centre for linking different data sets, maintaining all statistical packages, and providing the data. The research was supported by the National Institute for Health Research using Official Development Assistance funding [INSPIRED 16/136/102] and Health Data Research UK which receives its funding from HDR UK Ltd (HDR-5012) funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation (BHF) and the Wellcome Trust. The views expressed in this publication are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. JMD is supported by an Independent Fellowship funded by Research England’s Expanding Excellence in England (E3) fund. ERP holds Wellcome Trust New Investigator Award. This research was funded in whole, or in part, by the Wellcome Trust [102820/Z/13/Z].

PY - 2022/5/9

Y1 - 2022/5/9

N2 - Type 2 diabetes (T2D) is a complex chronic disease characterized by considerable phenotypic heterogeneity. In this study, we applied a reverse graph embedding method to routinely collected data from 23,137 Scottish patients with newly diagnosed diabetes to visualize this heterogeneity and used partitioned diabetes polygenic risk scores to gain insight into the underlying biological processes. Overlaying risk of progression to outcomes of insulin requirement, chronic kidney disease, referable diabetic retinopathy and major adverse cardiovascular events, we show how these risks differ by patient phenotype. For example, patients at risk of retinopathy are phenotypically different from those at risk of cardiovascular events. We replicated our findings in the UK Biobank and the ADOPT clinical trial, also showing that the pattern of diabetes drug monotherapy response differs for different drugs. Overall, our analysis highlights how, in a European population, underlying phenotypic variation drives T2D onset and affects subsequent diabetes outcomes and drug response, demonstrating the need to incorporate these factors into personalized treatment approaches for the management of T2D.

AB - Type 2 diabetes (T2D) is a complex chronic disease characterized by considerable phenotypic heterogeneity. In this study, we applied a reverse graph embedding method to routinely collected data from 23,137 Scottish patients with newly diagnosed diabetes to visualize this heterogeneity and used partitioned diabetes polygenic risk scores to gain insight into the underlying biological processes. Overlaying risk of progression to outcomes of insulin requirement, chronic kidney disease, referable diabetic retinopathy and major adverse cardiovascular events, we show how these risks differ by patient phenotype. For example, patients at risk of retinopathy are phenotypically different from those at risk of cardiovascular events. We replicated our findings in the UK Biobank and the ADOPT clinical trial, also showing that the pattern of diabetes drug monotherapy response differs for different drugs. Overall, our analysis highlights how, in a European population, underlying phenotypic variation drives T2D onset and affects subsequent diabetes outcomes and drug response, demonstrating the need to incorporate these factors into personalized treatment approaches for the management of T2D.

KW - Type 2 diabetes

UR - https://www.scopus.com/pages/publications/85129772777

U2 - 10.1038/s41591-022-01790-7

DO - 10.1038/s41591-022-01790-7

M3 - Article

C2 - 35534565

SN - 1078-8956

VL - 28

SP - 982

EP - 988

JO - Nature Medicine

JF - Nature Medicine

ER -