TY - JOUR
T1 - Polygenic risk scores predict diabetes complications and their response to intensive blood pressure and glucose control
AU - Tremblay, Johanne
AU - Haloui, Mounsif
AU - Attaoua, Redha
AU - Tahir, Ramzan
AU - Hishmih, Camil
AU - Harvey, François
AU - Marois-Blanchet, François Christophe
AU - Long, Carole
AU - Simon, Paul
AU - Santucci, Lara
AU - Hizel, Candan
AU - Chalmers, John
AU - Marre, Michel
AU - Harrap, Stephen
AU - Cífková, Renata
AU - Krajčoviechová, Alena
AU - Matthews, David R.
AU - Williams, Bryan
AU - Poulter, Neil
AU - Zoungas, Sophia
AU - Colagiuri, Stephen
AU - Mancia, Giuseppe
AU - Grobbee, Diederick E.
AU - Rodgers, Anthony
AU - Liu, Liusheng
AU - Agbessi, Mawussé
AU - Bruat, Vanessa
AU - Favé, Marie Julie
AU - Harwood, Michelle P.
AU - Awadalla, Philip
AU - Woodward, Mark
AU - Hussin, Julie G.
AU - Hamet, Pavel
N1 - Funding Information:
This work was supported by Genome Québec, Canadian Institutes of Health Research (CIHR), Ministère de l’Économie et de l’Innovation du Québec (MEIE), Consortium Québécois sur la Découverte du Médicament (CQDM), OPTITHERA, Servier and Canada Research Chair in Predictive Genomics to PH. JH is a Fonds la Recherche du Québec en Santé (FRQS) Junior 1 Research Scholar supported by the Institute for Data Valorization (IVADO) and Fondation de l’Institut de Cardiologie de Montréal (FICM). This research has been conducted using data from UK Biobank, a major biomedical database: www.ukbiobank.ac.uk . The study funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.
Funding Information:
JT and PH report grants from Servier and OPTITHERA during the conduct of the study and have a patent (number 62/685.642) applied for on 15 June 2018, N/Réf.: 019231-0002, licensed to OPTITHERA. JC reports grants and personal fees from Servier during the conduct of the study and grants from Idorsia outside the submitted work. MM reports personal fees from Servier, Novo Nordisk, Merck Sharp & Dohme outside the submitted work. MM is the president of a not-for-profit French Foundation entitled Fondation Francophone pour la Recherche sur le Diabète. He receives no personal fee for this function, but this foundation receives grants from the Association Française des Diabétiques and from Sanofi, Eli Lilly, Novo Nordisk, Merck Sharp & Dohme, Roche and Abbott. BW reports personal fees from Servier, Daiichi Sankyo, Boehringer Ingelheim and Novartis outside the submitted work. NP has received personal speaker fees from Servier, Takeda and Novo Nordisk, and advisory board activities from AstraZeneca and Novo Nordisk, and has received grants for his research group relating to diabetes mellitus from Diabetes UK, NIHR Efficacy and Mechanism Evaluation Programme (EME), Julius Clinical and the British Heart Foundation with a pending grant from Novo Nordisk. NP holds no stocks or shares in any such companies. SZ reports fees from Sanofi, AstraZeneca, Novo Nordisk and MSD Australia outside the submitted work. GM reports personal fees from Boehringer Ingelheim, Daiichi Sankyo, Ferrer, MEDTRONIC, Menarini International, Merck, Novartis, Recordati and Servier outside the submitted work. AR is one of the inventors on several patents filed by The George Institute for Global Health on Compositions for the Treatment of Hypertension. None of the inventors have a financial interest in these planned products. He is seconded to work for George Health Enterprises (the social enterprise arm of The George Institute for Global Health). He has received investment to develop fixed-dose combination products containing aspirin, statin and BP-lowering drugs. AR sits on a Data and Safety Monitoring Board for Idorsia. MW reports personal fees from Amgen and Kirin outside the submitted work. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.
Funding Information:
We thank J.-L. Chiasson, Honorary Professor of Medicine at Universit? de Montr?al for his insightful comments on the manuscript. We also thank M.-R. Guertin and P. Dumas (CRCHUM and Medpharmgene, Montreal, Qu?bec, Canada) for their clinical and organisational assistance with the ADVANCE and CLINPRADIA studies. JT and PH report grants from Servier and OPTITHERA during the conduct of the study and have a patent (number 62/685.642) applied for on 15 June 2018, N/R?f.: 019231-0002, licensed to OPTITHERA. JC reports grants and personal fees from Servier during the conduct of the study and grants from Idorsia outside the submitted work. MM reports personal fees from Servier, Novo Nordisk, Merck Sharp & Dohme outside the submitted work. MM is the president of a not-for-profit French Foundation entitled Fondation Francophone pour la Recherche sur le Diab?te. He receives no personal fee for this function, but this foundation receives grants from the Association Fran?aise des Diab?tiques and from Sanofi, Eli Lilly, Novo Nordisk, Merck Sharp & Dohme, Roche and Abbott. BW reports personal fees from Servier, Daiichi Sankyo, Boehringer Ingelheim and Novartis outside the submitted work. NP has received personal speaker fees from Servier, Takeda and Novo Nordisk, and advisory board activities from AstraZeneca and Novo Nordisk, and has received grants for his research group relating to diabetes mellitus from Diabetes UK, NIHR Efficacy and Mechanism Evaluation Programme (EME), Julius Clinical and the British Heart Foundation with a pending grant from Novo Nordisk. NP holds no stocks or shares in any such companies. SZ reports fees from Sanofi, AstraZeneca, Novo Nordisk and MSD Australia outside the submitted work. GM reports personal fees from Boehringer Ingelheim, Daiichi Sankyo, Ferrer, MEDTRONIC, Menarini International, Merck, Novartis, Recordati and Servier outside the submitted work. AR is one of the inventors on several patents filed by The George Institute for Global Health on Compositions for the Treatment of Hypertension. None of the inventors have a financial interest in these planned products. He is seconded to work for George Health Enterprises (the social enterprise arm of The George Institute for Global Health). He has received investment to develop fixed-dose combination products containing aspirin, statin and BP-lowering drugs. AR sits on a Data and Safety Monitoring Board for Idorsia. MW reports personal fees from Amgen and Kirin outside the submitted work. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/9
Y1 - 2021/9
N2 - Aims/hypothesis: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk. Methods: We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 individuals with type 2 diabetes in the UK Biobank study. Results: The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events (p = 6.3 × 10−21 and p = 9.6 × 10−31, respectively) and a 4.4-fold (p = 6.8 × 10−33) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk individuals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. Conclusions/interpretation: This novel multiPRS model stratified individuals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy. Graphical abstract: [Figure not available: see fulltext.]
AB - Aims/hypothesis: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk. Methods: We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 individuals with type 2 diabetes in the UK Biobank study. Results: The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events (p = 6.3 × 10−21 and p = 9.6 × 10−31, respectively) and a 4.4-fold (p = 6.8 × 10−33) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk individuals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. Conclusions/interpretation: This novel multiPRS model stratified individuals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy. Graphical abstract: [Figure not available: see fulltext.]
KW - ADVANCE trial
KW - Cardiovascular complications
KW - Genetics
KW - Polygenic risk score
KW - Prediction
KW - Renal complications
KW - UK Biobank
UR - http://www.scopus.com/inward/record.url?scp=85109288365&partnerID=8YFLogxK
U2 - 10.1007/s00125-021-05491-7
DO - 10.1007/s00125-021-05491-7
M3 - Article
C2 - 34226943
AN - SCOPUS:85109288365
SN - 0012-186X
VL - 64
SP - 2012
EP - 2025
JO - Diabetologia
JF - Diabetologia
IS - 9
ER -