Polygenic Risk Testing at the Time of Diagnosis of Diabetes Could Help Prevent Its Micro- and Macrovascular Complications

Abstract

Cardiovascular and renal complications of T2D represent a human and societal burden. Early detection of susceptibility to complications could help their prevention. Clinical scores are useful to predict hard outcomes but genomic score can be applied earlier than a risk factor based score and thus save morbidity. We have constructed a polygenic risk score (PRS) based on genetic variants associated to risk factors and outcomes of T2D available from GWAS catalog and tested it on 5,000 genotyped Caucasian subjects with T2D of ADVANCE trial and its 5 year extension in ADVANCE-ON. We selected 620 SNPs which in combination with geo-ethnic principal component, age of onset and diabetes duration achieved a highly significant prediction of outcomes, including cardiovascular (AUC=0.80) and total mortality (AUC=0.77), equalling and surpassing such clinical scores as Framingham and UKPDS. The highest positive predictive values for micro- and macro-vascular prevalent cases were 81% and 78%, respectively. Individuals within the highest tertile of genetic risk for total prevalence of both microvascular and macrovascular events, had significantly higher cardiovascular death than subjects with the lowest genetic score (p=2.02x10-12). The number needed to treat to prevent one CV death over 5 years by ADVANCE therapies, was 12 in subjects with high PRS (p=0.0045) compared to 45 (p=0.14) in subjects with low PRS. Cox cumulative hazard plots demonstrated persistence of benefits for all cause and cardiovascular mortality in high PRS tertile over 10 years of intensive blood pressure control, while for glucose intensive therapy the benefit was restricted to the high PRS group for end-stage renal disease. We conclude that the use of a PRS that detects the risk of micro- and macrovascular complications at the time of T2D diagnosis could effectively assist in preventive and therapeutic measures to attenuate diabetes complications. Disclosure P. Hamet: Consultant; Self; Servier. F. Harvey: None. M. Haloui: None. M. Woodward: None. R. Tahir: None. F. Marois-Blanchet: None. C. Long: None. M. Marre: Board Member; Self; Abbott. Consultant; Self; AstraZeneca. Board Member; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Eli Lilly and Company. Board Member; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; Sanofi. Board Member; Self; Servier. S. Harrap: Research Support; Self; Servier. J. Chalmers: Research Support; Self; Servier. Other Relationship; Self; Servier. J. Tremblay: Consultant; Self; Servier.