1477-P: Polygenic Risk Score (PRS) Derived from Common Variants of Monogenic Diabetes Genes (MDG) Predicts Young Onset Diabetes (YOD) and Cardiovascular(CV)-Kidney Complications
Authors: KWAN O CHUN , FAN BAOQI , TSOI SANDRA T.F. , TAM CLAUDIA H. , WAN RAYMOND , LAU ERIC S.H. , SHI MAI , LIM CADMON K.P. , CHOW ELAINE , KONG ALICE P. , MA RONALD C. , LUK ANDREA , CHAN JULIANA C. 
Published: June 2024

Introduction & Objectives: Monogenic diabetes are caused by rare mutations in genes usually implicated in β-cell reserve/function. Whether their common variants could jointly influence risk of YOD diagnosed before 40 years and CV-kidney events is underexplored. We hypothesized a positive association of a weighted PRS derived from common variants of MDG with these outcomes.
Methods: We constructed three weighted PRS with common variants (minor allele frequency&gt;0.01) of 34 MDG based on three r2 thresholds (0.2, 0.4, 0.6) of linkage disequilibrium (LD), from a discovery cohort of adults with [n=453, median age (interquartile range) = 40.0 (35.0-47.0)] and without [n=405, age=56.7 (50.3-61.0)] YOD who had whole exome sequencing data followed by validation in an independent cohort with array-based genotyping. We further tested association of the best performer with incident CV-kidney events in a cohort of type 2 diabetes (T2D).
Results: 135 single nucleotide polymorphisms were used to construct the PRS based on LD r2 threshold 0.2 which performed the best at validation in an independent cohort (920 YOD + 4909 non-YOD) where per standard deviation (SD) rise in PRS was associated with 8% increased risk of YOD after adjusting sex and BMI (OR 1.08, p=0.047). In an independent cohort of T2D free of CV-kidney events at baseline [n=2313, age = 53.4 (45.4-61.7), disease duration = 4.0 (1.0-9.0)], per SD rise in PRS was associated with 16%, 9% and 10% increased risk of incident CV (HR 1.16, p&lt;0.001), kidney (HR 1.09, p=0.011) and CV-kidney events (HR 1.10, p=0.003) respectively after adjusting sex, baseline age and metabolic control. Those at top 20% PRS and baseline diabetes duration (DD) 5 to &lt;10 years had higher hazards of incident CV-kidney events than those at bottom 20% PRS and DD ≥10 years (HR 1.66, p=0.019) by direct comparison.
Conclusion: Common variants of MDG jointly affected the risk of YOD and CV-kidney complications.

Disclosure
C. O: Other Relationship; Novo Nordisk. B. Fan: None. S.T.F. Tsoi: None. C.H. Tam: None. R. Wan: None. E.S.H. Lau: None. M. Shi: None. C.K.P. Lim: None. E. Chow: Research Support; Merck KGaA. Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Research Support; Medtronic. Speaker's Bureau; Zuellig Pharma Holdings Pte. Ltd., Abbott. A.P. Kong: Speaker's Bureau; Abbott. Advisory Panel; Merck Sharp & Dohme Corp. Speaker's Bureau; Boehringer-Ingelheim, Bayer Inc., AstraZeneca. Other Relationship; Dexcom, Inc. Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. Advisory Panel; Kyowa Kirin Co., Ltd., Abbott. R.C. Ma: Advisory Panel; AstraZeneca. Other Relationship; Bayer Inc., Boehringer-Ingelheim. Advisory Panel; Merck & Co., Inc. Other Relationship; Roche Diagnostics, Novo Nordisk. Advisory Panel; Takeda Pharmaceutical Company Limited. Other Relationship; GemVCare Ltd. A. Luk: Research Support; Novo Nordisk, Amgen Inc., Merck Sharp & Dohme Corp., Roche Pharmaceuticals, Biogen, Boehringer-Ingelheim, Shanghai Junshi Biosciences CO.Ltd. J.C. Chan: Research Support; AstraZeneca, Hua Medicine. Consultant; Sanofi. Research Support; Servier Laboratories. Consultant; Viatris Inc. Research Support; Merck & Co., Inc. Stock/Shareholder; GemVCare Ltd. Board Member; Asia Diabetes Foundation. Speaker's Bureau; Zuellig Pharma Holdings Pte. Ltd. Advisory Panel; Bayer Inc. Speaker's Bureau; Boehringer-Ingelheim.

Funding
Health and Medical Research Fund, Health Bureau, the HKSAR Government (CFS-CUHK2); Research Impact Fund, the Research Grants Council Hong Kong (R4012-18); Hong Kong Genome Institute