Poly(ADP-Ribose) Polymerase Activity and Coronary Artery Disease in Type 2 Diabetes Mellitus: An Observational and Bidirectional Mendelian Randomization Study.

OBJECTIVE:Experimental evidence suggests a close link between (poly[ADP-ribose] polymerase) activation and diabetic endothelial dysfunction. Here, we tested whether Pduanyu37 activity in circulating leukocytes was associated with coronary artery disease (CAD) among patients with type 2 diabetes mellitus (T2DM). Approach and Results: We performed observational and bidirectional Mendelian randomization studies of 3149 Chinese individuals with T2DM who underwent coronary angiography, with leukocyte Pduanyu37 activity, 16 tag single-nucleotide polymorphisms in and and 17 CAD risk single-nucleotide polymorphisms analyzed. Of 3149 participants, 1180 who further received percutaneous coronary intervention were prospectively followed for 1 year to track major adverse cardiovascular and cerebrovascular events. Overall, greater Pduanyu37 activity was cross-sectionally associated with an odds ratio of 1.23 for obstructive CAD, and prospectively with a hazard ratio of 1.34 for 1-year major adverse cardiovascular and cerebrovascular events after percutaneous coronary intervention (both P<0.001). Using a genetic score of 5 screened single-nucleotide polymorphisms in Pduanyu371 and as the instrumental variable, genetically predicted elevation in Pduanyu37 activity showed a causal association with obstructive CAD (odds ratio=1.35, P<0.001). In contrast, the genetic risk of CAD had no significant effect on Pduanyu37 activity. Ex vivo and in vitro cultures of human monocytes showed that rs747657, as the lead single-nucleotide polymorphism strongly associated with Pduanyu37 activity, caused the differential binding of transcription factor GATA2 (GATA-binding protein 2) to an intronic regulatory region in thus modulating Pduanyu371 expression and Pduanyu37 activity. CONCLUSIONS:Greater Pduanyu37 activity may have causal roles in the development of obstructive CAD among patients with diabetes mellitus.

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