Novel genetic marker predicts CHD risk in Chinese patients with T2DM

Researchers from the Chinese University of Hong Kong (CUHK) have discovered PDE1A rs10171703 as a novel genetic marker for coronary heart disease (CHD) in Chinese patients with type 2 diabetes mellitus (T2DM), indicating its potential utility for predicting CHD risk in this patient population.

“We can use this marker [ie, PDE1A rs10171703] to identify Chinese T2DM patients at high CHD risk. These findings provide foundation for precision care in diabetes,” said Professor Ronald Ma of the Department of Medicine and Therapeutics, CUHK.

To identify genetic variants associated with CHD in Chinese patients with T2DM, the researchers performed two-stage genome-wide association studies (GWAS) across three independent T2DM studies in Hong Kong (namely, Hong Kong Diabetes Register [HKDR], and Hong Kong Diabetes Biobank [HKDB] phase I and II studies). In stage 1, 6,616,004 biallelic variants were prioritized with meta-analysis of two studies (ie, HKDR and HKDB phase I study) involving 2,517 T2DM cases with CHD and 6,424 T2DM controls without cardiovascular disease (CVD; including CHD, stroke or peripheral vascular disease). Subsequently, the top 110 variants from stage 1 were analyzed in stage 2 with the HKDB phase II study (cases, n=1,079; controls, n=2,474). [Diabetes Care 2023;46:1271-1281]

Two-stage GWAS analysis showed that PDE1A gene was associated with CHD in Chinese patients with T2DM (p=1.9 x 10^-9–0.0181). With each copy of the PDE1A rs10171703 C allele, there was a 1.21-fold increased risk of developing CHD (odds ratio [OR], 1.21; 95 percent confidence interval [CI], 1.13–1.30; p=2.4 × 10^-8).

However, in replication analyses, no significant association was found between PDE1A rs10171703 and CHD in European T2DM patients from a prospective cohort (n=5,040; p=0.6879), and a modest association with CHD was found in the general population based on data from six cohort studies (n=51,442–547,261; hazard ratio [HR], 1.01–1.07; p=1.3 x 10^-3–0.1854). [Cardiovasc Diabetol 2004;3:9; Nat Genet 2020;52:669-679; Nat Genet 2020;52:1169-1177; Circ Genom Precis Med 2020;13:e002670; Circ Res 2018;122:433-443; medRxiv2022;doi:10.1101/2022.03.03.22271360; Nat Genet 2017;49:1450-1457]

“Despite the smaller sample size in our study vs previous GWAS research, we identified PDE1A rs10171703 [as a novel genetic marker] for CHD in Chinese patients with T2DM,” the researchers noted.

PDE1A rs10171703 may guide individualized treatment goals

Importantly, PDE1A rs10171703 demonstrated pleiotropic effects on blood pressure (BP) in Chinese patients with T2DM. In phenome-wide association study, PDE1A rs10171703 was associated with elevated BP (diastolic BP: β, 0.332; p=0.0297) (systolic BP: β, 0.595; p=0.0208) and development of hypertension (OR, 1.09; p=0.0174). [Diabetes Care 2023;46:1271-1281]

Cox regression analysis showed interaction effects of PDE1A rs10171703 genotype with BP goal attainment (ie, <130/80 mm Hg) on risks of CHD (p_interaction=0.0155) and myocardial infarction (MI; p_interaction=5.1 × 10^-4). In patients carrying the CC genotype, BP goal attainment was associated with a 40 percent reduction in CHD risk (HR, 0.60; 95 percent CI, 0.51–0.72; p=2.9 × 10^-8). No significant effects were observed among those carrying the CT (p=0.0726) or TT genotype (p=0.6946).

For MI, BP goal attainment was associated with a 45 percent reduced risk in CC genotype carriers (HR, 0.58; 95 percent CI, 0.45–0.75; p=3.6 × 10^-5) but a 3-fold increased risk in TT genotype carriers (HR, 3.02; 95 percent CI, 1.36–6.70; p=6.7 × 10^-3). No significant effects were found in CT genotype carriers (p=0.2614).

“In our study in Chinese patients with T2DM, PDE1A rs10171703 modulated the effect of BP goal attainment on CVD. Further validation is warranted to guide future treatment in diabetes,” the researchers commented.