Identification of a Common Variant for Coronary Heart Disease at PDE1A Contributes to Individualized Treatment Goals and Risk Stratification of Cardiovascular Complications in Chinese Patients With Type 2 Diabetes

Abstract

Objective: In this study we aim to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications.

Research design and methods: We performed a two-stage genome-wide association study for CHD in Chinese patients with T2D (3,596 case and 8,898 control subjects), followed by replications in European patients with T2D (764 case and 4,276 control subjects) and general populations (n = 51,442-547,261). Each identified variant was examined for its association with a wide range of phenotypes and its interactions with glycemic, blood pressure (BP), and lipid controls in incident cardiovascular diseases.

Results: We identified a novel variant (rs10171703) for CHD (odds ratio 1.21 [95% CI 1.13-1.30]; P = 2.4 × 10-8) and BP (β ± SE 0.130 ± 0.017; P = 4.1 × 10-14) at PDE1A in Chinese T2D patients but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1 × 10-4). Patients with CC genotype of rs10171703 had >40% reduction in either cardiovascular events in response to BP control (2.9 × 10-8 < P < 3.6 × 10-5), those with CT genotype had no difference (0.0726 < P < 0.2614), and those with TT genotype had a threefold increase in MI risk (P = 6.7 × 10-3).

Conclusions: We discovered a novel CHD- and BP-related variant at PDE1A that interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes, only when our findings are validated.

Graphical abstract

Figure 1

Study design and workflow. Step 1: to identify novel loci for increased risk of diabetes cardiovascular complications, we conducted a meta-analysis of two GWAS for CHD in Chinese patients with T2D. We followed up the top signals in an additional cohort of Chinese patients with T2D and further performed replication in multiple populations. Finally, the PDE1A locus was identified. Step 2: to understand the pleiotropy and the underlying biological function of the PDE1A locus, we examined this locus in associations with 1) seven types of diabetes cardio-renal complications using two different study designs (i.e., case-control and prospective designs) and 2) a wide spectrum of phenotypes using the publicly available data. We also performed bioinformatic analyses for the PDE1A locus, including the eQTL analysis, and the transcriptome-wide association study. Step 3: to explore the potential clinical utility of personal genetic information, we investigated the effect of each ABC goal on diabetes cardiovascular risk according to different genotypes of PDE1A rs10171703. CHF, congestive heart failure; GIANT, Genetic Investigation of ANthropometric Traits; MAF, minor allele frequency; UKB, UK Biobank.

Figure 2

Results for two-stage genome-wide association and replication studies. A: Manhattan plot for the meta-analysis of GWAS from the HKDR study and the HKDB phase 1 study. The y-axis represents the −log₁₀ P value, and the x-axis represents the 6,616,004 analyzed biallelic SNPs. The dashed red horizontal line corresponds to the threshold of significance (P < 1 × 10⁻⁵). There are 110 points with P < 1 × 10⁻⁵, and the label localizes the novel susceptibility locus to CHD discovered in the current study. B: Quantile-quantile (Q-Q) plot for the meta-analysis of GWAS from the HKDR study and the HKDB phase 1 study. The dotted line corresponds to the null hypothesis. C: Forest plot for the association between PDE1A rs10171703 and CHD for all studied populations. ORs and 95% CIs were reported according to the C allele of rs10171703 (i.e., the CHD-associated risk allele). †HR and 95% CIs were reported according to the C allele of rs10171703. P value was obtained from logistic regression model. §P value was obtained from Cox regression model. D: Regional plot of the PDE1A locus. The purple circle and diamond represent the SNP rs10171703 identified from the meta-analysis of GWAS in the HKDR study and the HKDB phase 1 study (genome-wide scan), and the meta-analysis in the HKDR study and the HKDB phase 1 and 2 studies (all cohorts of Chinese patients with T2D), respectively. Other SNPs are colored according to level of LD, which is measured by r², with the sentinel SNP. The recombination rates estimated from the 1000 Genomes project Asian data are shown. The genes in the interval are indicated in the bottom panel. chr, chromosome.

Figure 3

Modulating influence of PDE1A rs10171703 on the association between BP control and new-onset cardiovascular complications among Chinese patients with T2D. These analyses were conducted in the combined cohort of the HKDR study and the HKDB phase 1 and 2 studies. Cumulative probability of new-onset CHD (A) and MI (B) is shown according to the combinations of PDE1A rs10171703 genotypes and the status of BP control. P_interaction was the P value of the interaction term obtained from the Cox regression model including two main effects (PDE1A rs10171703 and achievement of BP target [i.e., SBP <130 mmHg and DBP <80 mmHg]), the interaction term of main effects, and the covariates (the study cohorts [HKDR study, HKDB phase 1 and 2 studies], enrollment year, sex, age, duration of diabetes, and principal components). P values and HRs and 95% CIs were obtained from the Cox regression model assessing the association between the achievement of BP target (“yes” [coded as 1] vs. “no” [coded as 0]) and diabetic cardiovascular complications, with adjustment for study cohorts, enrollment year, sex, age, duration of diabetes, and PCs, stratified by the genotypes of rs10171703. Numbers of patients entering various time intervals in each category are shown in the bottom panel of each plot.