Multilocus Genetic Risk Score for Hypertension Associates with Systolic Blood Pressure in People with Type 2 Diabetes Patients: Discovery and Replication Cohorts

Genetic loci that contribute to type 2 diabetes (T2D) susceptibility have been identified. However, the genetic determinants of hypertension risk in T2D are limited. We aimed to investigate the genetic architecture of hypertension risk in T2D. We performed a genome-wide association study in a T2D cohort composed of 454 hypertensive and 545 non-hypertensive patients, and replicated the results in a second independent T2D cohort composed of 563 hypertensive patients and 359 nonhypertensive patients. Eighteen genetic loci exhibited associations with hypertension risk in these two cohorts with combined odds ratios (ORs) ranging from 1.16 to 2.75 after adjusting for age, gender, body mass index, and comorbidities (p = 0.0423 to 0.00592). A genetic risk score (GRS) was created by combing these risk alleles weighted by their estimated effect sizes (log OR). T2D patients with weighted GRS > 19 showed 6-fold increase in hypertension risk (OR: 5.77, 95% confidence interval: 3.91-8.51) compared to patients with weighted GRS < 15. Receiver-operating characteristic (ROC) curves of the regression models showed that the area under the curve (AUC) improved when the weighted GRS (AUC = 0.6799) was added to a model that included the covariates with conventional risk factors (AUC = 0.8295). We also observed a regression tendency, which showed that each weighted GRS increased systolic blood pressure by 2.10 mm Hg (slope = 2.10; p = 0.0001). These 18 genetic loci are associated with hypertension risk and systolic blood pressure levels in T2D and are implicated for further functional studies on hypertension occurrence in T2D. Funding Statement: This study was supported by grants from the China Medical University (CMU102-PH-01), the China Medical University Hospital (DMR-105-031, DMR-105-098, DMR-107-042, DMR-108-113, and DMR-108-114), the National Science Council, the Ministry of Science and Technology, Taiwan (MOST 105-2314-B-039 -037 -MY3, MOST 106-2320-B-039-020, MOST 106-2320-B-039-030, and MOST 106-2320-B-039 -017 -MY3), and China Medical University under the Aim for Top University Plan of the Ministry of Education, Taiwan. Declaration of Interests: The authors declare no conflicts of interest relevant to the contents of this paper. Ethics Approval Statement: All study participants provided informed consent, and the study design was approved by the appropriate ethics review boards.