Genetic Predisposition to Type 2 Diabetes and Risk of Subclinical Atherosclerosis and Cardiovascular Diseases Among 160,000 Chinese Adults

Abstract

In observational studies, type 2 diabetes is associated with two- to fourfold higher risk of cardiovascular diseases (CVD). Using data from the China Kadoorie Biobank (CKB), we examined associations of genetically predicted type 2 diabetes with CVD among ∼160,000 participants to assess whether these relationships are causal. A type 2 diabetes genetic risk score (comprising 48 established risk variants) was associated with the presence of carotid plaque (odds ratio 1.17 [95% CI 1.05, 1.29] per 1 unit higher log-odds of type 2 diabetes; n = 6,819) and elevated risk of ischemic stroke (IS) (1.08 [1.02, 1.14]; n = 17,097), nonlacunar IS (1.09 [1.03, 1.16]; n = 13,924), and major coronary event (1.12 [1.02, 1.23]; n = 5,081). There was no significant association with lacunar IS (1.03 [0.91, 1.16], n = 3,173) or intracerebral hemorrhage (ICH) (1.01 [0.94, 1.10], n = 6,973), although effect estimates were imprecise. These associations were consistent with observational associations of type 2 diabetes with CVD in CKB (P for heterogeneity >0.3) and with the associations of type 2 diabetes with IS, ICH, and coronary heart disease in two-sample Mendelian randomization analyses based on summary statistics from European population genome-wide association studies (P for heterogeneity >0.2). In conclusion, among Chinese adults, genetic predisposition to type 2 diabetes was associated with atherosclerotic CVD, consistent with a causal association.

Figure 1

Observational and genetic associations of type 2 diabetes with risk of cardiovascular and microvascular diseases. Risk estimates expressed as the relative risk of the outcomes among individuals with type 2 diabetes compared with individuals without type 2 diabetes. Microvascular diseases defined as diabetic retinopathy (ICD-10 E10.3, E11.3, E12.3, E13.3, E14.3, H36.0), nephropathy (ICD-10 E10.2, E11.2, E12.2, E13.2, E14.2, N08.3), or neuropathy (ICD-10 E10.4, E11.4, E12.4, E13.4, E14.4, G73.0, G99.0, G59.0, G63.2, M14.6). Observational analyses, based on 489,549 participants, stratified by age at risk, sex, and study area and adjusted for education, smoking, alcohol consumption, physical activity, BMI, and SBP. Genetic analyses, using externally weighted GRS based on 48 type 2 diabetes–related SNPs (T2D-GRS48w) among 164,815 participants, adjusted for age, sex, and study area. Squares represent HRs or ORs, with area inversely proportional to the variance of the log HR/OR. Horizontal lines represent corresponding 95% CIs. Nonfatal myocardial infarction: observational risk estimate 1.97 (95% CI 1.78, 2.18), genetic risk estimate 2.72 (95% CI 0.99, 7.49), P for heterogeneity 0.53.