Genetic relations between type 1 diabetes, coronary artery disease and leukocyte counts

Type 1 diabetes is associated with excess coronary artery disease (CAD) risk even when known cardiovascular risk factors are accounted for. Genetic perturbation of haematopoiesis that alters leukocyte production is a novel independent modifier of CAD risk. We examined whether there are shared genetic determinants and causal relationships between type 1 diabetes, CAD and leukocyte counts.

Genome-wide association study summary statistics were used to perform pairwise linkage disequilibrium score regression and heritability estimation from summary statistics (ρ-HESS) to respectively estimate the genome-wide and local genetic correlations, and two-sample Mendelian randomisation to estimate the causal relationships between leukocyte counts (335,855 healthy individuals), type 1 diabetes (18,942 cases, 501,638 control individuals) and CAD (122,733 cases, 424,528 control individuals). A latent causal variable (LCV) model was performed to estimate the genetic causality proportion of the genetic correlation between type 1 diabetes and CAD.

There was significant genome-wide genetic correlation (r_g) between type 1 diabetes and CAD (r_g=0.088, p=8.60 × 10^-3) and both diseases shared significant genome-wide genetic determinants with eosinophil count (r_g for type 1 diabetes [r_g(T1D)]=0.093, p=7.20 × 10^-3, r_g for CAD [r_g(CAD)]=0.092, p=3.68 × 10^-6) and lymphocyte count (r_g(T1D)=-0.052, p=2.76 × 10^-2, r_g(CAD)=0.176, p=1.82 × 10^-15). Sixteen independent loci showed stringent Bonferroni significant local genetic correlations between leukocyte counts, type 1 diabetes and/or CAD. Cis-genetic regulation of the expression levels of genes within shared loci between type 1 diabetes and CAD was associated with both diseases as well as leukocyte counts, including SH2B3, CTSH, MORF4L1, CTRB1, CTRB2, CFDP1 and IFIH1. Genetically predicted lymphocyte, neutrophil and eosinophil counts were associated with type 1 diabetes and CAD (lymphocyte OR for type 1 diabetes [OR_T1D]=0.67, p=2.02^-19, OR_CAD=1.09, p=2.67 × 10^-6; neutrophil OR_T1D=0.82, p=5.63 × 10^-5, OR_CAD=1.17, p=5.02 × 10^-14; and eosinophil OR_T1D=1.67, p=5.45 × 10^-25, OR_CAD=1.07, p=2.03 × 10^-4. The genetic causality proportion between type 1 diabetes and CAD was 0.36 ± 0.16 (p_LCV=1.30 × 10^-2), suggesting a possible intermediary causal variable.

This study sheds light on shared genetic mechanisms underlying type 1 diabetes and CAD, which may contribute to their co-occurrence through regulation of gene expression and leukocyte counts and identifies cellular and molecular targets for further investigation for disease prediction and potential drug discovery.