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

Hypothesis/Aim: Type 1 diabetes (T1D) is associated with excess coronary artery disease (CAD) risk even when known cardiovascular risk factors are accounted for. Genetic perturbation of hematopoiesis that alters leukocyte production is a novel independent modifier of CAD risk. We examined whether there are shared genetic determinants and causal relationships between leukocyte counts, T1D, and CAD. Methods: Genome-wide association studies (GWAS) summary statistics were utilized to perform pairwise linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics (rho-HESS) to respectively estimate the genome-wide and local genetic correlations, and two-sample Mendelian randomization (MR) to estimate the causal relationships between leukocyte counts (335 855 healthy subjects), T1D (18 942 cases, 501 638 controls), and CAD (122 733 cases, 424 528 controls). Results: There was significant genome-wide genetic correlation (rg) between T1D and CAD (rg = 0.088; P = 9.0e-03) and both diseases shared significant genome-wide genetic determinants with eosinophil count (rg(T1D) = 0.093, P = 7.20e-03; rg(CAD) = 0.092, P = 3.68e-06) and lymphocyte count (rg(T1D) = -0.052, P = 2.80e-02; rg(CAD) = 0.1761, P = 1.82e-15). Sixteen independent loci showed stringent Bonferroni significant local genetic correlations between leukocyte counts, T1D and/or CAD. Cis-genetic regulation of the expression levels of genes within loci that are shared between T1D and CAD were 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 T1D and CAD (lymphocyte odds ratio (OR)T1D = 0.667, P = 2.02e-19; ORCAD =1.085, P = 2.67e-06; neutrophil ORT1D = 0.82, P = 5.63e-05; ORCAD = 1.17, P = 5.02e-14; and eosinophil ORT1D: 1.67, P = 4.45e-25; ORCAD: 1.07; P = 2.02e-03). Conclusions/Interpretations: This study sheds light on shared genetic mechanisms that underlie T1D and CAD, which may contribute to their co-occurrence through regulation of gene expression and leukocyte counts. This study also identifies molecular targets for further investigation for disease prediction and potential drug discovery.