Using the unbiased approach of human genetics we have identified independent loss of function mutations in the gene encoding the pancreatic exocrine chymotrypsin-like elastase 2A (CELA2A), which contribute to early-onset atherosclerosis, impaired glucose tolerance/type2 diabetes (T2D), hypertension, hypertriglyceridemia, and obesity in outlier kindreds [45] (Fig. 1). Here, CELA2A is linked to obesity due to melanocortin 4 receptor deficiency.