Functional ADAM12 variants modulate proteolytic activity and influence metabolic traits

The high prevalence of insulin resistance and metabolic syndrome in Kuwait increases the risk of type 2 diabetes (T2D) and cardiovascular diseases development. Although the genetic contribution to insulin resistance and metabolic syndrome is established, the role of a disintegrin and metalloprotease 12 (ADAM12) in insulin resistance and T2D remains unclear. Our GWAS has identified four novel ADAM12 variants, namely, ADAM12-K170R rs112264074 [NP_003465.3:p.Lys170Arg], ADAM12-R176W rs140497576 [NP_003465.3:p.Arg176Trp], ADAM12-M662V rs115100580 [NP_003465.3:p.Met662Val], and ADAM12-I908V rs41303603 [NP_003465.3:p.Ile908Val]. These variants were associated with different metabolic traits, including FBG, HbA1c, low- (LDL) and high-density lipoprotein (HDL), total cholesterol (TC), and diastolic and systolic blood pressure. Using an independent replication cohort, the association of ADAM12-I908V with FBG was confirmed, and an association with HbA1c, LDL, and TC was found. In addition, ADAM12-K170R showed associations with waist-hip ratio in diabetic patients, and ADAM12-M662V associated with HDL, TC, and HbA1c in healthy controls, while ADAM12-R176W variant was not detected in the replication cohort. Moreover, we examined the impact of ADAM12 variants on its proteolytic activity and results show that 176W and 662V variants had higher activity in cell lysate supernatants, but only 662V and 908V variants had higher activity in intact cells, suggesting that enzyme activity dysregulation may contribute to the development of metabolic syndrome and T2D.