Causal relationships of Janus kinase 2 with chronic kidney diseases: a two-sample Mendelian randomisation study

The role of Janus kinase (JAK) 2 in chronic kidney disease (CKD) remains unreported. This Mendelian randomisation (MR) study investigates the causal associations of JAK2 with CKD and provides references for the identification of possible therapeutic targets and the prevention of renal dysfunction.

Summary data for JAK2 and various CKD endpoints are extracted from genome-wide association study findings provided by the MRC Integrative Epidemiology Unit and FinnGen. The causal relationships are assessed using inverse variance weighted estimates, weighted median and MR-Egger regression. To ensure rigour, reverse MR, radial MR and leave-one-out approaches are employed for sensitivity analyses, with Cochran's Q used to assess heterogeneity.

Inverse variance weighted estimates indicate potential two-way causal associations between JAK2 and membranous nephropathy (MN) (odds ratio [OR] = 1.138, 95% confidence interval [CI]: 1.073-1.206; reverse causal association: OR = 1.040, 95% CI: 1.002-1.079). Sensitivity analyses demonstrate that these relationships are relatively robust. An underlying causal relationship between JAK2 and estimated glomerular filtration rate is identified (OR = 0.996, 95%CI 0.993-1.000); however, this becomes non-significant after the radial MR test (P > 0.05). In addition, polycystic kidney disease exhibits a potential causal relationship with JAK2 (OR = 1.066, 95%CI 1.009-1.127).

Elevated relative expression of JAK2 may represent a potential risk factor for the occurrence of MN. Conversely, patients with MN may exhibit high relative expression of JAK2. These two-way causal associations may inform future efforts aimed at the prevention of CKD and the identification of possible therapeutic targets.