A Mendelian Randomization-Based Approach to Identify Early and Sensitive Diagnostic Biomarkers of Disease

Background: Identifying markers of chronic kidney disease (CKD) that occur early in the disease process and are specific to loss of kidney function rather than other underlying causes of disease may allow earlier, more accurate identification of patients who will develop CKD. We therefore sought to identify diagnostic blood markers of early CKD that are caused by loss of kidney function by using an innovative “reverse Mendelian randomization” (MR) approach. Methods: We applied this technique to genetic and biomarker data from 4147 participants in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, all with known type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance. Two-sample MR was conducted using variants associated with creatinine-based eGFR (eGFR crea ) from the CKDGen Consortium (n = 133814) to estimate the effect of genetically decreased eGFR crea on 238 serum biomarkers. Results: With reverse MR, trefoil factor 3 (TFF3) was identified as a protein that is increased owing to decreased eGFR crea (β = 1.86 SD per SD decrease eGFR crea ; 95% CI, 0.95–2.76; P = 8.0 × 10 −5 ). Reverse MR findings were consistent with epidemiological associations for incident CKD in ORIGIN (OR = 1.28 per SD increase in TFF3; 95% CI, 1.18–1.38; P = 4.58 × 10 −10 ). Addition of TFF3 significantly improved discrimination for incident CKD relative to eGFR crea alone (net reclassification improvement = 0.211; P = 9.56 × 10 −12 ) and in models including additional risk factors. Conclusions: Our results suggest TFF3 is a valuable diagnostic marker for early CKD in dysglycemic populations and acts as a proof of concept for the application of this novel MR technique to identify diagnostic biomarkers for other chronic diseases.