SLC6A19 (BOAT1) Allelic Series: Loss of Function Is Associated with Improved Kidney Function

Background: Chronic kidney disease (CKD) remains a significant health burden despite recent advances in care, including development of inhibitors of the sodium-dependent glucose transporter SLC5A2 (SGLT2). A burden test incorporating predicted loss of function (pLOF) and rare missense variants (MAF <1%) identified SLC6A19 as among the strongest effects in the genome for improved kidney function (UK biobank: serum creatinine, beta = -0.13, p = 4.58e-35). The gene SLC6A19 encodes the protein BoAT1, a sodium-dependent neutral amino acid transporter involved in the uptake of free amino acids from the diet and minimizing loss of amino acids via the urin Methods: Here, we built an allelic series of variants that impact SLC6A19 function or expression levels composed of aggregated pLOF and rare predicted damaging missense variants, a known hypomorphic missense variant (D173N, rs121434346), and an eQTL variant (rs11133665). We then tested these variants for an association to biomarkers of kidney function and disease risk across multiple biobanks. Results: A meta-analysis for serum creatinine, a marker of kidney function, was performed across multiple large-scale datasets (UK Biobank, deCODE, CKDGen: > 600,000 individuals). The hypomorphic variant D173N (rs121434346) is associated with decreased serum creatinine (beta: -0.15, p: 7.2e-24) in deCODE and UK Biobank meta-analysis. Aggregated UK Biobank pLOF variants (beta: -0.15, p: 1.02e-04) and missense variants (MAF<0.001) (beta: -0.08, p-value: 3e-13) are associated with decreased serum creatinine. Consistent results for the SLC6A19 allelic series were obtained for estimated glomerular filtration rate (eGFR) and serum cystatin C, suggesting loss of function of SLC6A19 is associated with improved markers of kidney function. Conclusion: An allelic series of functional SLC6A19 variants is robustly associated with serum and urine markers related to kidney function, with loss of function of SLC6A19 conferring reno-protection, and suggests inhibition of SLC6A19 is a potential therapeutic approach for CKD. Funding: Commercial Support - Maze Therapuetics