Abstract
Pharmacogenomics is a field with origins in the study of monogenic variations in drug metabolism in the 1950s. Perhaps because of these historical underpinnings, there has been an intensive investigation of 'hepatic pharmacogenes' such as CYP450s and liver drug metabolism using pharmacogenomics approaches over the past five decades. Surprisingly, kidney pathophysiology, attendant diseases and treatment outcomes have been vastly under-studied and under-theorized despite their central importance in maintenance of health, susceptibility to disease and rational personalized therapeutics. Indeed, chronic kidney disease (CKD) represents an increasing public health burden worldwide, both in developed and developing countries. Patients with CKD suffer from high cardiovascular morbidity and mortality, which is mainly attributable to cardiovascular events before reaching end-stage renal disease. In this paper, we focus our analyses on renal function before end-stage renal disease, as seen through the lens of pharmacogenomics and human genomic variation. We herein synthesize the recent evidence linking selected Very Important Pharmacogenes (VIP) to renal function, blood pressure and salt-sensitivity in humans, and ways in which these insights might inform rational personalized therapeutics. Notably, we highlight and present the rationale for three applications that we consider as important and actionable therapeutic and preventive focus areas in renal pharmacogenomics: 1) ACE inhibitors, as a confirmed application, 2) VDR agonists, as a promising application, and 3) moderate dietary salt intake, as a suggested novel application. Additionally, we emphasize the putative contributions of gene-environment interactions, discuss the implications of these findings to treat and prevent hypertension and CKD. Finally, we conclude with a strategic agenda and vision required to accelerate advances in this under-studied field of renal pharmacogenomics with vast significance for global public health.
Highlights
Chronic kidney disease (CKD) represents an increasing public health burden [1]
The frequency of the CYP3A5*3 allele is significantly correlated with distance from the equator and has similar geographic distribution than the AGT M235T, a variant associated with blood pressure and hypertension [69]
We found the 3435T ABCB1 and CYP3A5*1 variants to interact with dietary salt intake for their effect on ambulatory blood pressure [30]
Summary
Chronic kidney disease (CKD) represents an increasing public health burden [1]. CKD prevalence in adults varies from 5% to 16% worldwide [2,3,4,5,6]. A large collaborative meta-analysis including longitudinal data on more than 100,000 participants found that eGFR below 75 ml/min/1.73m2 and an UACR above 5 mg/g started to be associated with all-cause and cardiovascular mortality, independently of each other [11]. The kidney is a key organ for the balance of many endogenous and exogenous compounds including drugs. Some substances need to be actively maintained in the body (e.g., glucose, amino acids, etc.), while others need to be eliminated (e.g. urea, uric acid, exogenous compounds, etc.). When managing these various processes, the kidney may be damaged by the action of nephrotoxic substances (either endogenous or exogenous). Drugs used to treat renal pathologies acting on a protein encoded by a pharmacogene
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