Genetic associations of RAAS genes and chronic kidney disease: a systematic review and meta-analysis

Background Chronic kidney disease (CKD) and cardiovascular disease (CVD) are increasing public health burdens worldwide. The renin-angiotensin-aldosterone system (RAAS) regulates arterial blood pressure, extracellular volume, vascular resistance and tissue perfusion. RAAS activation is directly implicated in the progression of both CKD and CVD. RAAS blockade, using drugs targeting individual RAAS mediators and receptors, has proven to be both reno- and cardio-protective. Single nucleotide polymorphisms (SNPs) within RAAS genes - angiotensin-converting enzyme 1 (ACE1), angiotensinogen (AGT), angiotensin II receptor type 1 (AGTR1), angiotensin II receptor type 2 (AGTR2) and renin (REN) - have been evaluated for association with CKD, however their role as risk factors remains undetermined. Objectives To evaluate the association of RAAS gene polymorphisms with CKD using the largest population available (n=46,827). Research methods We performed a systematic review and meta-analysis to evaluate RAAS gene polymorphisms in CKD using both PubMed and Web of Science databases. Eligible papers included were published prior to January 2017 and matched the following criteria: humans, research case-control studies, genotype/allele frequencies, available data, kidney disease and English/Spanish language. Each individual RAAS gene polymorphism had to have been reported in at least three papers. Following further quality control, 108 studies met the inclusion criteria. This allowed for analysis of the influence of 12 variants located within ACE1, AGT, AGTR1 and REN. No SNPs within AGTR2 met all of the inclusion criteria. Results Significant associations were identified for rs699 located within AGT (OR=0.88; CI95%=0.79-0.97; P=0.01; I2=78%) and both rs4311 (OR=1.17; CI95%=1.04-1.32; P=0.009; I2=0%) and an insertion/deletion polymorphism (OR=0.83; CI95%=0.75-0.90; P=<0.0001; I2=83%) located within ACE1. Conclusions Through this analysis, two SNPs and one insertion/deletion polymorphism are significantly associated with CKD. Further genome-wide association studies and functional analyses of the RAAS gene polymorphisms will help define how variation in components of the RAAS pathway contributes to CKD.