Nitride oxide synthase 3 and klotho gene polymorphisms in the pathogenesis of chronic kidney disease and age-related cognitive impairment: a systematic review and meta-analysis

Background: While it has been known that the development of chronic kidney disease (CKD) and age-related cognitive impairment involves several mediators, the evidence in clinical practice only reveals nitride oxide synthase (NOS) and klotho. However, the evidence for this topic is conflicted. The aim of this study was to assess the role of NOS and klotho single nucleotide polymorphisms (SNPs) in the pathogenesis of CKD and age-related cognitive impairment. Methods: We performed a meta-analysis during October to December 2019. Paper collection was performed in major scientific websites, and we extracted information of interest from each paper. Data were analyzed using a Z-test with either random or fixed effect model. Results: Our initial assessment identified NOS3 G894T, NOS3 T786C, NOS3 4b/4a, klotho ( KL ) G395A, and KL C1818T as the gene candidate for our meta-analysis. Our pooled calculation revealed that NOS3 G894T was associated with the risk of both age-related cognitive impairment and CKD. Increased susceptibility to age-related cognitive impairment was observed in the GG genotype, and increased risk of CKD was found in patients with a single T allele and TT genotype for NOS3 nucleotide 894. For NOS3 4b/4a, increased risk of CKD was only found in 4a4a genotype. For NOS3 T786C, we failed to show the association with both CKD and age-related cognitive impairment. Subsequently, for KL G395A, A allele and GA genotype were found to correlate with increased susceptibility to CKD, while its correlation to age-related cognitive impairment was failed to clarify. For KL C1818T, our analysis failed to find the correlation with the risk of CKD. Conclusions: Our results reveal that the NOS3 G894T gene polymorphism has a crucial role in the pathogenesis of both CKD and age-related cognitive impairment.