Abstract
Patients with chronic kidney disease (CKD) have a 4-fold increased risk of developing apparent treatment-resistant hypertension (aTRH) compared with the general population. This study aimed to identify key genes and pathways associated with aTRH based on data from the Chronic Renal Insufficiency Cohort (CRIC) study. In this study, 823,094 whole-genome single-nucleotide polymorphisms (SNPs) of 3,024 patients (1,215 with aTRH defined by 2018 American Heart Association Scientific Statements and 1,809 without aTRH) were used for the analysis. First, we identified 997 significant (p<0.05) genes associated with aTRH using the SNP-set kernel association test (SKAT) analysis after controlling for race, gender, body mass index, and diabetes. The top 5 significant genes identified were NMNAT3 (p=1.2х10-4, coding for an enzyme that catalyzes nicotinamide adenine dinucleotide synthesis), SLC2A13 (p=1.4х10-4, coding for a glucose transporter), PTBP1 (p=1.7х10-4, coding for an RNA-binding protein that controls alternative splicing), IZUMO4 (p=1.9х10-4, coding for a protein that facilitates fertilization), and CCDC9 (p=1.9х10-4, coding for coiled-coil domain-containing protein 9). Next, we performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses based on significant genes obtained from SKAT analysis. The identified top 5 GO pathways were “Metaphase plate congression” (p=1.3х10-4), “Histone deacetylase binding” (p=1.3х10-4), “Transcription regulatory region DNA binding” (p=1.7х10-4), “Cytokine-mediated signaling pathway” (p=1.8х10-4), and “Phosphotyrosine residue binding” (p=6.6х10-4). The top 5 KEGG pathways identified were “RNA degradation” (p=1.1х10-4), “Viral carcinogenesis” (p=1.5х10-4), “PD-L1 expression and PD-1 checkpoint pathway in cancer” (p=5.2х10-4), “NF-kappa B signaling pathway” (p=6.5х10-4) and “Bacterial invasion of epithelial cells” (p=9.6х10-4). Thus, these findings may provide new insights into molecular mechanisms underlying aTRH in patients with chronic kidney disease, e.g., the NF-kappa B signaling pathway may contribute to the development of aTRH through enhanced inflammatory responses.
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