Abstract
Chronic kidney disease (CKD) causes progressive damage to kidney function with increased inflammation. This process contributes to complex amino acid changes. Indoleamine 2,3-dioxygenase (IDO) has been proposed as a new biomarker of CKD in previous studies. In our research, we performed a metabolite genome-wide association study (mGWAS) to identify common and rare variants associated with IDO activity in a Korean population. In addition, single-nucleotide polymorphisms (SNPs) selected through mGWAS were further analyzed for associations with the estimated glomerular filtration rate (eGFR) and CKD. A total of seven rare variants achieved the genome-wide significance threshold (p < 1 × 10−8). Among them, four genes (TNFRSF19, LOC105377444, LOC101928535, and FSTL5) associated with IDO activity showed statistically significant associations with eGFR and CKD. Most of these rare variants appeared specifically in an Asian geographic region. Furthermore, 15 common variants associated with IDO activity were detected in this study and five novel genes (RSU1, PDGFD, SNX25, LOC107984031, and UBASH3B) associated with CKD and eGFR were identified. This study discovered several loci for IDO activity via mGWAS and provided insight into the underlying mechanisms of CKD through association analysis with CKD. To the best of our knowledge, this is the first study to suggest a genetic link between IDO activity and CKD through comparative and integrated analysis.
Highlights
Chronic kidney disease (CKD) is caused by several factors, including diabetes, high blood pressure, and glomerulonephritis [1]
CKD is strongly associated with IDO activity, which degrades tryptophan to kynurenine in the kynurenine pathway [36]
IDO activity was positively correlated with CKD (OR = 12.65, 95% CI: 6.55–24.44) in a Korean population [21]
Summary
Chronic kidney disease (CKD) is caused by several factors, including diabetes, high blood pressure, and glomerulonephritis [1]. Metabolites that play important roles in numerous biological pathways are known as potential biomarkers of several diseases, including CKD [8,9,10]. Previous studies have reported that it is difficult to use creatinine to detect early kidney damage [12,13]. For this reason, new biomarkers that can identify kidney damage at an early stage are needed. Indoleamine 2,3-dioxygenase (IDO) is an enzyme involved in the metabolism of tryptophan belonging to the kynurenine pathway It is induced by pro-inflammatory cytokines [14]. To the best of our knowledge, metabolite GWAS (mGWAS) for IDO activity associated with CKD has not been reported yet. To find a biological link between genetic loci and CKD, we further analyzed associations of single-nucleotide polymorphisms (SNPs) related to IDO activity with CKD and eGFR
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