Gene–metabolite–cardiac associations in the Chronic Kidney Disease in Children (CKiD) study

Background Characterizing gene–metabolite–cardiac associations in childhood chronic kidney disease (CKD) has the potential to identify new research directions or therapeutic targets for mitigating the excessive cardiovascular risk in childhood CKD. Methods The Chronic Kidney Disease in Children (CKiD) is a prospective cohort that recruited children with eGFR 30–90 ml/min/1.73 m 2 across 54 North American centers. Predictor and outcome variables included genotypes, metabolite levels, left ventricular mass index (LVMI) z-score, and left ventricular filling pressure (E/e’). Multivariable linear regression analyses assessed metabolite associations with either LVMI z-score or E/e’, adjusting for age, sex, CKD duration, glomerular etiology, renin-angiotensin-aldosterone-system blockade, hypertension, anemia, dyslipidemia, eGFR, and proteinuria. Significance was based on the Benjamini–Hochberg False Discovery Rate <0.05. Metabolites associated with cardiac markers were carried forward for a metabolite–genome-wide association study (mGWAS). Linear regression calculated the residual metabolite variability not explained by age, sex, and eGFR. Linear regression assessed metabolite residual variability versus genetic variant dosage at the Bonferroni-corrected genome-wide significance threshold (corrected for number of metabolites assessed). Results 556 unique participants with 574 metabolites and ~8.4 million SNPs were included. Sphingomyelin (d18:2/d18:1) and hypotaurine were associated with LVMI z-score. Isobutyrylglycine and 3beta-hydroxy-5-cholestenoate were associated with E/e’. Multiple genetic variants associated with these metabolites at p < 1.25E-8 ( p < [5E-8]/4, Bonferroni-corrected genome-wide significance threshold). Conclusions We identified metabolites associated with cardiac markers in children with CKD. We identified genetic associations with variability in these metabolites. Collectively, these gene–metabolite associations suggest roles for inflammation, increased oxidative stress, mitochondrial and energy dysmetabolism, and gut microbial dysbiosis in mediating cardiac pathology in childhood CKD.