Associations of FGF21 and GDF15 with mitochondrial dysfunction in children living with perinatally-acquired HIV: A cross-sectional evaluation of pediatric AIDS clinical trials group 219/219C.

Greg S Gojanovich,Marilyn Crain,Elizabeth J Mcfarland,Margarita Silio,Mariana Gerschenson,Brian Kirmse,Mitchell E Geffner,Carly Broadwell,Russell B Van Dyke,Denise L Jacobson,Jennifer Jao,Brad Karalius,Qigui Yu

doi:10.1371/journal.pone.0261563

Abstract

In persons living with HIV, mitochondrial disease (MD) is difficult to diagnose, as clinical signs are non-specific with inconsistent patterns. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are mitokines elevated in MD patients without HIV, and associated with cardiometabolic comorbidities in adults living with HIV. We assessed relationships of these biomarkers with MD in children living with perinatally-acquired HIV infection (CPHIV). Cross-sectional study of CPHIV from Pediatric ACTG 219/219C classified by Mitochondrial Disease Criteria (MDC) that defines scores 2-4 as "possible" MD. Each case with MDC equaling 4 (MDC4; n = 23) was matched to one randomly selected control displaying no MDC (MDC0; n = 23) based on calendar date. Unmatched cases with MDC equaling 3 (MDC3; n = 71) were also assessed. Plasma samples proximal to diagnoses were assayed by ELISA. Mitokine distributions were compared using Wilcoxon tests, Spearman correlations were calculated, and associations with MD status were assessed by conditional logistic regression. Median FGF21 and GDF15 concentrations, respectively, were highest in MDC4 (143.9 and 1441.1 pg/mL), then MDC3 (104.0 and 726.5 pg/mL), and lowest in controls (89.4 and 484.7 pg/mL). Distributions of FGF21 (paired Wilcoxon rank sum p = 0.002) and GDF15 (paired Wilcoxon rank sum p<0.001) differed in MDC4 vs MDC0. Mitokine concentrations were correlated across all participants (r = 0.33; p<0.001). Unadjusted odds ratios of being MDC4 vs MDC0 were 5.2 [95% confidence interval (CI): 1.06-25.92] for FGF21 and 3.5 (95%CI: 1.19-10.25) for GDF15. Relationships persisted after covariate adjustments. FGF21 and GDF15 levels may be useful biomarkers to screen for CPHIV with mitochondrial dysfunction.

Highlights

Mitochondrial dysfunction, without intervention, can result in multi-organ diseases that severely impact quality of life
Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels may be useful biomarkers to screen for children living with perinatally-acquired HIV infection (CPHIV) with mitochondrial dysfunction
Increased mitochondrial dysfunction, indicated by reduced mitochondrial DNA or oxidative phosphorylation (OXPHOS) levels, and interrelated cardiometabolic complications, such as insulin resistance (IR) and cardiovascular disease, have been observed in children living with perinatally-acquired HIV infection (CPHIV)

Summary

Introduction

Mitochondrial dysfunction, without intervention, can result in multi-organ diseases that severely impact quality of life. Increased mitochondrial dysfunction, indicated by reduced mitochondrial DNA (mtDNA) or oxidative phosphorylation (OXPHOS) levels, and interrelated cardiometabolic complications, such as insulin resistance (IR) and cardiovascular disease, have been observed in children living with perinatally-acquired HIV infection (CPHIV). Biomarkers associated with dysfunction or overt mitochondrial disease (MD), e.g. symptoms meeting clinically-defined Mitochondrial Disease Criteria (MDC) of Wolf and Smeitink [1], in CPHIV have not been validated as done for adults and children living in the absence of HIV infection [2, 3]. FGF21 and GDF15 are biomarkers for MD in non-HIV settings, and are indicators of cardiometabolic complications in adults living with HIV. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are mitokines elevated in MD patients without HIV, and associated with cardiometabolic comorbidities in adults living with HIV. Cross-sectional study of CPHIV from Pediatric ACTG 219/219C classified by Mitochondrial Disease Criteria (MDC) that defines scores 2–4 as “possible” MD

Methods

Results

Conclusion