Acylcarnitines and Genetic Variation in Fat Oxidation Genes in HIV-infected, Antiretroviral-treated Children With and Without Myopathy

the Pediatric HIV/AIDS Cohort Study

doi:10.1097/INF.0000000000003586

Acylcarnitines and Genetic Variation in Fat Oxidation Genes in HIV-infected, Antiretroviral-treated Children With and Without Myopathy

the Pediatric HIV/AIDS Cohort Study

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Mitochondrial toxicity resulting in myopathy and lactic acidosis has been described in antiretroviral (ARV)-exposed patients. We hypothesized that myopathy in HIV-infected, ARV-treated children would be associated with metabolic (acylcarnitines) and genetic (variants in metabolic genes) markers of dysfunctional fatty acid oxidation (FAO). Methods: Acylcarnitine profiles (ACP) were analyzed for 74 HIV-infected children on nucleoside reverse transcriptase inhibitor (NRTI)-containing ARV. Thirty-seven participants with ≥2 creatine kinase measurements >500 IU (n = 18) or evidence of echocardiographic cardiomyopathy (n = 19) were matched with 37 participants without myopathy. Single nucleotide polymorphisms (SNPs) in FAO genes were also evaluated. Results: Abnormal ACP was 73% (95% CI: 56%-86%) and 62% (95% CI: 45%-78%) in the myopathic and nonmyopathic groups, respectively. No significant association was found between myopathy and having an abnormal ACP (OR = 2.10, P = 0.22). In univariate analysis, a 1-year increase in NRTI use was associated with a 20% increase in odds of at least 1 ACP abnormality [OR (95% CI) = 1.20 (1.03-1.41); P = 0.02), and a 1-year increase in protease inhibitor use was associated with 28% increase in the odds of having at least 1 ACP abnormality [OR (95% CI) = 1.28 (1.07-1.52); P = 0.006). Three SNPs, all in the gene for the carnitine transporter (SLC22A5), were associated with the cardiomyopathy phenotype. Conclusion: FAO appears to be altered in HIV-infected children with and without myopathy, but abnormal FAO does not fully explain myopathy in ARV-exposed children. Further study of SLC22A5 variation in ARV-exposed people is warranted carnitine transporter dysfunction-related cardiomyopathy may be treatable.

Original language	English (US)
Pages (from-to)	E306-E311
Journal	Pediatric Infectious Disease Journal
Volume	41
Issue number	8
DOIs	https://doi.org/10.1097/INF.0000000000003586
State	Published - Aug 1 2022

Funding

The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, the National Cancer Institute, the National Institute on Alcohol Abuse and Alcoholism, the Office of AIDS Research, and the National Heart, Lung, and Blood Institute through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102) (Principal Investigator: George R Seage III; Program Director: Liz Salomon) and the Tulane University School of Medicine (HD052104) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Ellen Chadwick; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson). This study is funded by National Institutes of Health (full funding statement below). B.M.K’s effort on this work was partially funded through the following awards from the National Institutes of Health: UL1TR000075 and KL2TR000076.

Keywords

HIV
acylcarnitines
cardiomyopathy
fatty acid oxidation
myopathy

ASJC Scopus subject areas

Pediatrics, Perinatology, and Child Health
Microbiology (medical)
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1097/INF.0000000000003586

Cite this

@article{f764c55c2d264a66b50e696814c31986,

title = "Acylcarnitines and Genetic Variation in Fat Oxidation Genes in HIV-infected, Antiretroviral-treated Children With and Without Myopathy",

abstract = "Background: Mitochondrial toxicity resulting in myopathy and lactic acidosis has been described in antiretroviral (ARV)-exposed patients. We hypothesized that myopathy in HIV-infected, ARV-treated children would be associated with metabolic (acylcarnitines) and genetic (variants in metabolic genes) markers of dysfunctional fatty acid oxidation (FAO). Methods: Acylcarnitine profiles (ACP) were analyzed for 74 HIV-infected children on nucleoside reverse transcriptase inhibitor (NRTI)-containing ARV. Thirty-seven participants with ≥2 creatine kinase measurements >500 IU (n = 18) or evidence of echocardiographic cardiomyopathy (n = 19) were matched with 37 participants without myopathy. Single nucleotide polymorphisms (SNPs) in FAO genes were also evaluated. Results: Abnormal ACP was 73% (95% CI: 56%-86%) and 62% (95% CI: 45%-78%) in the myopathic and nonmyopathic groups, respectively. No significant association was found between myopathy and having an abnormal ACP (OR = 2.10, P = 0.22). In univariate analysis, a 1-year increase in NRTI use was associated with a 20% increase in odds of at least 1 ACP abnormality [OR (95% CI) = 1.20 (1.03-1.41); P = 0.02), and a 1-year increase in protease inhibitor use was associated with 28% increase in the odds of having at least 1 ACP abnormality [OR (95% CI) = 1.28 (1.07-1.52); P = 0.006). Three SNPs, all in the gene for the carnitine transporter (SLC22A5), were associated with the cardiomyopathy phenotype. Conclusion: FAO appears to be altered in HIV-infected children with and without myopathy, but abnormal FAO does not fully explain myopathy in ARV-exposed children. Further study of SLC22A5 variation in ARV-exposed people is warranted carnitine transporter dysfunction-related cardiomyopathy may be treatable.",

keywords = "HIV, acylcarnitines, cardiomyopathy, fatty acid oxidation, myopathy",

author = "{the Pediatric HIV/AIDS Cohort Study} and Brian Kirmse and Charlotte Hobbs and Lisa Aaron and Grace Montepiedra and Marshall Summar and Williams, {Paige L.} and Smith, {Caitlin J.} and {Van Dyke}, Russell and Chunli Yu and Ryckman, {Kelli K.} and William Borkowsky and Ellen Chadwick and Sanders, {Margaret Ann} and Kathleen Malee and Yoonsun Pyun and Mary Paul and Shelley Buschur and Chivon McMullen-Jackson and Lynnette Harris and Murli Purswani and Baig, {Mahboobullah Mirza} and Alma Villegas and Robinson, {Lisa Gaye} and Sandra Navarro and Patricia Garvie and Burchett, {Sandra K.} and Rebecca Pinsky and Cassidy, {Adam R.} and Andrew Wiznia and Marlene Burey and Ray Shaw and Arry Dieudonne and Linda Bettica and Juliette Johnson and Karen Surowiec and Chen, {Janet S.} and Taesha White and Mitzie Grant and Katherine Knapp and Jamie Russell-Bell and Megan Wilkins and Erick Odero and Midnela Acevedo-Flores and Heida Rios and Vivian Olivera and Margarita Silio and Medea Gabriel and Patricia Sirois and Spector, {Stephen A.} and Megan Loughran",

year = "2022",

month = aug,

day = "1",

doi = "10.1097/INF.0000000000003586",

language = "English (US)",

volume = "41",

pages = "E306--E311",

journal = "Pediatric Infectious Disease Journal",

issn = "0891-3668",

publisher = "Lippincott Williams and Wilkins",

number = "8",

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TY - JOUR

T1 - Acylcarnitines and Genetic Variation in Fat Oxidation Genes in HIV-infected, Antiretroviral-treated Children With and Without Myopathy

AU - the Pediatric HIV/AIDS Cohort Study

AU - Kirmse, Brian

AU - Hobbs, Charlotte

AU - Aaron, Lisa

AU - Montepiedra, Grace

AU - Summar, Marshall

AU - Williams, Paige L.

AU - Smith, Caitlin J.

AU - Van Dyke, Russell

AU - Yu, Chunli

AU - Ryckman, Kelli K.

AU - Borkowsky, William

AU - Chadwick, Ellen

AU - Sanders, Margaret Ann

AU - Malee, Kathleen

AU - Pyun, Yoonsun

AU - Paul, Mary

AU - Buschur, Shelley

AU - McMullen-Jackson, Chivon

AU - Harris, Lynnette

AU - Purswani, Murli

AU - Baig, Mahboobullah Mirza

AU - Villegas, Alma

AU - Robinson, Lisa Gaye

AU - Navarro, Sandra

AU - Garvie, Patricia

AU - Burchett, Sandra K.

AU - Pinsky, Rebecca

AU - Cassidy, Adam R.

AU - Wiznia, Andrew

AU - Burey, Marlene

AU - Shaw, Ray

AU - Dieudonne, Arry

AU - Bettica, Linda

AU - Johnson, Juliette

AU - Surowiec, Karen

AU - Chen, Janet S.

AU - White, Taesha

AU - Grant, Mitzie

AU - Knapp, Katherine

AU - Russell-Bell, Jamie

AU - Wilkins, Megan

AU - Odero, Erick

AU - Acevedo-Flores, Midnela

AU - Rios, Heida

AU - Olivera, Vivian

AU - Silio, Margarita

AU - Gabriel, Medea

AU - Sirois, Patricia

AU - Spector, Stephen A.

AU - Loughran, Megan

PY - 2022/8/1

Y1 - 2022/8/1

N2 - Background: Mitochondrial toxicity resulting in myopathy and lactic acidosis has been described in antiretroviral (ARV)-exposed patients. We hypothesized that myopathy in HIV-infected, ARV-treated children would be associated with metabolic (acylcarnitines) and genetic (variants in metabolic genes) markers of dysfunctional fatty acid oxidation (FAO). Methods: Acylcarnitine profiles (ACP) were analyzed for 74 HIV-infected children on nucleoside reverse transcriptase inhibitor (NRTI)-containing ARV. Thirty-seven participants with ≥2 creatine kinase measurements >500 IU (n = 18) or evidence of echocardiographic cardiomyopathy (n = 19) were matched with 37 participants without myopathy. Single nucleotide polymorphisms (SNPs) in FAO genes were also evaluated. Results: Abnormal ACP was 73% (95% CI: 56%-86%) and 62% (95% CI: 45%-78%) in the myopathic and nonmyopathic groups, respectively. No significant association was found between myopathy and having an abnormal ACP (OR = 2.10, P = 0.22). In univariate analysis, a 1-year increase in NRTI use was associated with a 20% increase in odds of at least 1 ACP abnormality [OR (95% CI) = 1.20 (1.03-1.41); P = 0.02), and a 1-year increase in protease inhibitor use was associated with 28% increase in the odds of having at least 1 ACP abnormality [OR (95% CI) = 1.28 (1.07-1.52); P = 0.006). Three SNPs, all in the gene for the carnitine transporter (SLC22A5), were associated with the cardiomyopathy phenotype. Conclusion: FAO appears to be altered in HIV-infected children with and without myopathy, but abnormal FAO does not fully explain myopathy in ARV-exposed children. Further study of SLC22A5 variation in ARV-exposed people is warranted carnitine transporter dysfunction-related cardiomyopathy may be treatable.

AB - Background: Mitochondrial toxicity resulting in myopathy and lactic acidosis has been described in antiretroviral (ARV)-exposed patients. We hypothesized that myopathy in HIV-infected, ARV-treated children would be associated with metabolic (acylcarnitines) and genetic (variants in metabolic genes) markers of dysfunctional fatty acid oxidation (FAO). Methods: Acylcarnitine profiles (ACP) were analyzed for 74 HIV-infected children on nucleoside reverse transcriptase inhibitor (NRTI)-containing ARV. Thirty-seven participants with ≥2 creatine kinase measurements >500 IU (n = 18) or evidence of echocardiographic cardiomyopathy (n = 19) were matched with 37 participants without myopathy. Single nucleotide polymorphisms (SNPs) in FAO genes were also evaluated. Results: Abnormal ACP was 73% (95% CI: 56%-86%) and 62% (95% CI: 45%-78%) in the myopathic and nonmyopathic groups, respectively. No significant association was found between myopathy and having an abnormal ACP (OR = 2.10, P = 0.22). In univariate analysis, a 1-year increase in NRTI use was associated with a 20% increase in odds of at least 1 ACP abnormality [OR (95% CI) = 1.20 (1.03-1.41); P = 0.02), and a 1-year increase in protease inhibitor use was associated with 28% increase in the odds of having at least 1 ACP abnormality [OR (95% CI) = 1.28 (1.07-1.52); P = 0.006). Three SNPs, all in the gene for the carnitine transporter (SLC22A5), were associated with the cardiomyopathy phenotype. Conclusion: FAO appears to be altered in HIV-infected children with and without myopathy, but abnormal FAO does not fully explain myopathy in ARV-exposed children. Further study of SLC22A5 variation in ARV-exposed people is warranted carnitine transporter dysfunction-related cardiomyopathy may be treatable.

KW - HIV

KW - acylcarnitines

KW - cardiomyopathy

KW - fatty acid oxidation

KW - myopathy

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AN - SCOPUS:85134632079

SN - 0891-3668

VL - 41

SP - E306-E311

JO - Pediatric Infectious Disease Journal

JF - Pediatric Infectious Disease Journal

IS - 8

ER -

Acylcarnitines and Genetic Variation in Fat Oxidation Genes in HIV-infected, Antiretroviral-treated Children With and Without Myopathy

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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