Nuclear-Mitochondrial interactions influence susceptibility to HIV-associated neurocognitive impairment.

S Smieszek, P Jia, D C Samuels, Z Zhao, J Barnholtz-Sloan, H Kaur, S Letendre, R Ellis, D R Franklin, T Hulgan, A Kallianpur, W S Bush

Journal: Mitochondrion 2019;46():247-255

PMID: 30026132

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Abstract

HIV-associated neurocognitive impairment (NCI) is a term established to capture a wide spectrum of HIV related neurocognitive deficits ranging in severity from asymptomatic to dementia. The genetic underpinnings of this complex phenotype are incompletely understood. Mitochondrial function has long been thought to play a role in neurodegeneration, along with iron metabolism and transport. In this work, we aimed to characterize the interplay of mitochondrial DNA (mtDNA) haplogroup and nuclear genetic associations to NCI phenotypes in the CHARTER cohort, encompassing 1025 individuals of European-descent, African-descent, or admixed Hispanic. We first employed a polygenic modeling approach to investigate the global effect of previous marginally associated nuclear SNPs, and to examine how the polygenic effect of these SNPs is influenced by mtDNA haplogroups. We see evidence of a significant interaction between nuclear SNPs en masse and mtDNA haplogroups within European-descent and African-descent individuals. Subsequently, we performed an analysis of each SNP by mtDNA haplogroup, and detected significant interactions between two nuclear SNPs (rs17160128 and rs12460243) and European haplogroups. These findings, which require validation in larger cohorts, indicate a potential new role for nuclear-mitochondrial DNA interactions in susceptibility to NCI and shed light onto the pathophysiology of this neurocognitive phenotype.

Address: Department of Population and Quantitative Health Sciences, and Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, United States. Electronic address: [email protected].; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United States.; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States.; Department of Population and Quantitative Health Sciences, and Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, United States.; Department of Genomic Medicine, Lerner Research Institute and Department of Medicine, Cleveland Clinic, Cleveland, OH, United States.; Department of Medicine, University of California San Diego, San Diego, CA, United States.; School of Medicine, Vanderbilt University, Nashville, TN, United States.; Department of Genomic Medicine, Lerner Research Institute and Department of Medicine, Cleveland Clinic, Cleveland, OH, United States; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States.; Department of Population and Quantitative Health Sciences, and Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, United States; Department of Genomic Medicine, Lerner Research Institute and Department of Medicine, Cleveland Clinic, Cleveland, OH, United States.

DOI: 10.1016/j.mito.2018.07.004

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https://medlineplus.gov/hiv.html

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https://scite.ai/reports/30026132

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-NT5E-1

MeSH Terms: AIDS Dementia Complex, Cell Nucleus, Genetic Association Studies, HIV Infections, Haplotypes, Humans, Mitochondria, Mitochondrial Proteins, Nuclear Proteins, Polymorphism, Single Nucleotide, Prospective Studies, Racial Groups