| Publication Abstract Display | | Type: Published Abstract | | Title: Mitochondrial DNA haplogroups and CSF neuroinflammation in the CHARTER cohort. | | Authors: Hulgan T, Samuels D, Ellis R, Bush W, Letendre S, Franklin D, Grant I, Kallianpur A | | Year: 2015 | | Publication: 2015 Annual Conference on Retroviruses and Opportunistic Infections | | Volume: Issue: Pages: | | Abstract:Background: Neurocognitive impairment (NCI) remains an important complication in the combination antiretroviral
therapy (CART) era, and is associated with neuroinflammation in cerebrospinal fluid (CSF). Mitochondrial DNA
(mtDNA) haplogroups are ancestry-related patterns of single-nucleotide polymorphisms that are associated with
differential mitochondrial function in model systems, neurodegenerative diseases in HIV-uninfected populations, and
HIV- and CART-associated outcomes in HIV-infected persons. We hypothesized that mtDNA haplogroups would be
associated with neuroinflammation in HIV-infected adults.
Methods: CHARTER is a U.S.-based observational study of HIV-infected adults who underwent standardized
neurocognitive assessments. Participants without confounding neurocognitive comorbidities and who consented to
DNA collection underwent mtDNA sequencing from whole blood. A subset also underwent lumbar puncture. IL-6, IL-8,
TNF-α (high-sensitivity), VEGF, IP-10, and novel soluble biomarkers of brain iron homeostasis, antioxidant defense,
and inflammation- ceruloplasmin (CP) and haploglobin (HP)- were measured in CSF by immunoassay. Haplogroups
were assigned using HaploGrep. Multivariable regression of mtDNA haplogroups and log-transformed CSF
biomarkers were stratified by genetic ancestry using whole-genome nuclear DNA genotyping (European [EA], African
[AA], or admixed Hispanic ancestry [HA]), and adjusted for age, sex, CART, detectable CSF HIV RNA, and CD4 nadir.
Results: Haplogroups could be assigned in 385 subjects with evaluable CSF (45% EA, 44% AA, 11% HA, 20%
female, median age 43 years, CD4 nadir 175 cells/mm3, 74% on CART). Statistically significant adjusted haplogroupbiomarker
associations included higher IP-10 in HA subjects with haplogroup B (N=12; p=0.03) and higher CP with
haplogroups L1 (N=32) and L2 (N=52) in AA subjects (p=0.02 and 0.01, respectively). Among EA subjects, mtDNA
haplogroups were not significantly associated with these CSF biomarkers. Several additional associations of IL-6, IL-
8, IP-10, and TNF-α with age, sex, CD4 nadir, CSF HIV detectability, and CART were observed independent of
mtDNA haplogroup.
Conclusions: We observed associations between mtDNA haplogroups and CSF IP-10 and CP in HA and AA
CHARTER subjects, respectively, independent of other potential confounders. These preliminary results suggest
novel mechanisms of neuroinflammation and perhaps NCI that merit further exploration. |
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