Mitochondrial DNA haplogroups and CSF neuroinflammation in the CHARTER cohort.

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: Conference on Retroviruses and Opportunistic Infections

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.