European Mitochondrial DNA Haplogroups are Associated with Cerebrospinal Fluid Biomarkers of Inflammation in HIV Infection.
BACKGROUND
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-negative populations, and chronic complications of HIV infection, including neurocognitive impairment. We hypothesized that mtDNA haplogroups are associated with neuroinflammation in HIV-infected adults.


METHODS
CNS HIV Antiretroviral Therapy Effects Research (CHARTER) is a US-based observational study of HIV-infected adults who underwent standardized neurocognitive assessments. Participants who consented to DNA collection underwent whole blood mtDNA sequencing, and a subset also underwent lumbar puncture. IL-6, IL-8, TNF-α (high-sensitivity), and IP-10 were measured in cerebrospinal fluid (CSF) by immunoassay. 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 Hispanic ancestry [HA]), and adjusted for age, sex, antiretroviral therapy (ART), detectable CSF HIV RNA, and CD4 nadir. A total of 384 participants had both CSF cytokine measures and genetic data (45% EA, 44% AA, 11% HA, 22% female, median age 43 years, 74% on ART).


RESULTS
In analyses stratified by the 3 continental ancestry groups, no haplogroups were significantly associated with the 4 biomarkers. In the subgroup of participants with undetectable plasma HIV RNA on ART, European haplogroup H participants had significantly lower CSF TNF-α (P= 0.001).


CONCLUSIONS
Lower CSF TNF-α may indicate lower neuroinflammation in the haplogroup H participants with well-controlled HIV on ART.
Vanderbilt Genetics Institute, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
David C
DC
Samuels
Genomic Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH.
Asha R
AR
Kallianpur
University of California San Diego, San Diego, CA.
Ronald J
RJ
Ellis
Case Western Reserve University, Cleveland, OH.
William S
WS
Bush
University of California San Diego, San Diego, CA.
Scott
S
Letendre
University of California San Diego, San Diego, CA.
Donald
D
Franklin
University of California San Diego, San Diego, CA.
Igor
I
Grant
Infectious Diseases, Vanderbilt University, Nashville, TN.
Todd
T
Hulgan
Cerebral Spinal Fluid; Cytokines; HIV; Inflammation; Interleukin-6; Interleukin-8; Mitochondrial DNA; Mitochondrial Haplogroups; Neuroinflammation; Tumor Necrosis Factor-alpha