Synergistic effects of MBL2/APP polymorphisms on neurocognitive impairment in CHARTER.

Type: Poster
Title: Synergistic effects of MBL2/APP polymorphisms on neurocognitive impairment in CHARTER.
Authors: Singh K, Deng Q, Fennema-Notestine C, Vaida F, Ellis RJ, Letendre SL, Franklin D, Rosario D, Heaton RD, Grant I, and CHARTER Group
Year: 2015
Publication: Conference on Retroviruses and Opportunistic Infections

Background: Mannose binding lectin (MBL), coded by MBL2, recognizes mannose laden glycans on HIV-1 gp120 and activates complement for virus opsonization. Also, via its cysteine rich region, MBL interacts with amyloid beta (coded by APP) presumably for clearing it by complement mediated lyses. We hypothesized that the synergistic effects of polymorphisms in APP promoter (rs364048) that enhances APP expression and MBL2 variants with lower MBL (A/O: rs1800450; rs1800451; rs5030737; H/L: rs11003125; Y/X: rs7096206; and P/Q: rs7095891), will predict neurocognitive (NC) outcomes in HIV-infected adults.

Methods: Of 563 subjects from the CHARTER (CNS HIV AntiRetroviral Therapy Effects Research) longitudinal cohort, 399 were on highly active antiretroviral therapy (HAART), 79 on non-HAART and 85 were antiretroviral-naive. 244 subjects were evaluated with single voxel magnetic resonance spectroscopy for brain metabolites choline (CHO), creatine (CR), N-Acetylaspartate (NAA) and myo-inositol (MI) in frontal white matter (FWM), frontal gray matter (FGM) and basal ganglia using LC Model. Associations of genotypes with neuroimaging outcomes were cross-sectionally examined by multivariate linear regression. Analyses adjusted for comorbidity, current CD4>=200, nadir CD4>=200, detectable plasma/CSF HIV RNA, and HCV serostatus. NC endpoints included global deficit score (0-5), global neurocognitive impairment (NCI, yes/no), and HIV-associated neurocognitive disorders (HAND). Logistic regression for comparing genotypes and Bonferroni correction were used.

Results: Of 563 subjects, 79% were males; 54% White and 43% Black. Presence of APP rs364048 and MBL2-A/O variants was associated with abnormal FWM (p=0.014) and a strong trend for HAND in subjects on HAART (p=0.06). Presence of MBL2-P/Q and rs364048 in those with HAART predicted worse NCI (p=0.013) and HAND (Unimpaired<ANI<MND<HAD) (p=0.011). Cases with both MBL2-Y/X and rs364048, and on HAART were associated with NCI (p=0.047), HAND (p=0.033), and strong trends for higher FWM-NAA (p=0.047) and FWM-CR (p=0.06). Presence of MBL2-H/L and rs364048 in those on HAART also predicted higher FGM-NAA (p=0.012).

Conclusions: Synergistic effects of higher APP and lower MBL expression due to presence of MBL2/APP polymorphisms, potentially facilitate complement activation, neuroinflammation and brain abnormalities leading to neurocognitive impairment. MBL2/APP genotypes are potential predictive biomarkers for HAND