| Publication Abstract Display | | Type: Poster | | Title: MBL2 promoter polymorphism rs7096206 predicts brain metabolite anomalies in HIV-infected adults. | | Authors: Singh K, Vaida F, Fennema-Notestine C, Ellis R, Letendre S, Franklin D, Deng Q, Rosario D, Corkran S, Heaton R, Grant I, and CHARTER Group | | Date: 03-03-2014 | | Abstract:Background: Complement mediated neuroinflammation is implicated in several neurodegenerative diseases. Complement 3 (C3) plays a key role in the complement cascade as its proteolytic fragments stimulate proinflammatory responses. Complementary factor H (CFH) regulates C3 activity and it can alter immune complex mediated neuroinflammatory responses. We hypothesized that loss of CFH function due to presence of a missense rs534399-G/T polymorphism (Val1007Leu codon change) will impair complement regulation leading to immune complex deposition, neuroinflammatory responses and neurocognitive impairment in HIV-infected adults.
Methods: 562 subjects from the CHARTER cohort were evaluated by logistic regression for association of CFH polymorphisms and clinical outcomes at baseline and longitudinally. Global impairment, inclusion review, race, sex, age, AIDS, CD4, nadir CD4, undetectable plasma/CSF, and antiretroviral status were included in the cross-sectional analysis. Functions between genes and correlated index were analyzed by logistic regression. Rs534399-G/T associations with brain structural volumes and single voxel magnetic resonance spectroscopy were cross-sectionally examined by linear regression in 244 subjects.
Results: Of the total 562 subjects studied, 79% were male; 44% White, 43% Black, and 11% were Hispanic. For rs534399-G/T polymorphism, wild type G/G, heterozygote G/T and homozygote variant T/T genotypes were present in 78.2%, 19.5% and 2.3% individuals respectively. Distribution of the genotypes did not differ by race/ethnicity, sex, age or AIDS diagnosis. The presence of rs534399-T allele was associated with the reduced odds of improvement in neurocognitive functioning over time (OR=0.58 [0.32, 0.95], p=0.04). In a novel correlation of neuroimaging volumetric data, the presence of T allele was associated with 17% less subcortical gray matter ([2.5%, 33.5%], p=0.009). Furthermore, the presence of T allele was associated with 12% more abnormal white matter ([1.3%, 22%], p=0.04). Neuroimaging volumetric analyses controlled for scanner and brain size.
Conclusions: Loss of CFH function due to the presence of rs534399-T allele was associated with neurocognitive impairment, loss of subcortical gray matter and presence of abnormal white matter in HIV-1 infected brain. CFH deficiency potentially leads to impairment of local complement regulation and homeostasis resulting in immune complex deposition, neuroinflammation and neurocognitive impairment. |
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