Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans.

TitleHost genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans.
Publication TypeJournal Article
Year of Publication2016
AuthorsLee SA, Mefford JA, Huang Y, Witte JS, Martin JN, Haas DW, McLaren PJ, Mushiroda T, Kubo M, Byakwaga H, Hunt PW, Kroetz DL
JournalAIDS
Volume30
Issue11
Pagination1807-15
Date Published2016 Jul 17
ISSN1473-5571
Abstract

OBJECTIVE: Plasma kynurenine/tryptophan ratio, a biomarker of indoleamine 2,3-dioxygenase-1 (IDO) activity, is a strong independent predictor of mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART) and may play a key role in HIV pathogenesis. We performed a genome-wide study to identify potential host genetic determinants of kynurenine/tryptophan ratio in HIV-infected ART-suppressed Ugandans.

DESIGN/METHODS: We performed genome-wide and exome array genotyping and measured plasma kynurenine/tryptophan ratio during the initial 6-12 months of suppressive ART in Ugandans. We evaluated more than 16 million single nucleotide polymorphisms in association with log10 kynurenine/tryptophan ratio using linear mixed models adjusted for cohort, sex, pregnancy, and ancestry.

RESULTS: Among 597 Ugandans, 62% were woman, median age was 35, median baseline CD4 cell count was 135 cells/μl, and median baseline HIV-1 RNA was 5.1 log10 copies/ml. Several polymorphisms in candidate genes TNF, IFNGR1, and TLR4 were associated with log10 kynurenine/tryptophan ratio (P < 5.0 × 10). An intergenic polymorphism between CSPG5 and ELP6 was genome-wide significant, whereas several others exhibited suggestive associations (P < 5.0 × 10), including genes encoding protein tyrosine phosphatases (PTPRM and PTPRN2) and the vitamin D metabolism gene, CYP24A1. Several of these single nucleotide polymorphisms were associated with markers of inflammation, coagulation, and monocyte activation, but did not replicate in a small US cohort (N = 262; 33% African-American).

CONCLUSION: Our findings highlight a potentially important role of IFN-γ, TNF-α, and Toll-like receptor signaling in determining IDO activity and subsequent mortality risk in HIV-infected ART-suppressed Ugandans. These results also identify potential novel pathways involved in IDO immunoregulation. Further studies are needed to confirm these findings in treated HIV-infected populations.

DOI10.1097/QAD.0000000000001124
Alternate JournalAIDS
PubMed ID27088321
PubMed Central IDPMC4925250
Grant ListUM1 AI069501 / AI / NIAID NIH HHS / United States
R01 MH054907 / MH / NIMH NIH HHS / United States
P01 AI076174 / AI / NIAID NIH HHS / United States
K24 MH087227 / MH / NIMH NIH HHS / United States
T32 AI060530 / AI / NIAID NIH HHS / United States
K23 GM112526 / GM / NIGMS NIH HHS / United States
UM1 CA181255 / CA / NCI NIH HHS / United States
U01 GM061390 / GM / NIGMS NIH HHS / United States
T32 AA007240 / AA / NIAAA NIH HHS / United States
UM1 AI069496 / AI / NIAID NIH HHS / United States
P30 AI027763 / AI / NIAID NIH HHS / United States
R56 AI100765 / AI / NIAID NIH HHS / United States
R21 AI078774 / AI / NIAID NIH HHS / United States
L30 AA015293 / AA / NIAAA NIH HHS / United States