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. 2016 Jul 17;30(11):1807-15.
doi: 10.1097/QAD.0000000000001124.

Host Genetic Predictors of the Kynurenine Pathway of Tryptophan Catabolism Among Treated HIV-infected Ugandans

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Free PMC article

Host Genetic Predictors of the Kynurenine Pathway of Tryptophan Catabolism Among Treated HIV-infected Ugandans

Sulggi A Lee et al. AIDS. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Schematic illustrating the potential contribution of IDO to ongoing immune dysfunction and increased risk of morbidity and mortality during treated HIV Infection. Abbreviations: IDO, indoleamine 2;3-dioxygenase; KT, kynurenine/tryptophan; 3-HAA, 3-hydroxyanthranilic acid; MΦ, macrophage; DC, dendritic cell; i-FABP, intestinal fatty acid binding protein; LPS, lipopolysaccharide; IFN-γ, interferon gamma; TNF-α , tumor necrosis factor alpha; TGF-β, transforming growth factor beta; sCD14, soluble CD14; sCD163, soluble CD163; IL-6, interleukin-6; sTNFR, soluble tumor necrosis factor receptor.
Figure 2
Figure 2
Manhattan plot for association analyses. Genome-wide association test results are shown as −log10transformed p-values for the linear mixed effects regression analyses of plasma log10KT ratio. Chromosomal location of SNPs is indicated on the x-axis. SNPs significantly (P<5.0×10−8) or suggestively (P<5.0×10−5) associated with plasma log10KT ratio are noted above the red or blue line, respectively.

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