title: Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: aDepartment of Medicine bDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California cDepartment of Medicine, Vanderbilt University School of Medicine dDepartment of Medicine, Meharry Medical College, Nashville, Tennessee, USA eDepartment of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland fRIKEN Center for Genomic Medicine, Kanagawa, Japan gDepartment of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda.
authors.forename: Sulggi A
authors.initials: SA
authors.lastname: Lee
authors.forename: Joel A
authors.initials: JA
authors.lastname: Mefford
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Martin
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Mclaren
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Helen
authors.initials: H
authors.lastname: Byakwaga
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hunt
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kroetz
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007737:Kynurenine / Q000097:blood / Q000378:metabolism*; D008297:Male; D008660:Metabolism; D010949:Plasma / Q000737:chemistry; D018570:Risk Assessment; D015398:Signal Transduction; D016019:Survival Analysis; D051193:Toll-Like Receptors / Q000378:metabolism; D014364:Tryptophan / Q000097:blood / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014454:Uganda
chemical_list: D044966:Anti-Retroviral Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan