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Whole Genome Analysis Identifies a Susceptibility Locus to HIV-1
Corinne Loeuillet*1, S Deutsch2, P Taffé3, M Rotger1, J Beckmann4, S Antonarakis2, and A Telenti1
1Univ Hosp, Univ of Lausanne, Switzerland; 2Univ of Geneva Med Sch and Univ Hosp Geneva, Switzerland; 3Swiss HIV Cohort Study Data Ctr, Lausanne; and 4Univ Hosp and Univ of Lausanne, Switzerland
Background: Advances in
large-scale analysis of human genomic variability provide unprecedented
opportunities to study the genetic basis of susceptibility to HIV-1. We report
on the use of an in vitro system for
the identification of susceptibility loci using whole genome linkage and
association analyses.
Methods: B lymphoblastoid cell lines (LBL) from 198
individuals (15 CEPH multigeneration pedigrees) were transduced with vesicular
stomatitis virus (VSV)-lentivirus-green fluorescent protein (GFP). Trait data (percentage
of GFP-positive cells and mean fluorescence intensity [MFI]) were used for
genome scan linkage analysis (2600 single nucleotide polymorphism [SNP]
markers). Linkage was confirmed by transduction of LBL from
56 independent HapMap individuals in a genome association analysis using 521
tag SNP on a 3-Mb region centered around the initial linkage assignment.
Candidate markers were assessed for association with CD4 T-cell permissiveness
in cells from 128 healthy blood donors. Association of a candidate marker with
disease progression in vivo was
investigated in a HIV-1-infected human cohort of 805 individuals.
Results: The
heritability of susceptibility to VSV-lentivirus-GFP in vitro was 0.53 and 0.43 for percentage of GFP+ cells
and MFI, respectively. Linkage analysis identified a locus on chromosome 8q24.3
(logarithm of odds [LOD] = 2.89, p = 2E-04).
Association analysis using LBL from unrelated individuals identified
SNP rs2572886G>A to be associated with the percentage of GFP trait (p = 1.8 E-5). Allele A of marker
rs2572886 is associated with 40% increase in susceptibility to the
VSV-lentivirus-GFP in LBL cells (p = 0.001),
and 57% increase in susceptibility to HIV 1 in CD4 T cells (p = 0.019). Allele A was associated with
greater viral load, and faster progression of immunosuppression in the
HIV-1-infected cohort.
Conclusions: We identified, using a multistep
procedure involving unbiased whole-genome linkage scan followed by association
studies, a novel locus on chromosome 8 that influences human susceptibility to
HIV-1. This is the first time a quantitative trait locus initially mapped by in vitro approaches, has also been shown
to be relevant in a clinical setting.
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