ausblenden:
Schlagwörter:
HIV-1 control; GWAS; heritability; infectious disease; genomics
Zusammenfassung:
Previous genome-wide associat
ion studies (GWAS) of HIV-1
–
infected
populations have been underpowered to detect common variants
with moderate impact on disease outcome and have not assessed
the phenotypic variance explained by genome-wide additive effects.
By combining the majority of available genome-wide genotyping
data in HIV-infected populations, we tested for association between
∼
8 million variants and viral load (HIV RNA copies per milliliter of
plasma) in 6,315 individuals of Eur
opean ancestry. The strongest sig-
nal of association was observed in the HLA class I region that was
fully explained by independent effects mapping to five variable
amino acid positions in the peptide binding grooves of the HLA-B
and HLA-A proteins. We observed a second genome-wide significant
association signal in the chemokine (C-C motif) receptor (CCR) gene
cluster on chromosome 3. Conditional a
nalysis showed that this signal
could not be fully attributed to the known protective
CCR5
Δ
32
allele
and the risk P1 haplotype, suggesting further causal variants in this
region. Heritability analysis demonstrated that common human ge-
netic variation
—
mostly in the HLA and CCR5 regions
—
explains 25%
of the variability in viral load. This study suggests that analyses in
non-European populations and of variant classes not assessed by
GWAS should be priorities for the field going forward.
