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What host factors are at play?
Paul de Bakker
Division of Genetics, Brigham and Women’s Hospital
Broad Institute of MIT and Harvard
B cell
CTL
NK
Th cell
DC
Unique advantages of human genetics Genotype assignment is randomized at meiosis
(formally, a randomized trial) Genotypes are unaltered by the disease
process We can develop good statistical rules when a
variant is consistent with null hypothesis (no association)
Therefore, can argue for causality
Evolution shaped allelic variation
50%
5%
0.5%
expected to reach high(er) frequency due to balancing
selection
most of genome consistent with neutral drift
deleterious variants are selected against
Allele frequency
common
not socommon
rare
Three approaches
common
not socommon
rare
50%
5%
0.5%
HapMap
1000 Genomes
Sequencing
Resource Approach
GWAS
Imputation+
newer chips
From Manolio, NEJM 2010
>1000 loci discovered through GWAS in various complex, polygenic traits
>1000 loci discovered through GWAS in various complex, polygenic traits
Science Aug 2007
First GWAS of VL points to MHC
Two SNP markers found that explain 15% of variance of VL
rs2395029 / proxy B*5701 rs9264942 / upstream HLA-C
Another SNP found associated with progression
CCR2/CCR5 only associated variant outside MHC
Confirmation in other studies
PLoS ONE Nov 2008
PLoS ONE Dec 2008
Confirmation in other studies
AIDS Jan 2009
Genes & Immunity Dec 2009
JID Feb 2009
rs9264942 / upstream HLA-Cnot associated
GWAS in other phenotypes
JID Oct 2009
JID Jan 2010
Genes outside MHC proposed but
validation needed
No signals outside MHC with large sample of VL (n=2500)
PLoS Genet 2009
Non-replication of published associations
A potential role for CD4:CD8 ratio in host control?
American Journal of Human Genetics. 2010
Variants in MHC associated with CD4:CD8 ratio
This variant is also associated with host control
Association with host control: P = 9 x 10-11
This raises the possibility that host control may (in part) be mediated by regulation of T cell
homeostasis
Summary
There has been virtually no success with candidate gene studies in terms of robustly pointing to true associations
Genome-wide association studies point unequivocally to SNP markers in the MHC associated with VL or (non-)progression
But no functional or causal variants pinpointed
What is needed?
We need large, well-phenotyped cohort in multiple populations or ethnicities
This is also true for studying rare variation (sequencing)
Logistical hurdles in low-resource settings where delivery of care is already poor
