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 so common rare

Three approaches common not so common rare 50% 5% 0.5% HapMap 1000 Genomes Sequencing ResourceApproach GWAS Imputation + newer chips

From Manolio, NEJM 2010 >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  rs / proxy B*5701  rs / 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 rs / upstream HLA-C not 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 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