1. What host factors are at play? Paul de Bakker Division of Genetics, Brigham and Women’s Hospital Broad Institute of MIT and Harvard pdebakker@rics.bwh.harvard.edu

2. B cell CTL NK Th cell DC

3. 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

4. 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

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

6. From Manolio, NEJM 2010 >1000 loci discovered through GWAS in various complex, polygenic traits

7. Science Aug 2007

8. 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

9. Confirmation in other studies PLoS ONE Nov 2008 PLoS ONE Dec 2008

10. Confirmation in other studies AIDS Jan 2009 Genes & Immunity Dec 2009

11. JID Feb 2009 rs9264942 / upstream HLA-C not associated

12. GWAS in other phenotypes JID Oct 2009 JID Jan 2010 Genes outside MHC proposed but validation needed

13. No signals outside MHC with large sample of VL (n=2500) PLoS Genet 2009

14. Non-replication of published associations

15. A potential role for CD4:CD8 ratio in host control? American Journal of Human Genetics. 2010

16. Variants in MHC associated with CD4:CD8 ratio

17. 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

18. 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

19. 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