Genetic determinants of infectious disease susceptibility

Abstract

Studies on infectious diseases have displayed strong evidence of genetic influences in determining the variable degrees of immune response to infection, and disease susceptibility among individuals. Having multiple adverse effects on disease burden, there is motivation to study host genetics in controlling immune response to infections. Recent advancement in genomics has helped to materialize the main objective of this thesis project, which is to identify genetic variation that influences susceptibility to infectious disease. The main study populations were drawn from Indonesia, where it is endemic for the infectious diseases studied in this thesis, and there is substantial interest to elucidate the genomic mechanisms of disease control in this population.

The first part of the research project is an association study on pulmonary tuberculosis (TB) susceptibility, conducted using two methodologies. We started with a hypothesis driven approach to replicate associations of candidate genes that had yet to be studied in Southeast Asians. With a much larger sample size and power to study the loci, there is significant evidence to reject these previous associations with pulmonary TB in our Indonesian cohort, as well as in the collaborative efforts with the European and African cohorts. This demonstrates the flaws of hypothesis dependent candidate gene design in studying complex traits, such as TB, where biological knowledge of disease mechanisms in humans is limited. For this reason, coupled with the introduction of high density single nucleotide polymorphisms (SNPs) array for performing comprehensive genome wide associations scan (GWAS), we had subsequently focused the remaining studies on GWAS, the hypothesis generating approach.

The results of the multi-stage GWAS on pulmonary TB susceptibility in Indonesians were validated independently in another Russian cohort, and the data suggests evidence of association (p-values = 0.0004-0.0067) with TB for multiple independent loci, many of which are located within or near genes involved in immune signaling. Mechanisms of immune defense suggested by some of the identified genes exhibit biological plausibility and may suggest novel pathways involved in the host containment of infection with TB.

Different pathogen strains may confer differences in pathogenicity; hence it is often challenging to identify host susceptibility factors without accounting for variability from the pathogen itself. As the purpose of immunization is to stimulate immune responses similar to those acquired naturally, we propose the use of vaccine response as a useful experimental model of natural infection for genetic and other functional studies of infection, in the second part of this project. The two-stage GWAS of post-vaccination antibody titer in 3,614 hepatitis B vaccinees from Indonesia?s Riau Archipelago had led to the identification of at least three independent signals within the human leukocyte antigen complex (HLA). These appear to implicate HLA-DR (rs3135363; p = 6.53x10-22; OR =1.53, 95% CI = 1.35-1.74); HLA-DP, previously associated with the risk of chronic hepatitis B infection (rs9277535; p = 2.91 x 10-12; OR = 0.72, 95% CI = 0.63-0.81); and a gene rich HLA Class III interval (rs9267665; p = 1.24x10-17; OR = 2.05, CI = 1.64-2.57). The substantial overlap of these variants and those identified by GWAS of chronic hepatitis B infection confirms vaccine response as a model for infection; while suggesting that the vaccine is least effective in those most at risk of lifelong infection, following exposure to the virus. In conclusion, this project has confirmed the importance of genetic determinants in infectious diseases, and introduced novel genes and pathways that had demonstrated roles in disease susceptibility after infection.