Genetic epidemiology of tuberculosis susceptibility: impact of study design

Abstract

Several candidate gene studies have provided evidence for a role of host genetics in susceptibility to tuberculosis (TB). However, the results of these studies have been very inconsistent, even within a study population. Here, we review the design of these studies from a genetic epidemiological perspective, illustrating important differences in phenotype definition in both cases and controls, consideration of latent M. tuberculosis infection versus active TB disease, population genetic factors such as population substructure and linkage disequilibrium, polymorphism selection, and potential global differences in M. tuberculosis strain. These considerable differences between studies should be accounted for when examining the current literature. Recommendations are made for future studies to further clarify the host genetics of TB.

Figure 1. Impact of variation in linkage disequilibrium (LD) in detection of disease risk alleles.

For all three scenarios, D is the underlying disease risk allele. (A) There is strong LD between D and marker #1 (M1), and weak LD between D and M2. In this situation, association will be detected with M1, depending on study power based on sample size, strength of genetic effect, and minor allele frequencies. (B) There is no LD between M1 and D but strong LD between M2 and D. Here, association will be detected only with M2 (again, depending on power). (C) There is weak LD throughout the region. Association will likely not be detected.

Figure 2. Linkage disequilibrium (LD) of the NRAMP1 gene for HapMap reference populations.

Yoruba (YRI), Maasai (MKK), Han Chinese (CHN), Utah Caucasians (CEU), and African Americans (ASW) are shown. The strength of LD is illustrated using the color scale shown in the figure key.