Genetic Susceptibility Within the Immune System Beyond Conventional Risk Factors: An Integrative Analysis in a Kazakh Cohort

Background/Objectives: Genetic factors are known to influence overall immune vulnerability to diseases, such as tuberculosis (TB); however, isolating the genetic component can be challenging as social and environmental causes, such as smoking, alcohol consumption, and unemployment, also drive disease risk. To reduce heterogeneity related to these factors, we performed a targeted immunogenetic association study of TB susceptibility in a Kazakh case-control cohort selected among individuals without the typical socioeconomic and nutritional risk factors linked to TB.

Methods

We performed genotyping using an immune-focused targeted array; after quality control at sample and variant level, removal of ancestry-based outliers, and adjustment for population stratification, the final dataset included 164 participants (84 cases, 80 controls) and 181,595 variants. We performed four complementary analyses: single-variant association testing using logistic regression with Firth correction where required adjusted for sex and genetic ancestry, gene-based aggregation testing, functional annotation, and polygenic risk scoring using existing multi-ancestry TB genetic resources.