Resistance to TST/IGRA conversion in Uganda: Heritability and Genome-Wide Association Study

Abstract

Background Pulmonary tuberculosis (TB) is one of the most deadly pathogens on earth. However, the majority of people have resistance to active disease. Further, some individuals, termed resisters (RSTRs), do not develop traditional latent tuberculosis (LTBI). The RSTR phenotype is important for understanding pathogenesis and preventing TB. The host genetic underpinnings of RSTR are largely understudied. Methods In a cohort of 908 Ugandan subjects with genome-wide data on single nucleotide polymorphisms, we assessed the heritability of the RSTR phenotype and other TB phenotypes using restricted maximum likelihood estimation (REML). We then used a subset of 263 RSTR and LTBI subjects with high quality phenotyping and long-term follow-up to identify DNA variants genome-wide associated with the RSTR phenotype relative to LTBI subjects in a case-control GWAS design and annotated and enriched these variants to better understand their role in TB pathogenesis. Results The heritability of the TB outcomes was very high, at 55% for TB vs. LTBI and 50.4% for RSTR vs. LTBI among HIV- subjects, controlling for age and sex. We identified 27 loci associated with the RSTR phenotype (P<5e-05) and our annotation and enrichment analyses suggest an important regulatory role for many of them. Interpretation The heritability results show that the genetic contribution to variation in TB outcomes is very high and our GWAS results highlight variants that may play an important role in resistance to infection as well as TB pathogenesis as a whole.

kimma: flexible linear mixed effects modeling with kinship covariance for RNA-seq data

“…Analyses were completed on the entire dataset as well as subsets of unrelated (kinship < 0.125, N = 55, 62 ) and related samples (at least one kinship > 0.125, N = 37, 36 ). Genes found to be significant for Mtb vs media in the related subset with kinship correction were extracted from genetic data with SNPs found on both the MEGAEX and Omni chip [18]. In total, 3382 of these 8525 DEGs had at least 1 pass-filter SNP within the gene transcript region (cis) to yield 10020 unique SNP-DEG pairs.…”

Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest‐neighbor feature selection

“…Our Mtb exposure outcome cohort derived from individuals participating in a household-contact study in an urban region of Kampala, Uganda (Mchenry et al, 2021;Stein et al, 2018Stein et al, , 2019. Individuals living with a confirmed, culture positive, clinically active tuberculosis case at enrollment were screened with tuberculin skin tests (TSTs) performed every 3 months for the first 2 years to identify individuals with latent Mtb infection and "Resisters" (Stein et al, 2018).…”

“…Genome-wide genotyping for the Mtb exposure outcome cohort is reported in a genome-wide association (GWA) study (Mchenry et al, 2021). Briefly, active cases from the original 2-year study (Stein et al, 2018) and those with latent Mtb infection and Resisters in the long-term follow-up study (Stein et al, 2019) were typed from a combination of the Illumina MEGA EX and Illumina Omni5 chips.…”

“…Accuracy of the HIBAG method specific to our sarcoidosis data set has previously been reported (Levin et al, 2014(Levin et al, , 2015. For our Mtb exposure data set, we implemented HIBAG using prebuilt classifiers with published parameter estimates, trained on samples of African ancestry (Zheng et al, 2014), to predict HLA-types from genome-wide genotypes (Mchenry et al, 2021;Stein et al, 2018Stein et al, , 2019. Before imputation, we filtered out all SNPs with missing call rate in excess of 0.01 and those with minor allele frequency less than 0.05.…”

“…Finally, the few existing HLA association studies in individuals of African ancestry indicate considerable deviation from the effects in other groups, the majority of which were identified in individuals of European or Asian populations (Fingerlin et al, 2015;Malkova et al, 2020;Tong et al, 2015;Yang et al, 2016). This study probed for HLA associations with outcomes of Mtb exposure in individuals from a densely populated region of Kampala, Uganda (Mchenry et al, 2021;Stein et al, 2018Stein et al, , 2019, whereas associations with sarcoidosis outcomes were assessed in Americans of African ancestry (ACCESS Research Group, 1999;Baughman et al, 2001;Rybicki et al, 2007). Uganda is a high-burden country for tuberculosis disease, with a recently estimated incidence of 196 per 100,000 (Global Tuberculosis Report, 2020); this is almost surely higher in the populous region of Kampala, with a recent estimate of 740 per 100,000 (Stein et al, 2018).…”