Allele-Specific Expression of Active TB in pediatric HIV individuals in Eswatini, Botswana and Uganda

Abstract

Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) has been declared a deadly combination by the World Health Organization (WHO) and about 1.4 million deaths are reported yearly. Sub – Saharan Africa has about 70% of the 36.9 million people living with HIV. HIV and TB coinfection has led to the expression of some genes. There are some known genetic loci associated with risk for active TB, however, these are population specific, and some have not been replicated. Equally gene expression signatures have been characterized for different populations and TB clinical phenotypes, however, there remains a knowledge gap in the genetic mechanism of active TB including the mechanism of regulation of gene expression. One possible mechanism of regulation of gene expression is through allelic imbalance /allele specific expression at specific heterozygous loci. Allele Specific Expression (ASE) or allelic imbalance (AI) is when one allele is expressed more than the other at a heterozygous loci. This study aimed at determining differential expression of alleles at heterozygous loci in children coinfected with active TB and HIV in three sub-Saharan African countries under the Collaborative African Genomics Network (CAfGEN) project, which are Botswana, Uganda and Eswatini. It also aimed at identifying genomic variants that plays a role in active TB pathogenesis in HIV positive pediatric individuals. The study utilized RNA sequence data from assented and consented HIV positive pediatric individuals with the cases being children diagnosed with active TB while the controls were age and sex matched children without TB. HaplotypeCaller was used for joint variant calling of variants and annovar with snpEff and SnpSift were used for annotation of variants. GATK ASEReadCounter was used for the allelic imbalance analysis. 144521, 44795 and 27401 variants were called, with 3.12 %, 2.64% and 5 % of them being exon variants from Uganda, Botswana and Eswatini respective. The majority of the called variants were SNPs. rs1050504 was found to be related to the pathogenesis of TB in Moroccan population. rs7256672 was found to be related to hypercholesterolemia. Another variant was rs9881 which is related to susceptibility of pulmonary TB in the Chinese population. 60% of all the analyzed variants showed an allelic imbalance and 40% did not show an allelic imbalance. This shows that active TB plays a role in the allelic imbalance at heterozygous site. More allelic imbalance studies need to be conducted with haplotypes in order to validate the obtained results so that the findings can be generalized.