Genetic Analysis of TB Susceptibility Variants in Ghana Reveals Candidate Protective Loci in SORBS2 and SCL11A1 Genes

Abstract

Despite advancements made toward diagnostics, tuberculosis caused by Mycobacterium africanum (Maf) and Mycobacterium tuberculosis sensu stricto (Mtbss) remains a major public health issue. Human host factors are key players in tuberculosis (TB) outcomes and treatment. Research is required to probe the interplay between host and bacterial genomes. Here, we explored the association between selected human/host genomic variants and TB disease in Ghana. Paired host genotype datum and infecting bacterial isolate information were analyzed for associations using a multinomial logistic regression. Mycobacterium tuberculosis complex (MTBC) isolates were obtained from 191 TB patients and genotyped into different phylogenetic lineages by standard methods. Two hundred and thirty-five (235) nondisease participants were used as healthy controls. A selection of 29 SNPs from TB disease-associated genes with high frequency among African populations was assayed using a TaqMan® SNP Genotyping Assay and iPLEX Gold Sequenom Mass Genotyping Array. Using 26 high-quality SNPs across 326 case-control samples in an association analysis, we found a protective variant, rs955263, in the SORBS2 gene against both Maf and Mtb infections (PBH = 0.05; OR = 0.33; 95% CI = 0.32–0.34). A relatively uncommon variant, rs17235409 in the SLC11A1 gene was observed with an even stronger protective effect against Mtb infection (MAF = 0.06; PBH = 0.04; OR = 0.05; 95% CI = 0.04–0.05). These findings suggest SLC11A1 and SORBS2 as a potential protective gene of substantial interest for TB, which is an important pathogen in West Africa, and highlight the need for in-depth host-pathogen studies in West Africa.

Macrophage susceptibility to infection by Ghanaian Mycobacterium tuberculosis complex lineages 4 and 5 varies with self-reported ethnicity

“…For instance, it was reported that 5-lipoxygenase ( ALOX5 ) variants are associated with ethnicity and susceptibility to TB in Ghana ( Herb et al., 2008 ). Another recent study in Ghana on host susceptibility to TB has suggested two potentially protective genes, SLC11A1 and SORBS2 ( Asante-Poku et al., 2022 ). Further investigations looking into the distribution of genetic variants in Ewes compared to other Ghanaian ethnic groups are needed to further our mechanistic understanding of the macrophage phenotypes presented in this study.…”

Association of SLC11A1 Polymorphisms With Tuberculosis Susceptibility in the Chinese Han Population

“…In addition, the results of three meta-analysis studies showed that SLC11A1 polymorphisms ((D543N, 3′UTR TGTG ins/del, INT4, [GT]n), rs3731865, and rs17235416)) were significantly associated with TB risk (Li et al, 2011;Meilang et al, 2012;Archer et al, 2015). Recently, rs17235409 (SLC11A1) has been observed with an even stronger protective effect against Mtb infection in Ghana (Asante-Poku et al, 2021). SLC11A1 genetic variation and low expressions have been reported to cause immune response impairment in TB patients (Shahzad et al, 2022).…”

“…Genetic variants of SLC11A1 have been reported to be significantly associated with both autoimmune and infectious disease susceptibility (Archer et al, 2015;Shahzad et al, 2022). Although numerous studies have shown that the single-nucleotide polymorphisms (SNPs) of SLC11A1 were associated with the risk of TB in different populations (Wu et al, 2013;Harishankar et al, 2018;Asante-Poku et al, 2021), whether polymorphisms in and near the SLC11A1 gene are associated with susceptibility to TB in the northwest Chinese Han population has not yet been reported.…”

Interleukin 6 and interferon gamma haplotypes are related to cytokine serum levels in dogs in an endemic Leishmania infantum region

“…Specifically, twenty-four polymorphisms have been analysed in the SLC11A1 gene in 40 dogs of different canine breeds, and two of them were associated with increased risk for CanL [22]. The SLC11A1 gene is related to autoimmune and infectious diseases in humans, such as fibrosis progression in hepatitis C, Crohn's disease, type-1 diabetes mellitus and tuberculosis [23][24][25][26]. In L. infantum infection, this gene controls the replication of intracellular parasites [27], and its haplotypes TAG-9-145 and TAG-8-141 are found more frequently in Boxer dogs than other canine breeds and, given that the CanL is elevated in this breed, the authors conclude that this gene could be related to leishmaniasis susceptibility [28].…”