The haplotype association analyses were performed for the genetic SNPs under investigation and their potential link to TB susceptibility (Table 3). The analysis of CD14 polymorphisms revealed a higher prevalence of the CG haplotype in both TB patient groups. Additionally, a correlation was observed between the TG haplotype and increased susceptibility to TB.
The results indicate that the CD14 rs2569190 and rs2569191 polymorphisms are associated with an increased susceptibility to TB in the Kurdish population, aligning with the role of CD14 in innate immunity. CD14, primarily located on monocytes and macrophages, is essential for recognizing bacterial components through TLRs, triggering immune responses such as cytokine secretion and cell proliferation. Variations in the CD14 promoter region, including rs2569190 and rs2569191, have been shown to affect CD14 expression, potentially influencing immune responses to Mtb.
This study found that the T allele and TT genotype of the rs2569190 polymorphism in the CD14 gene are associated with an increased risk of TB, particularly within the Iranian population. Consistent with these findings, Alavi-Naini et al. reported that individuals carrying the TT genotype had a 3.5-fold higher risk of developing TB compared to those with the CC genotype.
A meta-analysis of seven studies involving various populations (Iran, Turkey, China, Korea, Mexico, Poland, and the USA) also showed a significant association between the T allele/TT genotype and increased TB risk. However, results were not consistent across all populations -- e.g., a study in Turkey found no significant link -- indicating potential population-specific differences. The deviation from HWE in the TB patient group for rs2569190 may suggest a potential association between this polymorphism and disease susceptibility. However, factors such as population stratification and other confounding variables must also be taken into account, which calls for further investigation.
This study is the first to suggest a potential association between the CD14 rs2569191 polymorphism and susceptibility to TB. Our findings indicate that the G allele is linked to an increased risk of TB infection. Evidence regarding rs2569191 remains relatively limited. Two studies that reported a significant association between the G allele and an increased risk of tuberculosis, consistent with the present study's observation of a higher frequency of the GG genotype among TB patients. These findings suggest that rs2569191 may play a role in TB susceptibility; however, further research is needed to confirm its impact across different populations. The presence of HWE in the healthy control group for rs2569191 strengthens the significance of the deviation observed in the tuberculosis patient group, suggesting a potential role for this polymorphism in the pathogenesis of TB within this population.
Haplotype analysis showed that the CG haplotype was more frequent among TB patients, while the TG haplotype was associated with an increased risk of developing TB. These findings suggest a possible interaction or synergistic effect between the two CD14 promoter polymorphisms in influencing TB susceptibility. Further functional research is needed to clarify how these specific haplotypes affect CD14 gene expression and the resulting protein function in response to Mtb infection.
According to Gu et al. both SNPs (rs2569190 and rs2569191) have the potential to significantly influence the transcriptional activity of the CD14 promoter, which may, in turn, affect CD14 expression. As a result, individual differences in CD14 expression and the inflammatory response to TB could be attributed to CD14 polymorphisms. However, the study also found that TB patients with the CD14 rs2569191 GG genotype exhibited similar levels of membrane-bound CD14 and soluble CD14 compared to those with other genotypes, suggesting that the functional consequences of these polymorphisms may be context-dependent or influenced by additional regulatory factors.
There is increasing evidence suggesting that CD14 signaling plays a crucial role in the host response to intracellular bacterial pathogens such as Mtb. Elevated levels of soluble CD14 have been detected in the sera and bronchoalveolar lavage fluid of patients with active TB. However, the exact impact of CD14 expression levels on the progression of TB remains insufficiently understood. It is hypothesized that an increase in CD14 expression induced by Mtb could contribute to the immune pathogenesis of TB by enhancing interactions with mannosylated lipoarabinomannan. This interaction may lead to increased production of transforming growth factor β, which could suppress immune responses. Additionally, there is evidence indicating that CD14 plays a significant role in regulating immunoglobulin E (IgE) responses, as it promotes T helper 1 (Th1) differentiation while inhibiting Th2-dependent IgE responses.
This investigation has several limitations. First, the study was conducted at a single center and focused specifically on Iranian Kurds, which may limit the applicability of the findings to other ethnic groups. Iran is a genetically diverse country, comprising Persians, Azeris (Turks), Arabs, Baluchis, Gilaks, Mazandaranis, Lors, Turkmen, and others. Given the heterogeneity in genetic susceptibility to tuberculosis across different populations and geographic regions, the results may not be fully representative of the broader Iranian population or other ethnic backgrounds. Second, while the sample size is sufficient for a candidate gene association study, larger, multi-center studies are necessary to confirm these findings and explore potential interactions with other genetic and environmental factors. The study focused solely on two polymorphisms within the CD14 promoter, but further research should investigate additional SNPs within the CD14 gene and its regulatory regions, as well as their functional implications on CD14 expression and protein function. Finally, this study did not include functional studies assessing CD14 expression levels in individuals with different genotypes or their in vitro responses to Mtb infection. Such investigations are essential to validate the biological significance of the observed associations.
In summary, our results highlight a significant association between the rs2569190 and rs2569191 polymorphisms in the CD14 gene promoter and the risk of tuberculosis in the Kurdish population of Iran. The TT genotype of rs2569190, the GG genotype of rs2569191, and the TG haplotype were all linked to an increased risk of developing TB. These findings deepen our understanding of the genetic factors that may influence susceptibility to TB and suggest a potential role for CD14 in the pathogenesis of this critical global health issue. Further research is needed to validate these results across diverse populations and to elucidate the functional mechanisms behind these genetic associations, which may eventually pave the way for the development of novel diagnostic and therapeutic strategies for TB.