Although the NFKB pathway was previously studied in BS [3, 7], NFKB1 A > G (rs4648068) SNP was not studied in BS patients before. Our results show that the GG genotype is significantly higher in patients with BS in comparison to controls, denoting a possible increased risk of developing the disease in individuals with NFKB1 A > G (rs4648068) SNP. Although previous genome-wide association studies (GWAS) didn’t identify our studied SNP as a possible candidate SNP in cases of BS [16], our study was conducted on the Egyptian population, a population that has a high prevalence of BS [17] but not yet studied by any GWAS before.

NFKB1 A > G (rs4648068) SNP was previously studied in multiple diseases, of which osteoporosis and cancers are of probable relation to our study.

The underlying mechanisms of osteoporosis are believed to be due to either the increased activity of osteoclasts, decreased activity of osteoblasts, or both. NFKB pathway is implicated in the pathogenesis of the disease so denosumab, a monoclonal antibody targeting the NFKB ligand-activated receptor (RANKL), was successfully used as a treatment of osteoporosis serving to slow bone breakdown [18].

In a study of postmenopausal Polish women, analysis of NFKB1 gene rs4648068 polymorphism showed that the GG genotype was more frequent in those with osteoporosis compared to controls [19]. Although it increases the risk of developing osteoporosis, another study found that NFKB1 rs4648068 A > G SNP was significantly associated with bone response to the treatment of zoledronic in postmenopausal Chinese women with osteoporosis [20]. Our studied SNP was also associated with a better response of the total hip bone mineral density to alendronate treatment in postmenopausal Chinese women with osteoporosis [21].

Interestingly, osteoporosis was studied in BS. Two previous studies found no significant relation between both [22, 23]. Another one found that BS can be a risk for osteoporosis, especially in the lumbar spine [24]. This needs future studies on larger scales to determine if there is a statistically significant relation between both or not. Our study may shed light on a possible link between both conditions, namely the NFKB pathway and its rs4648068 A > G SNP.

Inflammation plays an essential role in the development of most cancers, even without obvious signs of inflammation. The NFKB pathway is central to chronic inflammation in many cancers. Nearly, all known cancer pathways involve NFKB pathway activation [25]. NFKB1 rs4648068 A > G SNP was studied in different types of cancers.

In one study on the Chinese Han population, the NFKB1 rs4648068 A > G SNP was associated with a significantly increased risk of gastric cancer. Among the patients with cancer stomach, it was associated with higher clinical stage, lymph node involvement, and serosa invasion [9].

In another study conducted later on, the group of researchers proved a functional role of the NFKB1 rs4648068 A > G SNP in gastric cancer patients concluding that the studied SNP was associated with the transcriptional activity of NFKB1. Furthermore, the functional activity of this SNP site was verified by a cell biology experiment highlighting its important effects on cell proliferation and motility [26]. This study supports our notion that the NFKB1 rs4648068 A > G SNP has a functional role in different inflammation-based diseases, including BS. Although our study suggested an increased risk of developing BS in patients with NFKB1 rs4648068 A > G SNP, the functional relevance of those results needs to be replicated in BS cases in future studies.

In line with the previously mentioned studies, a study on the Pakistani population that was performed to evaluate the variants of the NFKB1 gene, GG genotype (rs4648068) was associated with a significantly increased risk of head and neck cancer [12]. NFKB1 rs4648068 SNP was also found different in patients with ovarian cancer in comparison to controls [10]. On the other hand, it was not significantly different in patients with non-medullary thyroid carcinoma compared to controls [11].

Interestingly, previous studies discussed the relation between malignancies and BS. A cohort from Korea found an increased risk of malignancies in patients with BS [27]. A previous systematic review and metanalysis also concluded the same relation [28]. Later on, a Turkish Cohort study found that the cancer risk in patients BS was approximately three times the cancer risk in the corresponding age and sex group. This highlighted the importance of cancer surveillance in BS patients [29].

Whether NFKB1 rs4648068 A > G SNP is a common SNP linking the risk of developing BS with the risk of malignancies is still a question that needs an answer.

Of all the different activity manifestations of BS, arthralgia is the only one that reached a statistically significant relation with our studied SNP. GG genotype seems protective against developing arthralgia. The role of the NFKB pathway was previously studied in autoimmune joint involvement, specifically in rheumatoid arthritis, and was found to have dual effects; pro-inflammatory and anti-inflammatory [30]. Our results point towards a probable anti-inflammatory role of NFKB1 rs4648068 A > G SNP in cases of arthritis of an autoimmune nature, at least in cases of BS.