Psoriasis and vitiligo are inflammatory autoimmune diseases with genetic factors playing a remarkable role in both diseases (1). Psoriasis is an inflammatory skin disease that is characterized by the development of scaly and erythematous plaques with a global prevalence of approximately 2% (2, 3). Its pathogenesis comprises intricate interactions between the adaptive immune system and the innate immune system (4). Meanwhile, vitiligo represents an autoimmune disease of the skin characterized by autoimmune melanocyte destruction, resulting in the related depigmentation patches affecting the skin in addition to mucosa (5). The prevalence of vitiligo is estimated at approximately 0.2–2% in varied populations (6). Genetic factors have a remarkable role in vitiligo and the risk related to these factors is estimated to reach 75–83%, leaving only approximately 20% for the other environmental factors (7).

One of the important components of innate immunity is mannose-binding lectin (MBL), and the defects of this molecule have been linked with different autoimmune diseases (8). This protein is one of the pattern-recognition molecules that are responsible for activating the complement system through the lectin pathway (9, 10). It is encoded by the MBL2 gene located on chromosome 10, and the presence of certain missense single nucleotide polymorphisms (SNPs) in this gene was associated with notable low levels of MBL (11). One of these specific mutations is rs1800450 in codon 54, which leads to the change of glycine to aspartic acid (12), with the variant allele represented by allele B and the wild-type one represented by allele A (13). Moreover, this missense mutation could impact the binding activity of MBL, leading to implications on its function (14). The presence of this SNP was linked with several autoimmune diseases such as rheumatoid arthritis (15) and systemic lupus erythematosus (16). However, the relationship between this SNP and autoimmune skin diseases, specifically vitiligo and psoriasis, was investigated by only a few studies showing conflicting results (17–20).

More studies are required to investigate the impact of this missense mutation on psoriasis and vitiligo diseases, especially in light of the increasing interest in the genetic association studies with different human diseases (21–24). By deciphering the nature of the relationship between this mutation and such chronic autoimmune diseases and their features, hopes could be raised to improve the guidelines for the prediction and management of these autoimmune conditions.

The study comprised an in silico analysis, an observational study regarding psoriasis patients, and an observational study regarding vitiligo patients. A chart demonstrating the outline of the study research is displayed in Figure 1.

Genetics were found to have primary roles in both psoriasis and vitiligo disorders (7, 33–36). SNPs signify the most prevalent type of genetic variation (37), with massive attention attracted to the missense SNP subtype that may result in pathogenic consequences (38). Despite the importance of MBL in the immune system and the discovered links between MBL2 polymorphisms and autoimmune diseases (39), only a few studies to our knowledge have addressed the association between these variants with vitiligo and psoriasis disorders.

By applying the in silico methods, the SNP was predicted to affect protein function and protein stability. Furthermore, a protein’s secondary structure plays crucial functions in both the structure and folding of the protein, demonstrating the relevance of this structure (40); therefore, secondary structure analysis was performed using the SOPMA server. The secondary structure analysis detected no change regarding the alignment of the selected position. Moreover, PTMs could influence protein functions and have the potential to impact many aspects of protein biology, such as stability, cellular localization, and interaction with co-factors (41). Therefore, PTM analysis was performed, which revealed a loss of SUMOylation in position 56 with this mutation. In addition, gene–gene interaction examination revealed the 20 genes with the strongest connections to the MBL2 gene, which might be affected by MBL2 variants. The significance of researching gene–gene interactions while examining disease–gene associations was demonstrated by the verified presence of interaction between various genetic loci (42). Furthermore, mutations that cause diseases show a tendency to cause instability in protein–protein interactions (43). Consequently, the interaction pattern of MBL in conjunction with other proteins was predicted using the STRING database showing the 10 most prominent interactors.

Our experimental analysis revealed genotype frequencies of 76.3, 21.7, and 2% for AA, AB, and BB, respectively, which were similar to previously conducted studies on Egyptian populations. A 2018 study conducted by Hammad et al. showed genotype frequencies of 79.7, 18.6, and 1.7% with AA, AB, and BB, respectively (44). Moreover, genotype frequencies in another Egyptian study by Gomaa et al. exposed genotype frequencies of 64.6, 28.8, and 6.7%, respectively (12). Although the heterozygous allele displayed a high frequency in these studies along with our study, other previous studies showed even more elevated frequencies with the AB allele (9, 45, 46). With only limited exceptions, these remarkably elevated frequencies of this variant allele and other MBL deficiency variant alleles were detected worldwide. It is noteworthy that the allele B has nearly substituted the allele A in specific Indian populations in South America (47). This distinct pattern has raised inquiries about MBL significance and whether these mutations are associated with some kind of biological benefits (48). Different models were introduced in pursuit of the clarification of this phenomenon, resulting in an unsettled debate (49, 50). One explanation assumed a gained protection with these variants due to the associating low MBL levels that could be advantageous in case of tissue damage resulting from a strong inflammatory response (51). This postulation gave explanation to some previous findings that favored the clinical outcome with genotypes of low MBL in case of some disorders; these genotypes were associated with less severe autoimmune manifestations in primary Sjögren’s syndrome (10); moreover, tuberculosis protection was correlated with heterozygosity in MBL alleles, which is responsible for low levels of MBL (52). Furthermore, similar protective benefit was found for these genotypes against visceral leishmaniasis (53). In addition, the elevated MBL levels were identified to confer an augmented risk of ischemic heart disease along with myocardial infarction in rheumatoid arthritis (54, 55). On the other hand, another explanation excluded the existence of selective pressure and displayed the absence of statistical support for this pressure (56, 57), further advocating the redundancy of MBL in human immunity as a result (57).

Subsequently, the association between codon 54 polymorphism and psoriasis risk was investigated. Nevertheless, no significant association was revealed with all genetic association models. Moreover, no significant correlation was discovered between rs1800450 SNP and the clinicopathological features of psoriasis. The significance of MBL and MBL deficiency in disease pathogenesis has been a source of ambiguity and queries as studies indicate that low or elevated MBL levels show a damaging, protecting, or no effect on susceptibility to diseases (51), which could also be the case here, as recent studies have revealed the important role of MBL in psoriasis pathogenesis. One study found that MBL may aggravate psoriatic skin inflammation by assisting the infiltration of the neutrophils in psoriatic lesions (58). Another study revealed that psoriasis patients displayed higher MBL levels than control subjects and that the level of MBL correlated positively with PASI score and psoriasis severity, and found that MBL assisted the differentiating and infiltrating processes of plasmacytoid dendritic cells in initial skin lesions of psoriasis, leading to the aggravation of disease severity (59). Therefore, the reason for the lack of protective effect with MBL-deficient genotypes needs to be explained. One suggested explanation for the neutrality of MBL deficiency in previous studies was by assuming the redundancy of MBL and the existence of adequate substituting immune mechanisms (9, 60), as other pathways or molecules have demonstrated that they may make up for the deficiency of MBL (57, 61, 62).

The scarcity of previous related studies addressing MBL2 variants and psoriasis was noticed. The previously conducted study in the Turkish population included 50 psoriasis vulgaris patients along with 53 control subjects and found a significant association between rs1800450 SNP and psoriasis (20), which differs from our findings and with the potential protective role of MBL as well. However, previous analyses related to the impacts of MBL2 variants have pointed out the role of underpowered studies in inconsistent results (63).

In addition, the analysis was extended to examine the relationship between codon 54 polymorphism and vitiligo risk as well. However, the analysis also did not reveal a significant association with all genetic association models. Furthermore, no significant correlation was uncovered between this SNP and clinicopathological features of vitiligo. To our knowledge, only a limited number of previous studies dealt with this topic. Our result complies with the findings of both Karkucak et al. and Dwivedi et al., who investigated this issue; Karkucak et al. conducted their study on a Turkish population comprising 101 vitiligo cases and 101 control subjects, reporting the absence of the association of vitiligo risk with rs1800450 SNP (18). Moreover, Dwivedi et al. conducted their study on an Indian population comprising 92 cases affected by generalized vitiligo and 94 control subjects, revealing the absence of the association of this disease with rs1800450 SNP and other MBL2 SNPs (17). However, one more Turkish study, including 40 vitiligo patients and 50 healthy subjects, was conducted that suggested a role for rs1800450 in vitiligo susceptibility (19). Complying with the findings of the two studies with a larger sample size gave robustness to our findings. These findings also suggested the notion of redundancy regarding MBL. Finally, the current study had its limitations as well. The patient sample size included in this preliminary study was relatively small. As a result, there is a need for further studies to be conducted on the Egyptian population with a larger patient sample size that encompasses diverse geographic areas. Furthermore, despite investigating the selected variant’s relationship with two autoimmune skin disorders through a combination of experimental and computational approaches, there is still a need for more forthcoming studies that analyze several genetic factors and combine them with environmental factors to understand the full picture regarding these complex diseases.

In conclusion, the in silico analysis forecasted the consequences of the presence of the selected mutation on the protein’s function, stability, PTMs, and secondary structures. Moreover, our analysis emphasized the same frequency pattern of the codon 54 variant among the Egyptian population in comparison with other populations and highlighted the unsettled ambiguity regarding this pattern. The studied variant showed no association with the risk of psoriasis and vitiligo as well. Furthermore, this mutation did not significantly correlate with the clinicopathological data for both diseases. These findings supported the redundancy of MBL and the worth of the compensatory mechanisms.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving humans were approved by the Research Ethics Committee at the Faculty of Medicine, Suez Canal University, Egypt. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants or their next of kin.

MB: Conceptualization, Investigation, Methodology, Writing – original draft. NT: Investigation, Writing – review & editing. RE: Funding acquisition, Writing – review & editing. DN: Funding acquisition, Writing – review & editing. DA: Funding acquisition, Writing – review & editing. EF: Funding acquisition, Writing – review & editing. WE: Writing – review & editing. HA: Conceptualization, Funding acquisition, Investigation, Methodology, Supervision, Writing – original draft.