Association of a new FCN3 haplotype with high ficolin-3 levels in leprosy

Abstract

Leprosy is a chronic inflammatory disease caused by Mycobacterium leprae that mainly affects the skin and peripheral nervous system, leading to a high disability rate and social stigma. Previous studies have shown a contribution of genes encoding products of the lectin pathway of complement in the modulation of the susceptibility to leprosy; however, the ficolin-3/FCN3 gene impact on leprosy is currently unknown. The aim of the present study was to investigate if FCN3 polymorphisms (rs532781899: g.1637delC, rs28362807: g.3524_3532insTATTTGGCC and rs4494157: g.4473C>A) and ficolin-3 serum levels play a role in the susceptibility to leprosy. We genotyped up to 190 leprosy patients (being 114 (60%) lepromatous), and up to 245 controls with sequence-specific PCR. We also measured protein levels using ELISA in 61 leprosy and 73 controls. FCN3 polymorphisms were not associated with disease, but ficolin-3 levels were higher in patients with FCN3 *2B1 (CinsA) haplotype (p = 0.032). Median concentration of ficolin-3 was higher in leprosy per se (26034 ng/mL, p = 0.005) and lepromatous patients (28295 ng/mL, p = 0.016) than controls (18231 ng/mL). In addition, high ficolin-3 levels (>33362 ng/mL) were more common in leprosy per se (34.4%) and in lepromatous patients (35.5%) than controls (19.2%; p = 0.045 and p = 0.047, respectively). Our results lead us to suggest that polymorphisms in the FCN3 gene cooperate to increase ficolin-3 concentration and that it might contribute to leprosy susceptibility by favoring M. leprae infection.

Adding MASP1 to the lectin pathway—Leprosy association puzzle: Hints from gene polymorphisms and protein levels

“…There is also strong evidence that intracellular C3 cleavage directs T cell activation towards the Th1 pole, which is associated with the paucibacillary presentation of the disease. Since the first suggestion of balancing selection operating on the polymorphism of the gene encoding mannose-binding lectin (MBL2) due to protection against leprosy [4], much has been done investigating the possible roles played by LP genes and their products on the susceptibility to this disease [5][6][7][8][9] [11][12][13][14][15].…”

AddingMASP1to the lectin pathway – leprosy association puzzle: hints from gene polymorphisms and protein levels

“…Genetic disease association studies shed light on a wide range of aspects from the onset of infection to disease cornification, by uncovering genes whose protein products may play pivotal roles in this pathology (48). This has been the case for several genes of the lectin pathway of complement; those encoding PRMs, MBL2 (3) (4) (14), FCN1 (5), FCN2 (4) and FCN3 (9) and the serine protease MASP2 (6) and the possible receptor for MBL encoded by CR1 (10). The evaluation of complement protein levels adds highly relevant information to this picture, as an indirect measure of gene expression, complement activation and consumption.…”

“…Protein levels were compared between the groups using nonparametric Mann-Whitney/Kruskal–Wallis tests (since their distribution did not pass Shapiro-Wilk normality test), using Graphpad Prism 5.01 (GraphPad Software, La Jolla, CA). The reduced model of multivariate logistic regression was used to adjust results for demographic factors; age, sex (factors that might influence protein levels (43)) and ethnic group, as well as for previously published MASP-2 levels, MBL2, MASP2, FCN1, FCN2 and FCN3 genotyping results (44) (3) (9) (45) using STATA v.9.2 (Statacorp, TX, USA). The P values obtained with multiple comparisons in the association studies were corrected with the Benjamini-Hochberg method.…”

“…One of the initiating proteins of this pathway is mannan-binding lectin, produced from the MBL2 gene. Since the first suggestion of a balancing selection operating on MBL2 polymorphisms due to protection against mycobacterial diseases (2), much has been done investigating the possible roles played by genes of the lectin pathway of complement and their products on susceptibility to leprosy and tuberculosis (3) (4) (5) (6)(7) (8) (9) (10)(11). However, the exact role played by the lectin pathway components is still under investigation.…”

“…Low MASP-2 levels, as well as MASP2 polymorphisms associated with low MASP-2 production, were associated with increased susceptibility to leprosy (6). Low MBL levels and corresponding MBL2 polymorphisms, in contrast, were associated with increased resistance (7) (3), and higher FCN-3 levels were more frequent in leprosy patients than in controls (9). It has also been suggested that complement receptor CR1 and CD91/calreticulin bind the collagenous chains of collectins and ficolins deposited on pathogens or altered cells, leading to their internalization, but that MASPs and MAps compete with this binding site, preventing this recognition (37) (38).…”