Leprosy association with low MASP-2 levels generated by MASP2 haplotypes and polymorphisms flanking MAp19 exon 5

• Published in: PloS one 2013-07, Vol.8 (7), p.e69054-e69054
• Main Authors: Boldt, Angelica Beate Winter, Goeldner, Isabela, Stahlke, Ewalda R S, Thiel, Steffen, Jensenius, Jens Christian, de Messias-Reason, Iara José Taborda
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Binding; Binding sites; Biology; Blood donors; Brazil; Disease Progression; Epidermal growth factor; Exons; Female; Ficolins; Gene Frequency; Gene Order; Genetic Predisposition to Disease; Genotypes; Haplotypes; Humans; Ingestion; Lectins; Leprosy; Leprosy - genetics; Leprosy - metabolism; Malaria; Male; Mannan; Mannose-binding lectin; Mannose-Binding Protein-Associated Serine Proteases - genetics; Mannose-Binding Protein-Associated Serine Proteases - metabolism; MASP-2 protein; Medicine; Microorganisms; Middle Aged; Multiplexing; Mycobacterium leprae; Patients; Plasmodium falciparum; Polymorphism, Genetic; Proteins; Serine; Serine proteinase; Tropical diseases; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069054

The gene MASP2 (mannan-binding lectin (MBL)-associated serine protease 2) encodes two proteins, MASP-2 and MAp19 (MBL-associated protein of 19 kDa), bound in plasma to MBL and ficolins. The binding of MBL/MASP-2 and ficolin/MASP-2 complexes to microorganisms activates the lectin pathway of complement and may increase the ingestion of intracellular pathogens such as Mycobacterium leprae. We haplotyped 11 MASP2 polymorphisms with multiplex sequence-specific PCR in 219 Brazilian leprosy patients (131 lepromatous, 29 borderline, 21 tuberculoid, 14 undetermined, 24 unspecified), 405 healthy Brazilians and 291 Danish blood donors with previously determined MASP-2 and MAp19 levels. We also evaluated MASP-2 levels in further 46 leprosy patients and 69 Brazilian controls. Two polymorphisms flanking exon 5 of MASP2 were associated with a dominant effect on high MASP-2 levels and an additive effect on low MAp19 levels. Patients presented lower MASP-2 levels (P = 0.0012) than controls. The frequency of the p.126L variant, associated with low MASP-2 levels (below 200 ng/mL), was higher in the patients (P = 0.0002, OR = 4.92), as was the frequency of genotypes with p.126L (P = 0.00006, OR = 5.96). The *1C2-l [AG] haplotype, which harbors p.126L and the deficiency-causing p.439H variant, has a dominant effect on the susceptibility to the disease (P = 0.007, OR = 4.15). Genotypes composed of the *2B1-i and/or *2B2A-i haplotypes, both associated with intermediate MASP-2 levels (200-600 ng/mL), were found to be protective against the disease (P = 0.0014, OR = 0.6). Low MASP-2 levels (P = 0.022), as well as corresponding genotypes with *1C2-l and/or *2A2-l but without *1B1-h or *1B2-h, were more frequent in the lepromatous than in other patients (P = 0.008, OR = 8.8). In contrast with MBL, low MASP-2 levels increase the susceptibility to leprosy in general and to lepromatous leprosy in particular. MASP2 genotypes and MASP-2 levels might thus be of prognostic value for leprosy progression.