High-producing MBL2 genotypes increase the risk of acute and chronic carditis in patients with history of rheumatic fever

Abstract

Rheumatic fever (RF) and its most severe sequela, chronic rheumatic heart disease (CRHD), are mediated by an abnormal immunological host response following a Streptococcus pyogenes oropharyngeal infection. Mannan-binding lectin (MBL), a collectin that activates complement, binds to N-acetylglucosamine, a molecule present on the streptococcus cell wall and on human heart valves. As high levels of MBL and MBL2 associated genotypes have previously been seen to be associated with CRHD, we investigated the association between MBL2 polymorphisms and the presence of acute carditis and arthritis in patients with a history of RF. Polymorphisms in exon 1 and in the X/Y promoter region of the MBL2 gene were determined by PCR-SSP in 149 patients with a history of RF and 147 controls. Genotypes associated with the high production of MBL ( YA/YA and YA/XA) were more frequent in the patients with acute (26/35, 74%) and chronic carditis (79/107, 74%) when compared to the controls (79/147, 54%; OR 2.48, 95% CI 1.09–5.67, p = 0.035 and OR 2.42, 95% CI 1.41–4.16, p = 0.001, respectively). Logistic regression analysis showed that MBL levels >2800 ng/ml increased the risk of CRHD (OR 2.91, 95% CI 1.41–6.03, p = 0.003). Among the RF patients without cardiac sequela, YA/YA and YA/XA genotypes were significantly associated with acute carditis when compared to the patients without this clinical manifestation (26/28, 93% vs. 9/14, 64%, OR 7.22, 95% CI 1.18–43.98, p = 0.031); on the other hand, arthritis was more frequently observed in those patients presenting MBL2 genotypes related to the low production of MBL (10/14, 71% vs. 10/28, 36%; p = 0.048, OR 0.22, 95% CI 0.05–0.89). We concluded that MBL2 genotypes associated with the high production of MBL seem to be involved in the pathogenesis of rheumatic carditis and its progression to CRHD.